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Research We Fund

With hundreds of projects currently underway, we fund scientists through our academic grant programs and biotech partners through our strategic venture philanthropy initiative. Use the filters below to find an LLS-funded project.

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Kimberly Stegmaier

Kimberly Stegmaier, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

New Targeted Therapies for Pediatric Acute Myeloid Leukemia

Our research focuses on the preclinical evaluation of new targeted therapies for high-risk subtypes of childhood AML. We are deploying screening approaches to delete each gene, one-by-one, to identify genes whose deletion leads to death of the leukemia cells. We will evaluate drugs developed against these targets in state-of-the-art models of pediatric AML. Our goal is to translate the most promising findings to clinical trials for children with these very poor outcome subsets of AML.

Program: Dare to Dream
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Walter

Roland Walter, MD PhD

Fred Hutchinson Cancer Center

Seattle, Washington
United States

211Astatine-CD123 Radioimmunotherapy for Cancer (Stem) Cell-Directed Treatment of Acute Leukemia

Because acute leukemias are very sensitive to radiation, radioisotopes are ideal payloads to arm antibodies against these difficult-to-cure, aggressive blood cancers. Here, we will develop fully human anti-CD123 antibodies carrying the highly potent alpha-emitter astatine-211 (211At) as a new therapy for acute leukemia. CD123 is broadly displayed on acute leukemia cells in most patients and overexpressed on leukemic stem cells but is only found on a small subset of normal blood cells, enabling the use of 211At-CD123 radioimmunotherapy in the transplant and non-transplant setting with limited toxicities to normal tissues.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
dr. Fehniger

Todd Fehniger, MD PhD

Washington University in St. Louis

St. Louis, Washington
United States

NK cell immunotherapy to reduce relapse after haploidentical transplant for high-risk pediatric AML

Leukemia recurrence remains the most common type of treatment failure after allogeneic hematopoietic cell transplant for children and young adults with high-risk acute myelogenous leukemia (AML), occurring in 40-50% of patients. Novel treatment strategies are needed to attain durable remissions and provide long-term cure. We have developed a novel memory-like (ML) NK cell immunotherapy that has demonstrated potent activity against AML in preclinical and early clinical studies. We propose a new clinical trial combining donor-derived ML NK cells adoptive cellular therapy with modified αβT cell-depleted haploidentical HCT to enhance graft-versus-leukemia and reduce relapse in pediatric and young adult patients with high-risk AML.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Venkata Lokesh Battula

Venkata Lokesh Battula, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Arming NK Cells to Target B7-H3+ AML Cells

In order to develop a novel immunotherapy approach to treating AML, we propose targeting B7-H3 (CD276), a promising immune checkpoint that has been reported to inhibit NK cell activation. We have generated a novel anti–B7-H3 monoclonal antibody (T-1A5) to block B7-H3 function, showing the best in vitro and in vivo activity against AML cells. We will test the hypothesis that combination strategies such as targeting B7-H3 along with BCL2 inhibition (venetoclax) or IL-15r agonist (NKTR-255) result in synergistic inhibition of AML growth.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 1, 2026
Dr. Wang

Jenny Wang, PhD

The University of Sydney

Sydney
Australia

Strategic combinations to overcome therapeutic resistance and relapse in acute myeloid leukemia

Acute myeloid leukemia (AML) is the most fatal type of leukemia and has a high rate of relapse following current therapies. We have recently uncovered that RSPO3-LGR4 pathway is a key regulator of leukemia-initiating cell activity and is exclusively activated in relapsed and refractory AML. Our project aims to investigate the mechanistic link between the pathway activation and therapy resistance, and design combination therapies that would overcome resistance and improve the treatment of relapsed leukemia.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Gottschalk

Stephen Gottschalk, MD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

CD70-directed CAR T-cell therapy for the treatment of relapsed/refractory pediatric AML

In this project, we will test an innovative therapy called CAR T-cell therapy for children with a type of cancer called AML. In the laboratory, we have identified and developed a powerful CAR T-cell therapy that targets a protein called CD70 on AML cells. We propose to now develop a clinical trial in which we will study the effects of this CD70.CAR T-cell therapy in children with AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Stahl

Maximilian Stahl, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Memory-like natural killer cells and venetoclax to eradicate measurable residual disease in AML

This proposal is to conduct a phase I (early phase) clinical trial to test whether the combination of the approved targeted therapy venetoclax with memory-like Natural Killer (NK) cells is safe and active in patients with acute myeloid leukemia (AML). Based on laboratory research at Dana-Farber Cancer Institute, we believe that the addition of memory-like NK cells obtained from an haploidentical (‘half matched’) donor will be able to eradicate residual leukemia cells left over after prior venetoclax treatment and hence prevent a future relapse of the disease. A total of 10 patients will be treated with two different doses of NK cells and a constant dose of venetoclax. We also plan scientific studies on patient samples to learn more about the function of NK cells when combined with venetoclax, evaluate for clearance of residual leukemia cells with this combination therapy and explore potential resistance mechanisms.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Genovese

Pietro Genovese, PhD

Boston Children's Hospital

Boston, Massachusetts
United States

Towards clinical testing of epitope editing to enable novel adoptive immunotherapies

Innovations in gene engineering have made it possible to reprogram immune cells to attack specific targets on cancer cells, allowing the first adoptive cellular immunotherapies, known as CAR T cells, to be approved by the FDA for the treatment B lymphoblastic leukemia. A similar approach is currently under development for AML, but in contrast to B-ALL, there is no leukemia-specific target which would be amenable to targeting by immune cells without incurring severe adverse effects. Here, we aim to modify normal bone marrow stem cells used for allogeneic transplantation to make them resistant to CAR-T cells, thus enabling targeting proteins essential for tumor survival without the risk of severe toxicity on the healthy tissue counterpart.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Schwede

Matthew Schwede, MD

Stanford University

Stanford, California
United States

Dynamic prediction of outcomes in acute myeloid leukemia using machine learning that integrates genotype and phenotype

Acute myeloid leukemia is life-threatening and heterogeneous, and although classification models help guide treatment, they do not use detailed phenotypic information or dynamically update with new data during a patient’s course. We will develop computational methods to extract both mutations and phenotype from the electronic health record. Machine learning models will be built that adapt to new data over time so that all clinically relevant data is used when personalizing a patient’s therapy.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Yonezawa

Taishi Yonezawa, PhD

Baylor College of Medicine

Houston, Texas
United States

Uncovering mechanisms of DNMT3A stability in hematologic malignancies

DNMT3A is a critical tumor suppressor in hematologic malignancies; DNMT3A protein levels affect both tumor latency and type. DNMT3A is regulated in part by protein stability, but the mechanisms remain incompletely understood. Here, I will dissect the mechanisms that regulate DNMT3A protein turnover using CRISPR screening and genetically engineered mouse leukemia models. This work will reveal whether its stabilization could contribute to a new therapeutic approach for hematologic malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Parsons

Tyler Parsons, PhD

Washington University in St. Louis

St. Louis, Missouri
United States

Mechanisms of Clonal Evolution in the Transformation of MPN to sAML

This research will investigate blood stem cell mutations associated with progression of myeloproliferative neoplasm (MPN) to secondary acute myeloid leukemia (sAML). Our preliminary data suggest that pre-leukemic cells with particular mutations may have a selective advantage in a background of certain MPN subtypes. We will confirm this by utilizing mouse models and both MPN and sAML primary patient samples. Ultimately, we will examine and test inhibition of mechanisms which drive MPN to sAML.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Mistry

Jayna Mistry, PhD

The Jackson Laboratory

Bar Harbor, Maine
United States

Bone Marrow Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoiesis Drives Clonal Hematopoiesis and Transformation to Myeloid Malignancy

This project focuses on how age-associated clonal hematopoiesis (CH) alters the bone marrow (BM) microenvironment, and whether this promotes transformation of CH to acute myeloid leukemia (AML). I will utilize single cell RNA-seq data, genetic knockout models, and targeted inhibitors to perturb the non-hematopoietic and hematopoietic compartments of a mouse model of CH. The goal is to determine if manipulation of the BM microenvironment can attenuate CH and prevent AML transformation.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Marinaccio

Christian Marinaccio, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Identification and characterization of genetic factors affecting MLL/KMT2A fusion proteins stability in MLL/KMT2A rearranged leukemias

MLL1/KMT2A rearranged leukemias are the most common blood cancer occurring in children characterized by dismal prognosis. Given the importance of fusion proteins in driving the disease, I will determine factors affecting the fusion protein stability through a CRISPR/Cas9 screening approach in an innovative model system where the MLL fusions are endogenously tagged with a fluorescent protein. This will facilitate development of molecular glue degraders specifically targeting the MLL fusions.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Lee

Anna Lee, PhD

NYU School of Medicine

New York, New York
United States

Investigating the molecular basis of mRNA processing in acute myeloid leukemia

Our research aims to discover key driving factors in leukemia that regulate mRNA processing. The proposed experiments utilize a combination of biochemical, cell-based, and high-throughput sequencing approaches using human leukemia cell lines and primary patient samples. These studies will reveal factors that are essential for leukemic maintenance, uncover molecular details of mRNA processing, and inform the development of novel therapeutic strategies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Jann

Johann-Christoph Jann, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Reactivation of transposable elements as novel enhancers in cohesin-mutant myeloid malignancies

The reason why some patients with clonal hematopoiesis progress to overt myeloid malignancies is not understood. I will revert epigenetic changes in isogenic in-vitro and in-vivo models of stepwise progression of cohesin-mutant myeloid neoplasia to mechanistically address how changes in genome organization and enhancer regulation drive clonal selection. These studies will improve our understanding of myeloid disease progression and inform therapeutic options to intercept this step.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Montefiori

Lindsey Montefiori, PhD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

Molecular basis and new therapeutic strategies in lineage ambiguous leukemia

Lineage-ambiguous leukemias are high-risk blood cancers with unclear biologic basis and suboptimal treatment options. Here, I will identify the cell of origin of lineage ambiguous leukemia and investigate new therapeutic strategies through in vitro and in vivo experimental modeling approaches and preclinical drug studies in patient-derived xenografts. These studies will clarify the cellular and molecular alterations driving lineage ambiguity and advance a new, rational therapeutic approach.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Zhang

Christine Zhang, PhD

Washington University in St. Louis

St. Louis, Washington
United States

Deciphering the role of p53 signaling in NPM1-mutant AML

NPM1c and TP53 mutations are exclusive in acute myeloid leukemia (AML) despite both being commonly present in patients, suggesting a fitness disadvantage for cells with co-occurring mutations. However, the mechanisms underlying this exclusivity have not been explored. This project will utilize novel models to dissect the importance of TP53 signaling in NPM1c+ (pre)-leukemic stem cells. Generated results may highlight therapeutic opportunities for improved risk management of NPM1c+ AML patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Liu

Yiman Liu, PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis

The goal of this proposal is to investigate the consequence of the chromatin reader eleven-nineteen-leukemia (ENL) gain-of-function mutations in the pathogenesis of leukemia. Our studies leverage the expertise in the molecular and chromatin biology of chromatin reader in leukemia utilizing mouse model, high resolution image, epigenomic and transcriptomic approaches. Our goal is to understand how chromatin reader contributes to cancer development, progression, and therapeutic outcome.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Collins

Cailin Collins, MD PhD

Stanford University

Palo Alto, California
United States

Investigating the role of preleukemia duration and clonal burden in progression to AML

The development of acute myeloid leukemia (AML) is preceded by a “preleukemic” phase in which mutated hematopoietic stem cells expand due to a fitness advantage. Our work uses prospective models and analysis of patient samples to study how the duration of preleukemia and how the preleukemic clonal burden affect progression to AML. Results of our studies will shed new light on AML pathogenesis and help guide clinical management of preleukemic conditions such as clonal hematopoiesis.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Wan

Liling Wan, PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Epigenetic Mechanisms in Acute Myeloid Leukemia

The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Pietras

Eric Pietras, PhD

University of Colorado Denver, Anschutz Medical Campus

Denver, Colorado
United States

Targeting the pathogenic 'fire triangle' of inflammation, metabolism and mutations in myeloid leukemogenesis

My lab is focused on understanding the pathogenic interplay between oncogenic mutations, chronic inflammation and aberrant metabolism as a driver of the evolutionary processes that culminate in lethal myeloid malignancies. We leverage mouse models and human patient samples to establish modalities for targeting this interplay throughout disease pathogenesis. My long-term goal is to improve patient outcomes by establishing therapies that prevent and/or delay evolution to acute leukemia.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Bjelosevic

Stefan Bjelosevic, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Metabolic Regulation of Leukemic Cell Fate

Cell-intrinsic metabolic processes are dysregulated in acute myeloid leukemia (AML) and can act to sustain an oncogenic state of differentiation arrest. Using AML cell lines and patient-derived material grown in sophisticated liquid culture medium that mimics human plasma, we will perform metabolically focused in vitro and in vivo CRISPR-Cas9 screens to reveal metabolic regulators of AML cell fate that can be exploited via dietary or pharmacologic intervention as a novel therapeutic strategy.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Rgenta

Rgenta Therapeutics, INC

TAP Partner

Cambridge, Massachusetts
United States

Supporting development of RNA-targeting molecules for blood cancers

In June 2023, LLS made an equity investment in Rgenta Therapeutics to "Support development of RNA-targeting molecules for blood cancers." 

Rgenta Therapeutics is developing a pipeline of oral, small-molecule RNA-targeting medicines with an initial focus on oncology and neurological disorders. Rgenta has a proprietary platform to mine the massive genomics data to identify targetable RNA processing events and to design small-molecule glues to modulate the interactions among the spliceosome, regulatory proteins, and RNAs. 

Rgenta is working closely with LLS TAP to further develop RNA-targeting molecules by supporting preclinical studies with the goal of moving towards clinical development in hematological malignancies. 

Program: Therapy Acceleration Program
Project Term: Start Date: June 30, 2023 End Date: September 19, 2023
Dimericon

Dimericon, LLC

TAP Partner

Zurich
Switzerland

Supporting development of dimericons (crosslinked helix dimers) for blood cancers

In May 2023, LLS made an equity investment in Dimericon to "Support development of dimericons (crosslinked helix dimers) for blood cancers." 

Dimericon is a private biotech company focused on exploring crosslinked helix dimers (Dimericons) as therapeutics and templates for small molecule development. Dimericon’s technology targets hard-to-drug intracellular protein-protein interactions using rationally designed mimetics of helix dimers. The Seed round of financing will support preclinical studies to further develop the current cFLIP inhibitor lead compound, DMRX1004, to be an IND ready clinical candidate in hematological malignancies.

Program: Therapy Acceleration Program
Project Term: Start Date: May 24, 2023 End Date: September 19, 2023
Dr. Mak

Tak Mak, PhD

Princess Margaret Cancer Centre, University Health Network

Toronto, Ontario
Canada

The Immune Niche in the Development of Hematological Malignancies and Implications for Novel Therapy

Our SCOR Program, composed of four complementary Projects supported by three shared Cores, is designed to determine how the immune niche and factors in its composition and regulation affect the initiation and progression of hematopoietic malignancies. Using genetically engineered mouse models, cell cultures and patient samples, the power of multi-omics analyses will be brought to bear to identify common drivers and expose underlying mechanisms. Findings from this work should reveal multiple candidate therapeutic targets whose exploitation may lead to the development of broadly applicable therapeutics for leukemias/lymphomas. Partnerships with pre-clinical and clinical trials experts at our home institutions and beyond will facilitate the translation of our findings to the bedside and potentially provide new hope to patients suffering from these devastating cancers.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027
Dr. Soiffer

Robert Soiffer, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Understanding and Overcoming Mechanisms of Immune Evasion after Allogeneic Transplant

Outcomes for patients with acute myelogenous leukemia who relapse after transplantation are dismal. This SCOR brings together an international group of collaborators with deep expertise in genomics, epigenetics, antigen presentation, and immune-regulation. They will focus on mechanisms of immune evasion by leukemia cells, identifying effective T cell responses to those evasive processes, and providing critical insights into the optimal approaches to model new and promising targets for immunotherapy with a goal of eliminating leukemia recurrence.

 

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027
Dr. Godley

Lucy Godley, MD PhD

Northwestern University

Evanston, Illinois
United States

CHEK2 as a predisposition gene for clonal hematopoiesis and hematopoietic malignancies

This proposal explores how inherited mutations in the DNA repair gene CHEK2 lead to blood cancers. Our work employs two unique resources: patient-derived cell lines and mice engineered with an inherited Chek2 variant that accurately models how bone marrow stem cells acquire DNA changes over time leading to bone marrow cancers. Our results may lead to new approaches that slow or prevent blood cancers in people with high risk.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Michael Kharas

Michael Kharas, PhD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Discovering the function and targeting dysregulated nuclear condensates in myeloid leukemia

Although molecular targeted therapy has dramatically changed how we treat cancer, the treatment for acute myeloid leukemia (AML) remains focused on the use of cytotoxic drugs with many patients eventually relapsing with their disease. Our studies have a uncovered a new nuclear structure that is dysregulated in myeloid leukemia. This proposal studies the identity and function of this nuclear body in human AML and strives to identify novel therapeutic strategies and targets in leukemia.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Jaiswal

Siddhartha Jaiswal , MD PhD

Stanford University

Stanford, California
United States

Uncovering the role of TCL1A as a driver of clonal hematopoiesis and hematological malignancies

Mutations in a diverse set of genes can lead to pre-cancerous expansion of blood stem cells, but the factors that mediate the growth of these mutant clones are unknown. We recently discovered that many of these mutations lead to abnormal activation of a gene called TCL1A. Consequently, TCL1A may be an attractive target for treating or preventing blood cancers, but little is known about its function. Here, we will uncover how TCL1A influences the biology of pre-cancerous blood stem cells.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Gill

Saar Gill, MD PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Role of the AML "Immunome" in response and failure of chimeric antigen receptor T cell therapy

Most patients with acute myeloid leukemia (AML) are not cured with chemotherapy alone, and most long-term survivors of AML have undergone an allogeneic stem cell transplant (also known as bone marrow transplant). The outlook is quite grim for patients whose AML relapses after transplant. We have developed a new type of treatment for AML called chimeric antigen receptor (CAR) T cells for these patients. The goal of this project is to investigate how to improve CAR T cells for AML.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Jones

Courtney Jones, PhD

Princess Margaret Cancer Centre, University Health Network

Toronto
Canada

Interrogation of glutathione biology in relapsed acute myeloid leukemia stem cells

Acute myeloid leukemia (AML) is a devastating blood cancer. Most AML patients will initially respond to standard therapy; however, for many patients the disease recurs resulting in patient death. Consequently, there is an urgent need to develop new therapeutic strategies for relapsed AML patients. The objective of our proposal is to understand and target properties specific to relapsed AML cells with the overall goal of improving relapsed AML patient outcomes.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Kathleen Sakamoto

Kathleen Sakamoto, PhD, MD

Stanford University

Palo Alto, California
United States

Niclosamide for the Treatment of Relapsed/Refractory Pediatric Acute Myeloid Leukemia

Niclosamide is an FDA approved anti-parasitic drug that is well tolerated and acts synergistically with chemotherapy to kill AML cells. We will conduct a Phase I clinical trial with niclosamide in combination with cytarabine for children with relapsed/refractory pediatric AML. ShRNA/CRISPR screens demonstrated that Bcl-2 is upregulated in niclosamide resistant cells. We will study the effects of the Bcl-2 inhibitor venetoclax in combination with niclosamide in pediatric AML.

Program: Translational Research Program
Project Term: Start Date: June 30, 2022 End Date: June 30, 2025
Dr. Nassar

Nicolas Nassar, PhD

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio
United States

Overcoming RAS-driven Mechanisms of Resistance in Leukemia

The mitogen-activated protein kinase (MAPK) pathway is activated in high-risk leukemia and is a hallmark of resistance to therapies. This project uses patient-derived xenograft models of relapsed pediatric ALL and AML with activated RAS/MAPK to test whether clinically relevant MAPK mutations activate the VAV3/RAC pathway and if pharmacological inhibition of that pathway by a small molecule we developed synergizes with a MAPK-inhibitor to provide a new treatment strategy for RAS-driven leukemia.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Wen

Hong Wen, PhD

Van Andel Research Institute

Grand Rapids, Michigan
United States

Investigating and targeting the histone acetylation reader protein ENL in acute leukemias

Leukemia often results from aberrant gene expression caused by epigenetic alterations. Previously we discovered a novel histone acetylation reader domain in the ENL protein and demonstrated that this domain is essential for the survival of a wide range of acute leukemias, making it an attractive therapeutic target. We will develop specific inhibitors of ENL activity in acute leukemias and will use mouse models to define the role of ENL mutations identified in patients in leukemogenesis.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. McNerney

Megan McNerney, MD PhD

The University of Chicago

Chicago, Illinois
United States

Genomic interrogation of high-risk myeloid neoplasms to identify new therapies

The long-term goal of my research program is to improve the outcomes for patients with high-risk myeloid blood cancers, particularly those with loss of chromosome 7 or CUX1. We are tackling this question using an arsenal of innovative methods and tools, including mouse models, human cells and patient samples, and state-of-the-art technologies to examine the cancer cell genome. Accomplishing this work will reveal new treatments and strategies for preventing blood cancers from arising.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Maxson

Julia Maxson, PhD

Oregon Health & Science University

Portland, Oregon
United States

Targeting the interplay between signaling and transcriptional dysfunction in myeloid leukemias

Our research program is focused on understanding the intersection between signaling and transcriptional dysfunction in myeloid leukemias. We leverage murine models, cell lines and human samples to uncover how biological context shapes the manifestation of oncogenic programs at the molecular level. Our long-term goal is to harness this knowledge to identify multipronged therapeutic strategies that improve outcomes for patients with myeloid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Lindsley

Coleman Lindsley, MD PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Genetic pathways of myeloid transformation and treatment response

Our central goal is to improve clinical outcomes in patients with myeloid malignancies through developing an enhanced mechanistic understanding of disease. We use multiomic analyses of primary patient samples combined with complementary laboratory models using mice and cell lines to generate and test our hypotheses. The results of our studies will help improve patient outcomes by identifying strategies to mitigate risk of disease progression/relapse and treatment toxicity.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Takahashi

Koichi Takahashi, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Understanding the clonal origin, evolution, and progression of myeloid malignancies

The overarching focus of my research is to understand the clonal origin, evolution, and progression of myeloid malignancies and biological and clinical factors that influence the process. We tackle this question by analyzing patient samples with integrated approach combining single-cell omics, evolutionary genetics, and computational analytics. The ultimate goal of our research is to develop clinical strategies for early detection, prevention, and treatments of myeloid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Baeten

Jeremy Baeten, PhD

Washington University in St. Louis

St. Louis, Washington
United States

Combined targeting of ATR and replicative stress in TP53-mutated AML

This research will test a promising new drug combination in acute myeloid leukemia (AML) carrying TP53 gene mutations, which is resistant to chemotherapy and has a median survival of less than 5 months. Our preliminary data show that TP53-mutated AML is selectively sensitive to the combination of an ATR inhibitor and decitabine. We will confirm activity of this novel drug combination using mouse models of leukemia and human AML samples and explore mechanisms of responsiveness.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2024
Dr. Booth

Christopher Booth, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Mechanisms of Pathogenesis by MYB Fusions in Blastic Plasmacytoid Dendritic Cell Neoplasm

The transcription factor MYB has long been associated with leukemia, but how it contributes to disease is poorly understood. Fusions of MYB to other proteins, causing MYB activation, are found in patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), but rare in other leukemias. I am using recently developed techniques to gain insight into how MYB fusions cause BPDCN. This will enable both new treatments for BPDCN and better understanding of the role of MYB in other leukemias.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2024
Dr. Luo

Qingyu Luo, MD PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Defining PIK3R5-related PI3K gamma dependency as a novel therapeutic target in blood cancers including BPDCN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive blood cancer without adequate treatment. In a genome-wide CRISPR interference screen, BPDCN was highly dependent on the PI3Kγ pathway and specifically the PIK3R5 adaptor subunit. A subset of leukemias may share this vulnerability. We will interrogate the mechanism of this unique dependency and integrate PIK3R5/PI3Kγ targeting with leukemia therapy. Our goal is to provide novel treatments for PIK3R5-dependent malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Ferrari De Andrade

Lucas Ferrari De Andrade, PhD

Icahn School of Medicine at Mount Sinai

New York, New York
United States

Optimizing MICA/B antibody for AML by selective binding to Fc activating receptors

Acute myeloid leukemia (AML) is a blood cancer characterized by poor clinical outcomes. We developed an antibody that inhibits AML in models by triggering anti-leukemia immunity. Now we developed a new version of this antibody with higher affinity to the leukocyte receptors that mediate anti-leukemia immunity. We will establish the ability of this optimized antibody to elicit greater inhibition of AML. The studies will generate important information about how to induce anti-leukemia immunity.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Jolanta Grembecka

Jolanta Grembecka, PhD

Regents of the University of Michigan

Ann Arbor, Michigan
United States

Targeted combination therapies for leukemia with NUP98 translocations

Leukemia patients with chromosomal translocations of the Nucleoporin (NUP98) gene suffer from very poor prognosis. In this project we will identify new treatment for these patients by combining menin inhibitor with FDA approved drugs. We will evaluate effectiveness, mechanism of action and biomarkers of treatment response to these combinations in advanced pre-clinical models of NUP98 leukemia. We expect these studies will lead to future clinical trials in AML patients with NUP98 translocations.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Verma

Amit Verma, MBBS

Albert Einstein College of Medicine

Bronx, New York
United States

Studies on clonal hematopoiesis in the 911 WTC first responders

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to WTC aerosolized dust and gases that contained known and suspected carcinogens including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, polychlorinated furans, dioxins and asbestos. Studies from Dr. Verma's group and others have reported an excess of cancer cases in the WTC-exposed Fire Department of the City of New York (FDNY) firefighters, including a trend towards higher incidence of multiple myeloma and leukemias. He now will be deep sequencing a large group of WTC-exposed firefighters to look for clonal hematopoiesis (CH) which is an acquisition of leukemia associated mutations associated with increases in the risk of hematologic cancer.

Program: Special Grants
Project Term: Start Date: June 1, 2022 End Date: September 19, 2023
Faron logo

Faron Pharmaceuticals, LTD

TAP Partner

Turku
Finland

A phase 1/2 study of Bexmarilimab, an anti-Clever1 monoclonal antibody, in combination with azacitidine or azacitidine/venetoclax in patients with AML, MDS or CMML

In June 2022, LLS made an equity investment in Faron Pharmaceuticals to "Support Clinical Development of the Bexmarilimab Program for Leukemia Indications."

Faron is a clinical stage biopharmaceutical company developing novel treatments for medical conditions with significant unmet needs caused by dysfunction of our immune system. The Company currently has a pipeline based on the receptors involved in regulation of immune response in oncology, organ damage and bone marrow regeneration. 

Bexmarilimab, a novel anti-Clever-1 humanized antibody, is its investigative precision immunotherapy with the potential to provide permanent immune stimulation for difficult-to-treat cancers through targeting myeloid function. A Phase 1 study (BEXMAB) of bexmarilimab in combination with azacitidine or azacitidine/venetoclax is currently enrolling AML, MDS or CMML patients in the US and Finland (NCT05428969).

Program: Therapy Acceleration Program
Project Term: Start Date: June 30, 2022 End Date: September 19, 2023
ImCheck

ImCheck Therapeutics, INC

TAP Partner

Marseille
France

A phase 1 expansion study of ICT01, an anti-BTN3A monoclonal antibody, in combination with azacitidine and venetoclax in patients with AML

In June 2022, LLS made an equity investment in ImCheck Therapeutics to "Support Clinical Development of the ICT01 Program for Blood Cancer Indications."

ImCheck Therapeutics is designing and developing a new generation of immunotherapeutic antibodies targeting butyrophilins, a novel super-family of immunomodulators.

ICT01 is a humanized, anti-BTN3A (also known as CD277) monoclonal antibody that selectively activates γ9δ2 T cells, which are part of the innate immune system that is responsible for immunosurveillance of malignancy and infections. A clinical trial (EVICTION) is currently enrolling a cohort expansion of ICT01 in combination with azacitidine and venetoclax in patients with acute myeloid leukemia (NCT04243499).

Program: Therapy Acceleration Program
Project Term: Start Date: June 13, 2022 End Date: September 19, 2023
Dr. Catherine Smith

Catherine Smith, MD

University of California San Francisco

San Francisco, California
United States

SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia

The goal of our work is to use a “bench to bedside and back” approach to develop new treatments for patients with relapsed/refractory AML. Through genetic analysis of patients who relapse or do not respond to standard and investigational treatments, we discover potential resistance mechanisms. In the lab, we test novel drugs and identify new drug targets that may address these resistance mechanisms when used in combination with other therapies. The overall goal of our research program is to improve treatment options and survival of patients with refractory AML.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Dr. Ann-Kathrin Eisfeld

Ann-Kathrin Eisfeld, MD

The Ohio State University

Columbus, Ohio
United States

Improving the outcomes of young Black adults diagnosed with acute myeloid leukemia

Young Black patients diagnosed with acute myeloid leukemia (AML) have significantly shorter survival compared to White patients. To comprehensively assess genetic, genomic and biologic contributors to the race-associated survival disparity, we propose a complementary approach that addresses major knowledge gaps in our current understanding of AML biology in Black patients, including the overdue characterization of the Black AML genome and subsequent delineation of biologic response to treatment.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Dr. Timothy Graubert

Timothy Graubert, MD

Massachusetts General Hospital

Boston, Massachusetts
United States

Exploiting Vulnerabilities in RNA Splicing to Treat Hematologic Malignancies

RNA splicing is a central metabolic pathway that is frequently perturbed in hematopoietic malignancies (HMs) that harbor mutations in spliceosome components (most commonly affecting SRSF2, SF3B1, U2AF1, or ZRSR2). These mutations are particularly prevalent in myeloid malignancies (e.g., MDS, MDS/MPN, sAML), but recent pan-cancer studies have implicated aberrant splicing in >30 tumor types. The Project Leaders have probed the molecular consequences of aberrant splicing and identified critical pathways that are amenable to targeted inhibition, including the DNA damage response (Graubert/Walter), the nonsense-mediated RNA decay (NMD) pathway (You/Walter), the spliceosome itself (Abdel-Wahab/Walter/Graubert), and others. To date, effective therapies for HMs have not capitalized on these unique vulnerabilities. The goal of this SCOR is to generate testable clinical hypotheses based on careful mechanistic studies in pre-clinical models and to rapidly move these ideas into the clinic in the near term.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Biotheryx

BioTheryX, INC

TAP Partner

San Diego, California
United States

A phase 1 study of BTX-1188, a dual target protein degrader, in patients with AML or NHL

In November 2010, LLS made an equity investment in BioTheryX originally to support the development of a promising LLS-funded project with Toronto-based University Health Network and is currently supporting "An Open Label, Escalating Multiple Dose Study to Evaluate the Safety, Toxicity, Pharmacokinetics, and Preliminary Activity of BTX-1188 in Subjects With Advanced Malignancies."

BioTheryX has a technology platform in the field of targeted protein degradation. This technology utilizes the body's own protein disposal system to selectively degrade and remove disease-causing proteins. It has potential applicability to a very broad range of disease targets, including a wide range of targets that have to date been considered "undruggable." 

BTX-1188 is a dual target protein degrader specifically engineered to degrade GSPT1 and IKZF1/3. A clinical study of BTX-1188 in patients with advanced hematologic (AML or NHL) and solid tumor malignancies is currently enrolling (NCT05144334).

Program: Therapy Acceleration Program
Project Term: Start Date: November 16, 2010 End Date: September 19, 2023
Caribou

Caribou Biosciences, INC

TAP Partner

Berkeley, California
United States

Supporting allogeneic CD371 (CLL-1) CAR development for acute myeloid leukemia

In February 2021, LLS made an equity investment in Caribou Biosciences to "Support allogeneic CD371 (CLL-1) CAR development for acute myeloid leukemia."

Caribou is a clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-012, Caribou’s third allogeneic CAR-T cell therapy, an allogeneic anti-CD371 CAR-T cell therapy for the treatment of relapsed or refractory acute myeloid leukemia (AML) is in preclinical development for the treatment of acute myeloid leukemia with a projected IND filing in the second half of 2023. CD371 is expressed on the surface of AML tumor cells and leukemic stem cells, but it is not expressed on normal hematopoietic stem cells, which makes it a compelling target for the treatment of AML. Caribou is applying their genome editing expertise to armor the CB-012 CAR-T product in order to drive persistence and seek maximum patient benefit.

 

Program: Therapy Acceleration Program
Project Term: Start Date: February 28, 2021 End Date: September 19, 2023
Jaroslaw Maciejewski

Jaroslaw Maciejewski, MD, PhD

Cleveland Clinic Foundation

Cleveland, Ohio
United States

HLA Mutations, GvH Resistance and Relapse Following Allogeneic Hematopoietic Stem Cell Transplant

This project investigates immunogenetic determinants of relapse following allogeneic stem cell transplant for myeloid neoplasia. Herein we will determine molecular modes of inactivation of HLA immunodominant peptide-presentation including HLA mutations, deletion and down modulation as a means of immunoescape. We will also study immunogenetic predictors of the strength of graft vs. leukemia according to the HLA divergence in the context of relapse, TCR repertoire diversity and HLA mutations.

Program: Translational Research Program
Project Term: Start Date: November 1, 2021 End Date: October 31, 2024
Kura

Kura Oncology, INC

TAP Partner

San Diego, California
United States

A phase 2 registration-directed clinical study of ziftomenib (KO-539), a menin inhibitor, in patients with NPM1-mutant relapsed or refractory AML

Starting in July 2010, LLS TAP supported a promising University of Michigan research project led by Jolanta Grembecka, PhD, to develop new treatments for patients with a rare and lethal subtype of leukemia. Through TAP, LLS engaged chemists to improve the properties that produced lead compounds that exhibited potent anti-leukemic activity. In 2014, LLS introduced Kura Oncology to the project that ultimately led to Kura Oncology completing a licensing agreement with the University of Michigan to continue to develop these molecules.

Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer with a pipeline that consists of small molecule drug candidates that target cancer signaling pathways.

Ziftomenib (KO-539) is selective small molecule inhibitor of menin. Ziftomenib is currently in a Phase 2 registration-directed clinical trial in patients with NPM1-mutant relapsed or refractory AML (NCT04067336). 

Program: Therapy Acceleration Program
Project Term: Start Date: December 22, 2014 End Date: September 19, 2023
Immune-Onc

Immune-Onc Therapeutics, INC

TAP Partner

Palo Alto, California
United States

A phase 1 expansion study of IO-202, an antibody targeting LILRB4, in combination with azacitidine/venetoclax in patients with monocytic differentiation AML and CMML

In March 2021, LLS made an equity investment in Immune-Onc Therapeutics to support the "Phase 1 Clinical Development of IO-202, An Antibody Targeting LILRB4, for the Treatment of AML with Monocytic Differentiation and CMML."

Immune-Onc is a private, clinical-stage cancer immunotherapy company dedicated to the discovery and development of novel myeloid checkpoint inhibitors for cancer patients. The company aims to translate unique scientific insights in myeloid cell biology and immune inhibitory receptors to discover and develop first-in-class biotherapeutics that reverse immune suppression in the tumor microenvironment. Immune-Onc has a differentiated pipeline with a current focus on targeting the Leukocyte Immunoglobulin-Like Receptor subfamily B (LILRB) of myeloid checkpoints. The company’s work builds on early research by Chengcheng (Alec) Zhang, Ph.D. at the University of Texas Southwestern Medical Center that was also funded by LLS grants.

IO-202 is a first-in-class antibody targeting the LILRB4 and has entered a phase 1 cohort expansion clinical trial (NCT0437243) for the treatment of AML (IO-202 in combination with azacitidine and venetoclax) and CMML (IO-202 in combination with azacitidine). 

Program: Therapy Acceleration Program
Project Term: Start Date: March 5, 2021 End Date: September 19, 2023
Ryvu

Ryvu Therapeutics, SA

TAP Partner

Krakow
Poland

A phase 1b study of RVU120, a novel CDK8 inhibitor, in patients with AML or high-risk MDS

In August 2017, LLS TAP partnered with Ryvu Therapeutics (formerly known as Selvita) to support "A Phase Ib Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome."

Ryvu Therapeutics is a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology using a proprietary discovery engine platform.

RVU120 (SEL120) is a highly selective first-in-class CDK8/CDK19 small molecule inhibitor. RVU120 is currently in a Phase I clinical trial in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome (NCT04021368), enrolling in the US and Poland. 

Program: Therapy Acceleration Program
Project Term: Start Date: August 7, 2017 End Date: December 31, 2023
Daniel Lucas

Daniel Lucas, PhD

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio
United States

Cellular Crosstalk In The Normal And Malignant Bone Marrow

We want to understand how leukemia inhibits blood production as this is one of the main causes of death in leukemia patients. We use new microscopy techniques developed by our group to image—for the first time—all types of blood cells and how they are eradicated by leukemia cells. Identification of the mechanisms through which leukemia inhibits blood production will be the foundation for new studies to develop drugs to maintain normal blood levels and prevent death in leukemia patients.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Jeffrey Magee

Jeffrey Magee, PhD, MD

Washington University School of Medicine in St. Louis

St. Louis, Missouri
United States

Neonatal origins of pediatric AML

Coming soon.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2026
Ravindra Majeti

Ravindra Majeti, PhD, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells in Human Myeloid Malignancies

It has been demonstrated that most cases of AML are associated with mutations in multiple genes. Dr. Majeti's studies will provide novel insights into the genetic events and other factors such as the microenvironment that affect in the development of myeloid malignancies, particularly AML. This study will have significant implications for the prevention and treatment of myeloid malignancies, particularly AML.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2023
Ravindra Majeti

Ravindra Majeti, PhD, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

Personalized Metabolic Targeting of Epigenetic AML Mutations Through the Alpha-Ketoglutarate Pathway

AML is characterized by founder mutations in epigenetic regulators that perturb alpha-ketoglutarate flux to block differentiation and rewire metabolism exposing new druggable vulnerabilities. By integrating bioenergetics and 5hmC profiling in primary cells, we have discovered unexpected 2-hydroxyglutarate-independent vulnerabilities for TET2, IDH1, IDH2, WT1, and CEBPA mutations. Here, we propose mutation-directed drug development for AML through targeting of the alpha-ketoglutarate pathway.

Program: Translational Research Program
Project Term: Start Date: October 1, 2020 End Date: September 30, 2023
Kasey Leger

Kasey Leger, MD

Seattle Children's Hospital

Seattle, Washington
United States

Cardioprotective Strategies and Cardiotoxicity Prediction in Children with Acute Myeloid Leukemia

We seek to reduce the adverse cardiac effects of chemotherapy in pediatric AML patients. We are assessing markers of heart function and injury to compare two clinical strategies for prevention of chemotherapy-induced heart injury. We are also developing a tool using these markers of heart function to characterize a child’s risk for cardiac dysfunction, which is critical to guiding safe chemotherapy delivery. By reducing the toxicity of therapy on the heart we hope to optimize delivery of effective chemotherapy and contribute to long-term leukemia cure without the burden of life-threatening heart disease during survivorship.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Soheil Meshinchi

Soheil Meshinchi, PhD, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

Novel Immunotherapeutic Development in Childhood AML

Dr. Soheil Meshinchi is taking a personalized medicine approach to identify immunotherapies for specific subsets of pediatric acute myeloid leukemia (AML). Pediatric AML remains a devastating disease with only a 60% survival rate. Survivors often have long-term quality of life issues related to the toxic chemotherapy used to treat their disease. A better knowledge of the molecular basis of pediatric AML will help identify targets for therapeutic intervention. Some of these targets may be mutants of normal genes, while others may be overexpression of normal genes, which would provide a therapeutic window in which targeting the overexpressed gene product may preferentially kill tumor cells. Dr. Meshinchi has surveyed the gene expression spectrum of pediatric AML and has identified several targets which are overexpressed in pediatric AML. One protein, CD74, is highly expressed in a subset of AMLs. Another target is CD70, which is highly expressed in about half of all pediatric AML cases that include a fusion of the MLL protein. Patients with MLL fusions have a worse outcome. Lastly, some infant AML patients have another kind of fusion protein paired with overexpression of the FOLR1 protein. All three proteins that Dr. Meshinchi has identified as being highly expressed in subsets of pediatric AML have much lower expression in healthy cells. Therefore, targeting these proteins is a logical choice. These three proteins are all expressed on the surface of the cell, making them accessible to targeting by special therapeutic antibodies called “antibody drug conjugates” (ADCs). ADCs have a toxic payload attached to them. When the antibody binds to its target on the cell surface, the cell takes in the ADC releasing the toxic payload, which then kills the cell. This immunotherapy approach is a highly specific, personalized approach for treating cancer. ADCs to each of the protein targets identified by Dr. Meshinchi are being clinically evaluated in other diseases, providing the opportunity to potentially repurpose those drugs for pediatric AML. Therefore, Dr. Meshinchi proposes to evaluate these ADCs in laboratory models of pediatric AML. Should any of these drugs show promise in these laboratory models, Dr. Meshinchi will propose clinical trials in pediatric patients through LLS’s Pediatric Acute Leukemia (PedAL) Master Clinical Trial. If any of the targets do not have an effective drug in the laboratory models, Dr. Meshinchi will create new ADCs using proven expertise currently available in his laboratory. Therefore, these studies present the possibility of new, targeted immunotherapy for specific subsets of pediatric AML patients, either rapidly through drug repurposing, or through the development of new ADCs. The goal is to improve the survival and quality of life for these vulnerable blood cancer patients.

Program: Dare to Dream
Project Term: Start Date: October 1, 2020 End Date: September 30, 2022
Soheil Meshinchi

Soheil Meshinchi, PhD, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

Multi-modal Immunotherapeutic Targeting of AML-restricted Targets in Infants and Children

Advances in understanding and management of AML in children has been stagnant for decades. Observed improvements in survival are more directly linked to improvements in supportive care or risk identification rather than advances in therapeutics. Excitement around FDA approval of two new IDH1/2 inhibitors did not reach the pediatric oncology community given paucity or absence of such mutations in children. This also highlights the stark differences between AML in older adults and that in younger patients. Thus, “trickle down therapeutics” where therapies that are developed in older adults are used effectively in children is a flawed concept. Discoveries and therapeutic development in younger patients must be prioritized if meaningful advances are to be made in curing AML in younger patients. Given that AML in children is not a priority for the pharmaceutical companies, alternate mechanisms for advancing therapeutics in children and young adults should be implemented.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Soheil Meshinchi

Soheil Meshinchi, PhD, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

Novel immunotherapeutic strategies in infants with high risk AML

Treatment of AML in infants is especially challenging given unique genetic make-up of the disease as well as specific susceptibilities of the host. We will leverage the RNA Seq data from over 2000 patients to discover and validate novel targets (cell surface proteins), and in collaboration with Dr. Correnti (Protein Scientist) and Dr. Fry (CART development expert) generate and test novel antibodies, ADCs, BiTEs and CARTs directed against leukemia-specific targets in infants.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Rajni Kumari

Rajni Kumari, PhD

Albert Einstein College of Medicine

Bronx, New York
United States

Role of HLX in leukemia induction and maintenance

We and others have shown how HLX overexpression keeps blood cells more immature by blocking their differentiation and promoting their proliferation, a characteristic which is inherent to AML. However, whether there is a causative role of HLX in the induction of AML is still unclear. Hence, the aim of my study is to better understand, using genetically engineered mice models, retroviral models, and human AML patient samples, how HLX drives AML at molecular level. This study will uncover potential therapeutic strategies for AML treatment in future.

Program: Career Development Program
Project Term: Start Date: April 1, 2021 End Date: March 31, 2024
Daisuke Nakada

Daisuke Nakada, PhD

Baylor College of Medicine

Houston, Texas
United States

Synergistic targeting of metabolic and epigenetic vulnerabilities in leukemia stem cells

Our lab is focused on identifying unique features that distinguishes acute myeloid leukemia (AML) stem cells from normal blood-forming stem cells. The cells that make more AML cells than others are called AML stem cells, and these cells need to be eradicated to achieve deep therapeutic responses. We believe targeting metabolism may achieve this goal and found strategies to target AML stem cell metabolism without harming normal stem cells. We hope that our study will lead to improved therapies against AML targeting metabolism to achieve deep remission with little toxicity.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Stephen Nimer

Stephen Nimer, MD

University of Miami

Coral Gables, Florida
United States

Interventional Epigenetics in Myeloid Malignancies

Myeloid malignancies like acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN) arise due to a combination of genetic mutations and epigenetic abnormalities that sustain the abnormal behavior of cancer cells. The genetic material of the cell is the “hard drive” full of instructions that allow cells to grow, have unique functions, and ultimately live or die. Epigenetics is the “software” of the cell, allowing access to the information from the hard drive in a controlled manner. This interplay between the hardware and the software culminates in gene expression, allowing the genetic material to be read and interpreted. Targeted therapy in other myeloid cancers only works for a fraction of patients. Most myeloid cancers have a constellation of mutations that, in combination, likely determine the outcome of patients. The genetic mutations in myeloid cancers often occur in genes that control the epigenetic regulation of gene expression. While it is not possible to correct the genetic abnormalities in cancer cells, it is becoming possible to target and reverse the epigenetic abnormalities, and either kill the cancer cell or make it behave more normally. The goal of this SCOR is to analyze basic mechanisms of disease in order to arrive at novel therapeutic strategies and develop biomarkers that can predict the likelihood of a therapeutic response.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2017 End Date: September 30, 2022
Thomas Koehnke

Thomas Koehnke, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

The role of truncating ASXL1 mutations in disease initiation and progression of human myeloid malignancies

N/A

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Stephen Oh

Stephen Oh, PhD, MD

Washington University in St. Louis

St. Louis, Missouri
United States

Leveraging dysregulated signaling networks for therapeutic benefit in myeloproliferative neoplasms

The objective of this project is to decipher mechanisms driving transformation of myeloproliferative neoplasms (MPNs) to secondary acute leukemia (sAML). We have identified increased expression of DUSP6 and RSK1 in sAML patient cells. Genetic/pharmacologic targeting suggest a role for DUSP6 and RSK1 in MPN development. We thus propose studies to determine how DUSP6 and RSK1 contribute to MPN pathogenesis, and to evaluate the therapeutic potential of DUSP6 and/or RSK1 inhibition for MPN patients.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Eirini Papapetrou

Eirini Papapetrou, PhD, MD

Icahn School of Medicine at Mount Sinai

New York, New York
United States

Studying the biology and therapeutic vulnerabilities of leukemia stem cells using AML-iPSCs

Acute myeloid leukemia (AML) is an aggressive blood cancer that still lacks effective therapies. Our goal is to identify therapeutic vulnerabilities for long-lasting remission or cure of AML by targeting the leukemia stem cells (LSCs), the cells that maintain the disease and re-grow it upon relapse. To this end, we leverage unique model systems of AML LSCs that we have developed using induced pluripotent stem cell (iPSC) technology. Our study may open new avenues for the therapy of AML.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Alex Kentsis

Alex Kentsis, PhD, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Targeting kinase-dependent dysregulation of transcription factor control in acute myeloid leukemia

Defining mechanisms of dysregulated gene control are central to understanding cancer and the development of effective therapies. Our research is focused on the mechanisms of gene control dysregulation in acute myeloid leukemia (AML), a refractory form of blood cancer that affects both children and adults. Using new methods for manipulating proteins, we are defining essential mechanisms by which AML cells enable cancer-causing gene expression. This work also allowed us to develop new drugs to specifically block this in cancer, but not healthy cells. Ongoing work aims to define precise mechanisms of cancerous gene control and develop definitive treatments for its control.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Carl June

Carl June, MD

The Trustees of the University of Pennsylvania, Medical Center

Philadelphia, Pennsylvania
United States

Pan-heme CAR: Anti-CD38 CAR T cells for myeloid, lymphoid and plasma cell malignancies

Our SCOR team has a razor-sharp focus on an exciting new treatment modality for blood cancers: chimeric antigen receptor (CAR) T cells. T cells can be trained to target cancer cells by genetic modification. In fact, previous support from the Leukemia & Lymphoma Society allowed us to successfully develop CAR T cells targeted to CD19, a pan-B cell marker. This treatment, generically called CART-19, was approved by the FDA in 2017 for the treatment of B-cell acute lymphoid leukemia (B-ALL) and in 2018 for some non-Hodgkin lymphoma (NHL), with promising results in other B cell malignancies such as chronic lymphocytic leukemia (CLL). Thus, the development of a single therapy for a single disease (initially, CLL) paid handsome dividends when translated to a broader range of CD19-expressing malignancies (ALL, NHL).

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2019 End Date: September 30, 2024
Craig Jordan

Craig Jordan, PhD

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado
United States

Therapeutic targeting of AML stem cells

Our SCOR team seeks to fundamentally reinvent the ways in which physicians diagnose and treat acute myeloid leukemia (AML). For over 40 years, AML has been treated with a combination of chemotherapy drugs that have major side effects and usually only provide short-term benefit to patients. Indeed, survival rates for most AML patients are dismal, and quality of life for these patients is poor. Consequently, improved strategies for AML are a huge priority for the field. We believe that the lack of progress against AML is due to a single, fundamental failure of existing therapies: While current therapies attack leukemia cells, they fail to act against the real root of the problem, namely leukemia stem cells. It’s like mowing over weeds in a lawn. If the roots are not removed, the weed (disease) will grow back. And like eradicating the roots of weeds, AML stem cells have proved difficult to treat. This is primarily due to the fact that AML stem cells within a given patient can exist in multiple forms, each of which has a differing response to therapy. In other words, while various drugs can often kill some AML stem cells in a patient, completely eradicating all the AML stem cells can be very difficult.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2018 End Date: September 30, 2023
Hao Jiang

Hao Jiang, PhD

University of Virginia

Charlottesville, Virginia
United States

Dissecting the role of a key epigenetic modulator in Mixed Lineage Leukemia

We study how a protein called Dpy30 controls blood cancers by regulating chromatin, the physical structure where our genes reside. We study how this protein controls addition of a specific chemical group onto chromatin, thereby regulating expression of genes for leukemia in cells and animals. We are also developing chemicals to inhibit Dpy30’s activity in leukemia. We hope to better understand the role of Dpy30 in leukemia and identify Dyp30-inhibiting chemicals for leukemia treatment.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
John Pimanda

John Pimanda, PhD

The University of New South Wales (UNSW)

, New South Wales
Australia

Optimising azacitidine responsiveness in myelodysplasia and acute myeloid leukaemia

Our research aim is to improve outcomes for high-risk myelodysplastic syndrome and associated acute myeloid leukaemia patients who are refractory to azacitidine or its derivative decitabine, the most effective pharmacotherapeutics for these blood cancers. To this end, we will identify and evaluate therapeutic alternatives for this population of patients by leveraging discoveries and using clinical samples collected from an on-going investigator initiated clinical trial.

Program: Translational Research Program
Project Term: Start Date: January 1, 2021 End Date: December 31, 2023
Daniel Pollyea

Daniel Pollyea, MD

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado
United States

Targeting Leukemia Stem Cells in the Clinical Setting: The Development of A Comprehensive Program

My focus is to develop a program in which novel therapies targeting leukemia stem cells (LSCs) are tested in clinical trials. This is achieved via partnership with laboratory-based colleagues who identify vulnerabilities in LSCs. Once recognized, we find or develop drugs to exploit these weaknesses through clinical trials for acute myeloid leukemia patients. The goal is to bring forward new therapies that result in deep and durable responses, which also have the potential to cure this disease.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Shan Lin

Shan Lin, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Identification of therapeutic targets sensitizing acute myeloid leukemia to BCL2 inhibitors

Venetoclax is a medication that can induce cell death of acute myeloid leukemia (AML), but its effectiveness needs to be further improved to benefit more patients. We are conducting a functional genetic screen to identify cooperating targets that enhance the efficacy of venetoclax and investigate the underlying molecular mechanism. Our study will provide valuable insights for understanding cell death regulation in AML and facilitating the clinical application of venetoclax for AML treatment.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Christopher Reilly

Christopher Reilly, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

The impact of telomere maintenance on intestinal mucosal injury and regeneration during allogeneic stem cell transplantation for myeloid malignancies.

Short telomeres, the protective caps at the ends of DNA, are associated with increased risk of fatal toxicity among stem cell transplant recipients. We will determine 1) the relationship between recipient telomere length and intestinal injury after transplant and 2) how telomere length influences intestinal healing in a transplant mouse model. The goal of this work is to identify transplant patients at increased risk of toxicity and design therapies to improve patient survival.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2023
Catriona Jamieson

Catriona Jamieson, PhD, MD

The Regents of the University of California, San Diego

La Jolla, California
United States

Detection and Targeting of Enzymatic Base Editing Deregulation in Leukemia Stem Cells

Dr. Jamieson is examining the role of two enzymes (APOBEC3 and ADAR1) known to mutate DNA and RNA, and their role in acute myeloid leukemia (AML) and disease relapse, particularly in elderly patients.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2023
Keisuke Ito

Keisuke Ito, PhD, MD

Albert Einstein College of Medicine

Bronx, New York
United States

Targeting mitophagy of leukemia stem cells for therapy

Enhancing the commitment of leukemia stem cells (LSCs) is a promising therapeutic strategy against blood cancer, but tracking the division pattern of individual cells has proved difficult. We have established a novel technical regimen to assess the behavior of individual LSCs and their cell fate in vivo. Genetic mouse models and mouse models engrafted with leukemia patient samples are also used. Our project seeks to elucidate the role of mitophagy in the control of LSC division balance, which may facilitate new therapy targeting these cells.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Helen Heslop

Helen Heslop, MD

Baylor College of Medicine

Houston, Texas
United States

Immunotherapy of Hematologic Malignancies

The overall goal of this SCOR proposal is to develop and clinically validate T-cell immunotherapies designed to produce antitumor activity without the toxicities associated with intensive chemotherapy. The effectiveness of T-cell immunotherapy for leukemia and lymphoma has now been amply demonstrated. Studies conducted in our previous SCOR have already led to multicenter trials and orphan drug designation of EBV-specific T cells for the treatment of EBV-positive NHL and to commercial licensing of our genetically modified T cells and a genetic safety switch engineered into effector T cells.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2018 End Date: September 30, 2023
Rizwan Romee

Rizwan Romee, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Cytokine induced memory-like NK cell immunotherapy to target post transplant relapse

Coming soon.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2026
Kathleen Sakamoto

Kathleen Sakamoto, PhD, MD

Stanford University

Palo Alto, California
United States

Niclosamide for the treatment of relapsed pediatric acute myeloid leukemia

Niclosamide is an FDA approved anti-parasitic drug that is well tolerated in adults and children. AML cells are sensitive to niclosamide, act synergistically with chemotherapy in vitro, and inhibit the proliferation of primary AML stem cells in vivo. We propose to examine the effects of niclosamide in combination with chemotherapy in animal models of AML and study the mechanism of action of niclosamide in AML cells in anticipation of a clinical trial in children with relapsed AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Michael Savona

Michael Savona, MD

Vanderbilt University Medical Center

Nashville, Tennessee
United States

Reaching out to underserved & minority patients with hematological diseases in the southeastern US

Vanderbilt-Ingram Cancer Center (VICC) is the only NCI designated cancer center that serves both adult and pediatric populations in TN, one of the highest cancer-mortality states in the country. In fact, TN rural dwellers encompass about 30-50% of the states’ population, many with lower per-capita income and high school graduation rates. Influencing cancer care by facilitating underserved and minority populations to access therapeutic clinical trials as well as those focused on screening and prevention strategies remains a cornerstone objective. The Vanderbilt Health Affiliated Network (VHAN) serves as the largest provider for an organized network of hospitals, clinics, and health systems across TN. This network encompasses 12 health systems and 61 hospitals. Within VHAN, the VICC has had a formal affiliation with Baptist Memorial Healthcare Corporation (BMHCC) since 2012. BMHCC is affiliated with 22 hospitals and provides care for 8000 new cancer patients (pts) annually covering 111 counties totaling 4.3 million people. This includes 44% of the 252 counties and parishes in the Delta Regional Authority, congressionally acknowledged as the most indigent population in the US. The primary objective of the VICC community center affiliation with BMHCC is to enhance the regional level of cancer care and to advance cancer research efforts. VICC has provided guidance on a regular basis to assist BMHCC in the establishment and implementation of the Minority and Underserved National Cancer Institute Community Oncology Research Program (NCORP) grant as a successful and sustainable program. BMHCC has become amongst the top recruitment sites for NCORP, with steady growth in the proportion of rural pts seen across the health system. VICC continues to be a resource for BMHCC on providing consultations, training, and best practices for specialized services such as clinical research, radiation oncology, cancer screening, stem cell transplantation and community engagement.

Program: IMPACT
Project Term: Start Date: April 1, 2021 End Date: March 31, 2026
Kevin Shannon

Kevin Shannon, MD

The Regents of the University of California, San Francisco

San Francisco, California
United States

Co-targeting BET bromodomain proteins and aberrant Ras signaling in pediatric AML

We will test rational drug combinations in accurate preclinical model systems that reflect the distinct genomic features of pediatric AML. The use of genetically accurate mouse models to inform clinical translation is particularly important in pediatric AML given its relatively low incidence and difficulties inherent in testing drug combinations in children. Our preliminary studies have identified combined BET and MEK inhibition as a particularly promising combination for pediatric AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Jolanta Grembecka

Jolanta Grembecka, PhD

Regents of the University of Michigan

Ann Arbor, Michigan
United States

ASH1L degradation as a new treatment for acute leukemia

This project is focused to develop small molecule degraders of ASH1L histone methyltransferase as a treatment for aggressive sub-types of AML and ALL with high expression of HOXA genes by utilizing the PROTAC (proteolysis targeting chimera) approach. Optimization of ASH1L degraders and their comprehensive evaluation in in vitro and in vivo leukemia models are proposed. We expect these studies will lead to new therapeutics for aggressive acute leukemias with high HOXA expression.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Christina Glytsou

Christina Glytsou, PhD

New York University School of Medicine

New York, New York
United States

Targeting mitochondrial dynamics in venetoclax-resistant acute myeloid leukemia

Although new targeted therapies have been discovered and approved for the treatment of various types of leukemia, in many cases patients do not respond or develop resistance to treatments. My LLS-funded studies shed light on the mitochondria adaptations which enable cancer cells escape cell death induced by the treatments, while suggesting novel therapeutic strategies.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2023
Maria Figueroa

Maria "Ken" Figueroa, MD

University of Miami

Coral Gables, Florida
United States

Epigenetic Deregulation of Hematopoietic Cells with Aging and Disease

Our lab is focused on understanding how age-related epigenetic deregulation contributes to driving the functional decline of the hematopoietic system we see as we age. We are using genome-wide sequencing approaches to understand the changes in human hematopoietic stem and progenitor cells (HSPC) with aging at epigenomic level, along with in vitro and in vivo modeling of key changes that we hypothesize are the responsible drivers of the aging decline phenotype. Our overarching goal is to identify key drivers of functional HSPC decline to ultimately develop methods for modulating these drivers and achieve HSC rejuvenation.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Gianpietro Dotti

Gianpietro Dotti, MD

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina
United States

Targeting cathepsin G in acute myeloid leukemia

We developed a chimeric antigen receptor (CAR) targeting an epitope of the myeloid associated antigen cathepsin G that is processed and presented in the contest of the MHC complex in myeloid leukemic cells. T cells expressing the cathepsin G specific CAR (CG1.CAR) recognize HLA-A2+ myeloid target cells expressing cathepsin G. We intend to study efficacy and safety of CG1.CAR-T cells in preclinical models in preparation of a phase I clinical study in patients with relapsed/refractory AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Courtney DiNardo

Courtney DiNardo, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Targeted therapy for AML expressing mutant RUNX1

Clinical outcome of high-risk Myelodysplastic Syndrome (MDS) and AML with mutant (mt) RUNX1 is relatively poor. Supported by our preclinical data, we propose a Phase Ib clinical trial of omacetaxine mepisuccinate (OM) and venetoclax along with correlative science studies in patients with relapsed MDS or AML exhibiting mtRUNX1. Studies proposed will also determine pre-clinical activity of novel, OM-based combinations against mtRUNX1-expressing, patient-derived, pre-treatment AML cells.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Courtney DiNardo

Courtney DiNardo, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

A precision-based all-oral combination of venetoclax, oral decitabine, and IDH1/2 targeted inhibition for patients with IDH1 or IDH2 mutated AML

My ultimate goal is to develop more effective, better tolerated, and individualized treatment for patients with AML. This project focuses on AML patients with IDH1 or IDH2 mutations, with a clinical trial evaluating a combination of three agents which are effective in IDH-mutated AML. While these therapies are not curative on their own, my hope is that this combination will lead to a practice changing all-oral, outpatient, and well-tolerated curative strategy for patients with IDH-mutated AML.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Timothy Ley

Timothy Ley, MD

Washington University School of Medicine in St. Louis

St. Louis, Missouri
United States

Improving risk assessment of AML with a precision genomic strategy to assess mutation clearance

We will enroll transplant-eligible patients with intermediate-risk AML, and define mutation clearance after recovery from induction using deep exome sequencing. Patients who clear all mutations will be consolidated with chemotherapy only (HiDAC). Patients who fail to clear all mutations will be offered an allogeneic transplant. This prospective study may improve outcomes for intermediate-risk patients by more precisely using transplantation in first remission.

Program: Translational Research Program
Project Term: Start Date: April 1, 2021 End Date: March 31, 2023
Brian Dalton

Brian Dalton, PhD, MD

Johns Hopkins University

Baltimore, Maryland
United States

Therapeutic modulation of serine availability for SF3B1-mutant myeloid malignancies

Mutations in the spliceosome gene SF3B1 are common in myeloid malignancies, but they are currently untargetable. Our previous work has shown that SF3B1 mutations reprogram energy metabolism and create vulnerability to restriction of the nonessential amino acid serine. Here we propose a preclinical project studying PEGylated cystathioinine beta synthase (pCBS), a recombinant enzyme that catabolizes serine, as a treatment for SF3B1-mutant myeloid malignancies.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Sisi Chen

Sisi Chen, PhD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Aberrant LZTR1 and RIT1 signaling as a driver of clonal hematopoietic disorders

Our research focuses on a novel mechanism of RAS protein regulation via the protein LZTR1, which is altered in leukemia and hinders the effectiveness of leukemia therapies. We will utilize mouse models and functional genomic studies to uncover how altered RAS degradation drives leukemia and identify novel drug targets. This effort will help us identify the clinical impact of alterations in this novel RAS pathway in patients and potential means to improve leukemia treatment.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Aditi Shastri

Aditi Shastri, MD

Albert Einstein College of Medicine

New York, New York
United States

Antisense inhibition of STAT3 as a therapeutic strategy against leukemic stem cells

STAT3 is over-expressed in highly purified leukemic stem & progenitor cells and its expression is associated with a worse prognosis. Inhibition of STAT3 by an anitsense oligonucleotide AZD9150 leads to decreased viability of leukemic stem cells in in vitro & in vivo models. In the proposed studies, we will comprehensively examine the role of STAT3 in AML stem cell dynamics, identify the mechanisms of its actions and determine the efficacy of clinically available STAT3 inhibitors.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Grant Challen

Grant Challen, PhD

Washington University in St. Louis

St. Louis, Missouri
United States

Synergism of cell-intrinsic and cell-extrinsic factors in the clonal evolution of pre-malignant HSCs

We study the mechanisms of clonal hematopoiesis (CH), a process by which mutations provide hematopoietic stem cells (HSCs) with a fitness advantage. CH can precede the development of blood cancer. We use cutting-edge techniques to understand the effects of these mutations on HSC behavior. Our long-term goal is to identify ways to inhibit the growth of these mutant HSCs while sparing normal HSCs in people with CH. This may someday provide a blood cancer prevention method by eliminating the cells which carry the initial cancer-driving mutations.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Liran Shlush

Liran Shlush, PhD, MD

Weizmann Institute of Science


Israel

Early diagnosis and treatment of pre-leukemia

In the current study we propose, based on our preliminary results, that we can reliably identify pre-AML cases out of the many individuals with age related clonal hematopoiesis (ARCH) based on clinical parameters thereby limiting the population that needs to undergo molecular testing. We have also developed a predictive model that can identify pre-AML cases years before diagnosis. We now propose to utilize this knowledge to treat high-risk individuals with ARCH, at a time point before they have developed disease, by targeting the driving alterations most associated with AML development.

Program: RTFCCR/LLS Prevention
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Jason Butler

Jason Butler, PhD

Hackensack Meridian Health

Edison, New Jersey
United States

Modulating Signaling Pathways in Endothelial Cells to Abate Leukemic Progression

We seek to elucidate the mechanisms by which aging of the vascular system contributes to the decline in blood stem cell function and leads to diseases such as hematopoietic malignancies. We have developed novel model systems that have led to the discovery of rejuvenation factors that can restore the functional capacity of an aging blood and vascular system. These studies lay the foundation for the development of therapeutic strategies to not only rejuvenate an aged blood system, but to also give a competitive advantage to non-malignant blood cells while directly targeting cancer cells following chemotherapy regimens commonly utilized to treat hematological malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Robert Signer

Robert Signer, PhD

The Regents of the University of California, San Diego

, California
United States

Targeting leukemia stem cells by disrupting translational fidelity

Dr. Signer is investigating how the process of building defective proteins (inaccurate protein synthesis) plays a role in the development of a type of blood cancer called acute myeloid leukemia (AML) in the hopes of developing targeted therapies to treat this condition.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2023
Tomasz Skorski

Tomasz Skorski, PhD, MD, DSc

Temple University

Philadelphia, Pennsylvania
United States

Precision medicine-guided drugging of DNA repair to induce synthetic lethality in AMLs

We will test if Gene Expression and Mutation Analysis (GEMA) could be applied as personalized medicine tool to identify individual patients with AML displaying specific preferences for repairing spontaneous and drug-induced DNA damage. These preferences will predispose leukemia stem and progenitor cells to synthetic lethality triggered by already approved as well as novel DNA repair inhibitors.

Program: Translational Research Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2021
Daniel Starczynowski

Daniel Starczynowski, PhD

Cincinnati Children's Hospital Medical Center

, Ohio
United States

Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies

Dr. Starczynowski is investigating the role and potential benefit of therapeutic targeting of a protein called UBE2N in acute myeloid leukemia (AML).

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2023
Kimberly Stegmaier

Kimberly Stegmaier, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Advancing New Therapeutic Strategies for Pediatric Acute Leukemias

Dr. Kimberly Stegmaier is performing pre-clinical research to identify promising therapeutic strategies for pediatric leukemia. Pediatric blood cancers comprise about 40% of all pediatric cancers. The most common pediatric blood cancer is acute lymphoblastic leukemia (ALL), which is curable in most patients through the use of chemotherapy. Though beneficial in the short term, destroying the cancer through chemotherapy often leads to long term health problems. For those that do not respond to chemotherapy, there are fewer therapeutic options. Another pediatric blood cancer is acute myeloid leukemia (AML), which is a more aggressive and lethal disease. Therefore, many pediatric acute leukemia patients require better therapeutic options, and a precision medicine approach targeting specific mutations will likely lead to a better clinical benefit.

Program: Dare to Dream
Project Term: Start Date: October 1, 2020 End Date: September 30, 2022
Alexandra Stevens

Alexandra Stevens, MD

Baylor College of Medicine

Houston, Texas
United States

Pediatric AML PDX Models and Drug Testing-Gateway to Novel PedAL Trials

Pediatric AML is a disease with poor outcomes and a need for improved therapeutic options. Pediatric AML is characterized by diverse lesions that often do not overlap with adult AML, which therefore means therapeutic development must be done using pediatric AML models. Recent advances in patient derived xenograft (PDX) modeling have made possible the successful development of PDX models of diverse pediatric AML subtypes.

Program: Dare to Dream
Project Term: Start Date: July 1, 2021 End Date: June 30, 2023
Sarah Tasian

Sarah Tasian, MD

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania
United States

Precision Medicine Inhibitor and Immunotherapy Approaches for High-Risk Childhood Leukemias

Dr Tasian’s scientific passion is successful development of precision medicine therapies for high-risk childhood leukemia. Her translational laboratory research program focuses upon investigation of kinase inhibitors and chimeric antigen receptor (CAR) T cell immunotherapies in childhood ALL and AML using primary patient specimens and patient-derived xenograft models. Through her laboratory and clinical research, she aspires to improve cure rates and minimize toxicities for children with leukemia.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Samuel Taylor

Samuel Taylor, PhD

Albert Einstein College of Medicine

Bronx, New York
United States

Pharmacological inhibition of the transcription factor PU.1 as a novel treatment for acute myeloid leukemia

Transcription factors are components of a cell which control our genetic information and are known to have altered function in diseases such as Acute Myeloid Leukemia (AML). I am investigating how we can better understand and use novel transcription factor drugs as therapy for AML. This involves using CLICK-chemistry drug localization studies and creating transcription factor occupancy maps of the genome. Overall, my work will help to understand the inner workings of transcription factors in disease and provide a new therapeutic option for the treatment of AML.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2021
Jennifer Trowbridge

Jennifer Trowbridge, PhD

The Jackson Laboratory

Bar Harbor, Maine
United States

Discovery of Aging-Driven Mechanisms Causing Clonal Hematopoiesis (CH) and its Progression to Hematological Malignancy

My research focuses on why and how risk of acute myeloid leukemia (AML) increases with aging. Studying naturally aged mouse models in combination with mice engineered to express mutations commonly found in human blood stem cells with aging, we are investigating whether certain inflammatory factors that increase during aging increase the risk of leukemia. My goal is to identify biomarkers to assess risk of AML development in aging individuals and define new therapeutic targets to prevent AML.

Program: Career Development Program
Project Term: Start Date: January 1, 2021 End Date: December 31, 2025
Juliette Bouyssou

Juliette Bouyssou, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Understanding sex differences in myeloid and dendritic differentiation and function to target high-risk leukemias including BPDCN

There are widely recognized but unexplained sex differences in cancer incidence and outcomes, including in blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive leukemia that occurs over 3 times more frequently in men. We aim to identify male-female differences in plasmacytoid dendritic cells, the blood cell involved in BPDCN, to better understand this disease. Our goal is to use what we learn to improve the treatment of BPDCN and related blood cancers for both men and women.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Katherine Borden

Katherine Borden, PhD

IRIC - Institute for Research in Immunology and Cancer

Montreal, Quebec
Canada

The oncogene eIF4E coordinates extracellular signalling in AML

The oncoprotein eIF4E is dysregulated in many cancers including AML. We show that eIF4E drives production of the glycosaminoglycan hyaluronan (HA). Further, HA elevation alters the surface architecture of high-eIF4E AML cells and this is required for eIF4E’s oncogenic activity. We will explore HA’s involvement in AML and the efficacy of depleting HA in patients using hyaluronidase in a Phase I trial in AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2021
Catherine Bollard

Catherine Bollard, MD

Children's Research Institute

Washington, District of Columbia
United States

T cells with native and chimeric receptors against multiple tumor targets for acute myeloid leukemia

Adoptive T cell therapies for acute myeloid leukemia face numerous hurdles such as limited target antigens, immunosuppressive tumor environment as well as the loss of efficacy due to downregulation of the targeted antigen. The goal of our project is to address some of these challenges with a single T cell product targeting multiple tumor associated antigens that have limited expression on healthy tissues via a novel combination of native T cell receptor and gene engineered CAR targeting.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Dane Vassiliadis

Dane Vassiliadis, PhD

The University of Melbourne

Parkville, Victoria
Australia

Targeting non-genetic mechanisms of therapeutic resistance in Acute Myeloid Leukaemia

Drug resistance in AML can develop via a non-genetic process which remains poorly understood. Using our novel cellular barcoding technology that can trace the growth of thousands of cancer cells, our research will identify genes that are switched on or off in AML cells that lead to drug resistance and relapse. This work will reveal the factors underpinning non-genetic drug resistance that may be targeted with new drugs to prevent relapse and ultimately improve quality of life and survival.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
George Vassiliou

George Vassiliou, PhD, MD

Wellcome Trust Sanger Institute

Cambridge
United Kingdom

Prevention of myeloid cancers by understanding their pre-clinical evolution

Here we propose to study blood DNA from 1500 people who have had extensive genetic and aging-related tests over many years as participants of the "Immunoageing" study (http://www.immunoageing.eu/index.html). We propose to study these people for the presence of age-related clonal hematopoiesis (ARCH) to understand what factors are associated with ARCH and its expansion. Our aim is to use these findings to help prevent ARCH from progressing to myeloid cancer in at risk individuals identified by future screening programs, which we and others developing separately.

Program: RTFCCR/LLS Prevention
Project Term: Start Date: July 1, 2018 End Date: December 31, 2022
Elvin Wagenblast

Elvin Wagenblast, PhD

University Health Network

Toronto, Ontario
Canada

Modeling the Initiation and Progression of Down Syndrome Associated Leukemia using CRISPR/Cas9 at Single Cell Resolution

Children with Down syndrome (Trisomy 21) have an increased risk of childhood leukemia and, in these cases, the initiating genetic alterations already occur during the development of the fetus. In 30% of newborns with Down syndrome, a pre-leukemia disease occurs, which in some cases can progress to acute myeloid leukemia. I am planning to determine why children with Down syndrome have an increased risk of developing leukemia with the goal to identify potential therapeutic targets.

Program: Career Development Program
Project Term: Start Date: April 1, 2021 End Date: March 31, 2023
Loren Walensky

Loren Walensky, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Precision targeting of BFL-1 and MCL-1 in pediatric leukemias to overcome treatment resistance

Pediatric leukemia cells hijack the BCL-2 family signaling network to overexpress a range of anti-apoptotic proteins, including BFL-1 and MCL-1, and thereby enforce cellular immortality and cause treatment resistance. Here, we will harness novel and unique stapled peptides with the capacity to selectively target BFL-1, MCL-1, and importantly, both targets simultaneously, in order to reactivate the cell death pathway in MCL-1 and BFL-1 dependent pediatric leukemias.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Venkata Lokesh Battula

Venkata Lokesh Battula, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Targeting immune checkpoint protein B7-H3 (CD276) in acute myeloid leukemia

We found that immune checkpoint protein B7-H3 is overexpressed in Acute Myeloid Leukemia (AML) cells compared to normal hematopoietic cells. We have developed four monoclonal antibodies (mAbs) which successfully block B7-H3 and activate NK cells to induce apoptosis in AML cells. In this proposal we propose to generate therapeutically relevant anti-B7-H3 chimeric recombinant mAbs and test their activity in vivo. In addition, we will identify the receptor for B7-H3 expressed on NK cells.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
G. Greg Wang

G. Greg Wang, PhD

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina
United States

Decipher and Target AML Cell Dependency on Epigenetic Mutations

The goal of our program aims to understanding the general roles of DNA methylation machineries in epigenetic regulation and cancerous transformation seen in hematological cancers. Routinely, we take a set of integrated biochemical, genomics, oncology, and medicinal chemistry approaches to tackle the broad and critical questions in this field. Our findings shall not only promote current understanding of how hematological malignancies occur but also help develop novel therapeutic approaches.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Kirsten Williams

Kirsten Williams, MD

Emory University

Atlanta, Georgia
United States

Initiation of a novel immunotherapeutic to safely eradicate acute leukemia

We propose to develop a novel personalized immunotherapy to treat patients with refractory acute myeloid leukemia. We have shown that tumor-specific T cells (TAA-T) can diminish leukemia disease burden after allogeneic stem cell transplant. We now propose to augment the efficacy of the TAA-T products in the autologous setting using IL-15 backpacks to enhance TAA-T function and enhance efficacy without increased toxicity in vivo.

Program: Translational Research Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2022