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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Robert Orlowski, PhD, MD
The University of Texas MD Anderson Cancer Center
Houston, TexasTargeting HSP70 to Immune Effector Cells to Overcome the Immune Suppressive Myeloma Microenvironment
Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma. Based on strong preliminary data, we propose additional studies to better understand how this antibody activates various types of immune cells, how it works against both cancer cells and modifies the immune environment in mouse models, and how it could work even better in combination with other agents against myeloma. Since this antibody is already being developed into a drug for phase I clinical trials, these studies will directly inform its use in the clinic against multiple myeloma, and possibly against other blood-related cancers such as B-cell lymphomas.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Roland Walter, MD PhD
Fred Hutchinson Cancer Center
Seattle, Washington211Astatine-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 ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
William Matsui, MD
The University of Texas at Austin
Austin, TexasStem cell features and Notch signaling in p53 deleted multiple myeloma
We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Nizar Bahlis, MD
University of Calgary
CalgaryDevelopment of a novel BCL2L1 armored CAR T-cell and a tumor-immune interactome in multiple myeloma
Novel immune approaches have revolutionized the treatment paradigms in multiple myeloma (MM) with deep responses seen in heavily pretreated patients. However responses are largely not durable with significant gaps remaining in our understanding of the mechanisms mediating the immune escape to to CAR T cells and T cell engagers. Harnessing the power of single cell immunogenomics and building on the knowledge we amassed to date, we plan to address these therapeutics and mechanistic challenges firstly through the informed design and clinical development of a BCL2L1 armoured BCMA-targeting CAR T cell, and secondly by establishing a dictionary of the MM-TME interactome through serial interrogation of primary MM cells and their immunome generating a dynamic risk prediction model to better guide the delivery of immuno-therapeutics.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Venkata Lokesh Battula, PhD
The University of Texas MD Anderson Cancer Center
Houston, TexasArming 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 ProgramProject Term: Start Date: July 1, 2023 End Date: June 1, 2026
Jenny Wang, PhD
The University of Sydney
SydneyStrategic 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 ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Mark Dawson, PhD
The University of Melbourne
MelbourneUnderstanding molecular determinants of immune evasion to CAR-T cells at single clone resolution
Cellular immunotherapies such CAR-T cells are now firmly established as major pillars of anti-cancer therapy particularly in B-cell malignancies. However, despite their remarkable success in mediating an objective clinical response in up to 90% of patients, long-term durable remissions remain confined to only a minority of patients. It is now increasingly apparent that genetic evolution through the acquisition of new mutations cannot solely explain the molecular basis for therapeutic resistance. Therefore, to meet our ambition of precision medicine we need a better understanding of both the genetic and non-genetic mechanisms of malignant clonal dominance and therapeutic adaptation. To address this important challenge, we have developed new ex vivo and in vivo (mouse models) of resistance to CAR-T therapy. These will be coupled to a synthetic clone tracing strategy termed SPLINTR (Single-cell Profiling and LINeage Tracing) using expressed barcodes. In this proposal we will use SPLINTR in our models to uncover the clone intrinsic properties of cancer cells that enable them to evade these pioneering cellular immunotherapies. This research will deliver a blueprint around which future clinical trial strategies could be enabled to improve outcomes with these ground-breaking therapies.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Shirong Li, PhD
Columbia University Medical Center
New York, New YorkTargeting GCK as a novel and selective therapeutic strategy against RAS mutated Multiple Myeloma
RAS/MAPK mutations are the key drivers in MM, which occurs in 50% of newly diagnosed and higher in relapsed MM patients. However, RAS remains undruggable in MM. We found that RAS mutation MM growth is highly dependent on germinal center kinase(GCK). The goal of this project is to develop small molecule inhibitors against GCK with the expected outcome to provide novel treatments for relapsed/refractory and especially multi-drug resistant MM with RAS mutation, as well as other B-cell malignancies.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Jennifer Woyach, MD
The Ohio State University
Columbus, OhioInhibition of PKCβ as a strategy for BTK inhibitor refractory CLL
Patients with CLL that have progressed on BTK inhibitors have high risk disease with few clinical options. Here we propose a novel, selective inhibitor of PKCβ, MS-553, as a strategy for these patients. Our project will evaluate this drug alone and in combination with venetoclax preclinically and will perform correlative studies from an ongoing phase 1/2 trial of this drug alone and in combination with venetoclax.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Stephen Gottschalk, MD
St. Jude Children's Research Hospital
Memphis, TennesseeCD70-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 ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Wendy Béguelin, PhD
Weill Cornell Medicine
New York, New YorkDiscovery and therapeutic targeting of novel mechanisms driving Double Hit Lymphomas
Double-hit lymphoma (DHL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL) defined by co-occuring MYC and BCL2 rearrangements. DHL has been linked to very poor outcomes when treated with R-CHOP chemotherapy. Effective treatments to prevent treatment failure remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for DHL that overcome chemotherapy resistance and defective immune surveillance to improve outcomes.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Yubin Zhou, PhD, MBBS
Texas A&M Institute of Biosciences and Technology
College Station, TexasDevelopment of mutant GTPase-specific degraders for peripheral T cell lymphoma treatment
This project aims to develop targeted therapies against peripheral T cell lymphoma (PTCL), a diverse group of aggressive blood cancers with poor clinical outcomes. This project is tightly relevant to cancer control and treatment, promising to advance our understanding on how blood cancers initiate and progress, and lead to new therapeutics for the treatment of peripheral T cell lymphoma (PTCL). We will develop targeted therapeutics to engage an oncogenic RHOA GTPase mutant to treat PTCL and other types of tumors with similar genetic backgrounds.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Qing Yi, MD PhD
Houston Methodist Research Institute
Houston, TexasDeveloping Novel CAR-T Cell Therapy For Hematologic Malignancies
We observed that patients with many hematologic cancers expressed high levels of DKK1 and generated novel human DKK1-A2 CAR-T cells that can kill cancer cells from HLA-A2+ patients with myeloma, lymphoma, or leukemia. We also found that Th9-polarized T cells have enhanced antitumor effects in vivo. In this proposal, we will determine 1) whether and how Th9-polarized DKK1-A2 CAR-T cells are promising effector T cells for immunotherapy of human patients, and 2) whether Th9-polarized DKK1-A2 CAR-T cells are associated with reduced on- and off-target toxicities. Completing these studies are critical for developing new and effective CAR-T therapy for patients with hematologic malignancies who are still dying from the disease.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Jing Yang, PhD
Houston Methodist Research Institute
Houston, TexasTargeting acetyl-CoA synthetase 2 to remodel obesity-evoked inflammatory microenvironment in myeloma
Our proposal aims to develop a novel strategy to improve therapeutic efficacy for patients with multiple myeloma by remodeling obesity-induced inflammatory microenvironment. We hypothesize that acetyl-CoA synthetase 2, which is stimulated by obesity, enhances inflammatory cytokine production from myeloma cells, leading to an inflammatory niche where anti-tumor function of CD8+ T cells is dampened, and tumor growth is promoted. Our study will be the first to explore a novel insight for how obesity impacts the interaction between myeloma cells and microenvironment. In preparation of using the inhibitor of acetyl-CoA synthetase 2 in the clinical setting, we will establish its potential as a single agent or in combination of other chemo- or immuno- drugs to treat myeloma.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Ruben Carrasco, MD PhD
Dana-Farber Cancer Institute
Boston, MassachusettsDeveloping selective inhibitors of the b-catenin/BCL9 transcriptional complex for myeloma therapy
The b-catenin/BCL9 transcriptional complex, is a novel dependency in multiple myeloma (MM). Disruption of this complex inhibits MM cell growth in culture and in MM xenograft models. Development of potent selective b-catenin/BCL9 inhibitors will provide valuable tools to further investigate their mechanism of MM inhibition. We have established a chemistry, structural biology, and molecular pathology platform to facilitate novel inhibitor development, and explore its translational potential in MM.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Maximilian Stahl, MD
Dana-Farber Cancer Institute
Boston, MassachusettsMemory-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 ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Caroline Arber, MD
Centre Hospitalier Universitaire Vaudois
LausanneDesigned biosensor to enhance CAR T cell therapy for multiple myeloma
We will develop a novel T cell therapy strategy for multiple myeloma (MM) that will combine existing chimeric antigen receptors (CARs) with a novel designed biosensor responding to soluble factors abundantly present in the MM bone marrow environment in patients. The biosensor will be expressed as novel type of chimeric receptor in T cells concomitantly with the CAR and signal the T cells to persist longer and keep eliminating cancer cells from the body. We will deeply characterize the effects of our novel biosensor in CAR T cells to precisely understand how the treatment works. If successful, we expect that CAR T cell therapy for MM can be made more efficient, and the same strategy could potentially also be applied to other cancer types.
Program: Translational Research ProgramProject Term: Start Date: September 1, 2023 End Date: August 31, 2026
Constantine Mitsiades, PhD, MD
Dana-Farber Cancer Institute
Boston, MassachusettsPharmacological strategies to enhance T- and NK-cell-based therapies in blood cancers
Although they represent a major therapeutic progress for blood cancers, CAR-T cells and other T-cell based therapies are subject to eventual development of resistance to many patients. Natural killer (NK) cell-based therapies are highly active against many types of blood cancer cells which are resistant to T cells, but in our CRISPR studies death receptor signaling defects emerge as a common downstream mechanism of resistance to both T- and NK-cell therapies. Building on extensive pharmacological and genomic screens, this project will specifically examine the role of SMAC mimetics and JAK/STAT inhibitors in enhancing the response of blood cancer cells (e.g., multiple myeloma, leukemias) to CAR-T or NK cell therapies. We will place emphasis of studies with patient-derived samples in vitro (Integrated Functional Immune Profiling Platform) and in vivo, including humanized bone marrow-like scaffolds, to provide a translationally-relevant simulation of the potential of these compounds to enhance the clinical activity of cell-based immunotherapies in blood cancers.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Steven Treon, MD PhD
Dana-Farber Cancer Institute
Boston, MassachusettsTargeting mutated MYD88 pro-survival signaling in B-cell malignancies
Our laboratory and those of others discovered highly recurring mutations in the gene MYD88 which are found in patients with various B-cell cancers including Waldenstrom’s Macroglobulinemia (95-97%), ABC Subtype of Diffuse B-cell Lymphoma (30-40%), Primary Central Nervous Lymphoma (80%), Marginal Zone Lymphoma (10%) and Chronic Lymphocytic Leukemia (5-10%). Our laboratory and those of others showed that mutated MYD88 triggers BTK, which is the target of BTK-inhibitors like ibrutinib, acalabrutinib and zanubrutinib though complete remissions are rare with these agents largely in part because other pro-survival molecules are activated by mutated MYD88 such as HCK and IRAK1. In these studies, we will develop potent and selective inhibitors to HCK and IRAK1, including PROTACs which inhibit and degrade these molecules, using lead molecules and scaffolds whose target selectivity and activity we previously validated. We will also investigate the mechanisms underlying the inactivation of the Inhibitor of BTK (IBTK) as a potential new target for development of inhibitors for use in MYD88 mutated lymphomas.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Margaret Shipp, MD
Dana-Farber Cancer Institute
Boston, MassachusettsAnalysis and Targeting of Tumor-Associated Monocytes/Macrophages that Inhibit PD-1 Blockade
Inhibition of a tumor-triggered immune exhaustion pathway, termed PD-1 blockade, enables immune effector cells to attack cancers. In classic Hodgkin Lymphoma (cHL), PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy. We have identified a major population of monocyte/macrophages in patients with cHL that inhibit tumor cell killing and limit the efficacy of PD-1 blockade. Our goal is to fully characterize these tumor-specific monocytes/macrophages and target their immunosuppressive and tumorigenic program for therapeutic benefit in patients with cHL and other lymphoid malignancies.
Program: Translational Research ProgramProject Term: Start Date: June 30, 2023 End Date: June 30, 2026
Pietro Genovese, PhD
Boston Children's Hospital
Boston, MassachusettsTowards 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 ProgramProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Jonathan Licht, MD
University of Florida
Gainesville, FloridaAdenylate Kinase 2-A Novel Therapeutic Target in Multiple Myeloma
We identified the adenine nucleotide regulator AK2 as a selective dependency in multiple myeloma (MM) that is more essential for survival of MM cells overexpressing the histone methyltransferase NSD2. Here, we propose a series of experiments to understand the role of AK2 in MM cell fitness and response to existing therapies and elucidate the molecular basis of the increased dependence on AK2 driven by NSD2 overexpression. This study will elucidate the effects of AK2 inhibition in MM and will credential the enzyme as a therapeutic target.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Christian Steidl, MD PhD
BC Cancer, The University of British Columbia
Vancouver, British ColumbiaTargeting aberrant non-canonical NF-κB pathway activation in B-cell lymphomas
The impact of biological heterogeneity on treatment outcomes is evidenced by a large proportion of lymphoma patients who experience relapsed/refractory disease. To address this knowledge gap, we sequenced primary lymphoma samples and found recurrent mutations in the non-canonical NF-kB pathway (NC NF-kB) and uncovered the NIK kinase as a targetable candidate. Our next steps focus on using advanced genetic modelling approaches to provide preclinical rationale for targeting NC NF-kB in lymphomas.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Kathleen Sakamoto, PhD, MD
Stanford University
Palo Alto, CaliforniaNiclosamide 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 ProgramProject Term: Start Date: June 30, 2022 End Date: June 30, 2025
Suman Paul, MBBS PhD
The Johns Hopkins University School of Medicine
BaltimoreTCR directed immunotoxins and antibody drug conjugates for the treatment of T cell malignancies
Few treatment options are available for T cell leukemias and lymphomas, collectively called T cell cancers that affect ~100,000 patients worldwide each year. The current proposal will generate new antibodies attached to drugs and toxins that kill the T cell cancers. Importantly, the antibodies will preserve enough healthy T cells to maintain a functioning immune system. These modified antibodies may improve patient outcome and limit side effects associated with traditional chemotherapies.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Nicolas Nassar, PhD
Cincinnati Children's Hospital Medical Center
Cincinnati, OhioOvercoming 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 ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Markus Muschen, PhD, MD
Yale University
New Haven, ConnecticutTargeting SYK:ZAP70 coexpression in refractory B-cell malignancies
The B-cell kinase SYK and its T-cell homolog ZAP70 have almost identical functions but are strictly segregated to B- and T-cells. We recently discovered that B-cell malignancies frequently coexpress ZAP70 and that only SYK but not ZAP70 can trigger negative B-cell selection and cell death. Here we test the hypothesis that ZAP70 enables malignant B-cell transformation, test pharmacological SYK-hyperactivation and validate ZAP70 as biomarker of patients who benefit from this approach.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Grant Challen, PhD
Washington University in St. Louis
St. Louis, MissouriPrecision Medicine For DNMT3A-Mutant T-cell ALL
T-cell ALL is an aggressive blood cancer with poor overall survival, high relapse rates, and significant treatment-related side effects. Using primary T-ALL patient samples, this project will study the importance of JAK/STAT signaling and the gene BIRC5 in the pathology of T-ALL driven by DNMT3A mutations using genetic and pharmacological tools. The goal of this proposal is to develop precision medicine approaches for DNMT3A-mutant adult T-ALL patients, a group with poor clinical outcomes
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Lucas Ferrari De Andrade, PhD
Icahn School of Medicine at Mount Sinai
New York, New YorkOptimizing 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 ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Alieen Rowan, PhD
Imperial College, University of London
LondonDetection and treatment of Adult T cell leukemia/lymphoma in the premalignant stage.
Clonally expanded T cells carrying somatic mutations circulate in the premalignant phase of Adult T cell leukemia/lymphoma (ATL). We will develop capture-sequencing of recurrent ATL-driver mutations for use as a diagnostic tool for the detection/characterization of ATL-like clones in individuals with high risk of ATL, and, in an aligned clinical study, we will test whether a novel monoclonal antibody (targeting C-C chemokine receptor 4) can eradicate these high-risk cells.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Alfred Garfall, MD
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PennsylvaniaAnti-Sox2 immunotherapy to prevent multiple myeloma relapse
Advances in multiple myeloma (MM) therapy have improved survival, but serial cycles of response and relapse still lead to treatment-refractory and fatal disease in nearly all patients. To specifically target mechanisms of MM relapse, we propose to develop an immunotherapy targeting Sox2, a stem-cell transcription factor implicated in clonogenic MM growth that enables relapse.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Marco Ruella, MD
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PennsylvaniaA First-in-human Clinical Trial of CD5 knocked-out Chimeric Antigen T Cells for T-cell Lymphomas
This proposal seeks to develop for the first time in humans a novel CD5 knocked out (KO) anti-CD5 chimeric antigen receptor T cell (CART) product for patients with relapsed or refractory T-cell lymphomas. In Aim#1, we will generate and test a clinical-grade CD5 KO CART5 product, and in Aim#2, we will perform a phase I clinical trial. This project is highly relevant to those parts of the LLS's mission that pertain to the development of personalized and novel therapies for cancer treatment.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Kirk Schultz, MD
University of British Columbia
VancouverA Polyomic Approach to Chronic Graft-versus-Host Disease (cGvHD) Biomarkers in Adults
Our team is the first to develop a polyomic pediatric cGvHD biomarker test for assessing the risk of developing cGvHD. A cooperative adult phase III clinical trial, CTTC1901, between Canada and Australia, focused on decreasing cGvHD (N=350 patients), offers an ideal opportunity to validate adult cGvHD biomarkers. This proposal will utilize the pediatric polyomic approach to validate a cGvHD risk assignment and diagnostic algorithm in adult hematopoietic stem cell transplant (HSCT).
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Richard Lock, PhD
The University of New South Wales
RandwickTherapeutic targeting of T-cell acute lymphoblastic leukemia using an AKR1C3-activated prodrug
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that is exceptionally difficult to cure after relapse. We have previously shown that T-ALL expresses high levels of the enzyme AKR1C3, leading to clinical trials of AKR1C3-activated prodrugs. This project will focus on identifying the determinants of responses to AKR1C3-activated prodrugs in T-ALL and optimizing the use of a second generation AKR1C3-activated prodrug, SN36008, in T-ALL patient-derived xenografts.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Ricky Johnstone, PhD
The University of Melbourne
Parkville, VictoriaDissecting the biology and exploiting the dependency of myeloma cells on P300/CBP
In recent work of our collaborating labs, the protein acetyltransferases P300 and CBP emerged as potent and preferential dependencies for multiple myeloma (MM) based on genetic depletion, catalytic inhibition or chemical degradation studies. Our current project will define distinct vs. redundant molecular and biological functions of P300/CBP in MM, identify the mechanisms of resistance to their inhibition/degradation and exploit these findings to develop new therapeutic modalities to treat MM.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Jane Oliaro, PhD
The University of Melbourne
MelbourneImproving CAR-T cell therapy outcomes for patients with for aggressive lymphoma and multiple myeloma
Despite the promise of CAR-T cell immunotherapy for patients with lymphoma and multiple myeloma, a significant proportion of patients fail to respond or relapse following treatment. This project will focus on the clinical translation of a new treatment designed to improve durable response rates by combining CAR-T cell therapy with a new class of anticancer drugs called SMAC-mimetics. The results will provide the evidence base to drive a first-in-human clinical trial of this combination strategy.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Randall Davis, MD
The University of Alabama at Birmingham
Birmingham, AlabamaImmunotherapeutic Targeting of FCRL1 in CLL
Evolving insights into the B cell-restricted FCRL1 surface protein reveal that it integrates with critical signaling pathways and is a promising immunotherapeutic target in CLL. Based on preclinical evaluation of novel FCRL1 monoclonal antibodies, we propose developing chimeric antigen receptor (CAR) T cells for targeting in unique mouse models and patient-derived cells. The results will form the basis for strategic drug development and clinical testing in CLL and related B cell malignancies.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Ravi Bhatia, MD
The University of Alabama at Birmingham
Birmingham, AlabamaPrediction and prevention of therapy-related myeloid neoplasms following autologous transplantation
The proposed studies will identify alterations in hematopoietic regulation that predict for risk for therapy-related myeloid neoplasm (TMN) and improve understanding of disease evolution to guide strategies to prevent TMN in patients receiving autologous hematopoietic cell transplantation (aHCT) for lymphoma. They will investigate alterations in hematopoietic function in peripheral blood stem cell used for aHCT, and serial evolution of hematopoietic defects leading to development of TMN.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Daniel Thomas, MD PhD
The University of Adelaide
AdelaideIdentification and Molecular Analysis of Pre-Myelofibrotic Stem Cells
Myelofibrosis is a severe myeloproliferative neoplasm with no known cure.We have obtained unique insights into the underlying mechanisms responsible for the emergence of myelofibrosis and designed new approaches to selectively control it. By combining our mutation-specific isolation methods with single cell sequencing, we will identify myelofibrosis-initiating stem cell populations, demonstrate efficacy of stem cell targeting and enumerate residual normal stem cells to inform a Phase I/II trial.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Suzanne Lentzsch, MD
Columbia University Medical Center
New York, New YorkTargeting the MMP-13/PD-1H signaling axis for multiple myeloma bone disease and immunosuppression
Multiple myeloma is an incurable blood cancer complicated by bone diseases and compromised immune system. Our work indicated that checkpoint inhibitor PD-1H(VISTA) functions as the MMP-13 receptor, and the MMP-13/PD-1H signaling axis plays a critical role in multiple myeloma induced bone disease and immunosuppression. Therefore, immunotherapy targeting the novel MMP-13/PD-1H interaction module represents a novel approach to cure this devastating cancer.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Joachim Yahalom, MD
Memorial Sloan Kettering Cancer Center
New York, New YorkImpact of sublethal radiation dose on tumor response, microenvironment and the immune system
Extremely low dose radiation can improve blood cancer outcomes. But the mechanisms of how sublethal radiation (SRT) affects tumors, the microenvironment and immune system remain unclear. We envision a broad, nuanced role for SRT with benefits across diverse clinical situations and propose 3 clinical trials with deep translational components. Each can be paradigm-changing, but are thematically unified to improve mechanistic understanding of how such exceptionally small doses might offer so much.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Jolanta Grembecka, PhD
Regents of the University of Michigan
Ann Arbor, MichiganTargeted 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 ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Noemí Puig Morón, MD PhD
Institute of Biomedical Research from Salamanca
SalamancaPeripheral blood-based disease monitoring by mass spectrometry in patients with multiple myeloma
The present project will investigate the ability of quantitative immune precipitation mass spectrometry (QIP-MS) to anticipate relapsed or progressive disease in peripheral blood samples from patients with multiple myeloma. In the context of the GEM2014MAIN trial (lenalidomide and dexamethasone plus or minus ixazomib as maintenance), we will assess the presence of disease by QIP-MS in parallel with conventional methods in serum and next generation flow in bone marrow samples.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Mala Shanmugam, PhD
Emory University
Atlanta, GeorgiaInvestigating anti-neoplastic effects of beta blockers in multiple myeloma
Multiple myeloma (MM) relies on the bone marrow (BM) niche to progress to refractory disease. We found that beta blockers alter BM niche elements fostering MM growth and also reduce MM cell survival. Our objective is to elucidate the cellular and metabolic basis of how beta adrenergic signals impact the BM niche and MM progression. Knowledge of the prophylactic and therapeutic utility of beta blockers in MM will unravel new means to target neural niche remodeling fueling this fatal malignancy.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Christopher Porter, MD
Emory University
Atlanta, GeorgiaTargeting Siglec15 to promote immune response to malignant B cells
The goal of this project is to explore a novel immunologic therapeutic target for hematologic malignancies, SIGLEC15 (Sig15). The central hypothesis is that Sig15 is aberrantly expressed in malignant B cells, is released to attenuate immune responses and can be targeted therapeutically to promote immune responses to malignant hematopoietic cells. This work will accelerate therapeutic exploitation of the immune system for the treatment of leukemia and lymphoma by targeting Sig15.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Ann-Kathrin Eisfeld, MD
The Ohio State University
Columbus, OhioImproving 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 ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Jaroslaw Maciejewski, MD, PhD
Cleveland Clinic Foundation
Cleveland, OhioHLA 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 ProgramProject Term: Start Date: November 1, 2021 End Date: October 31, 2024
Yan Liu, PhD
Indiana University
Indianapolis, IndianaDevelopment of therapeutic strategy for the treatment of MDS
TP53 mutations are present in 10% of MDS cases and are associated with reduced survival and poor prognosis. However, the effect(s) of TP53 mutations on MDS pathogenesis is unknown. We discovered that MDS cells with TP53 mutations display significant alterations in pre-mRNA splicing due to increased EZH2 activity. We will investigate the mechanisms by which TP53 mutations drive MDS pathogenesis and determine the impact of inhibition of EZH2 and the spliceosome on MDS cells with TP53 mutations.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Ravindra Majeti, PhD, MD
Board of Trustees of the Leland Stanford Junior University
Palo Alto, CaliforniaPersonalized 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 ProgramProject Term: Start Date: October 1, 2020 End Date: September 30, 2023
Sami Malek, MD
Regents of the University of Michigan
Ann Arbor, MichiganTargeting v-ATPase mutations and activated autophagic flux in follicular lymphoma
In this proposal we seek a mechanistic understanding how mutations in ATP6V1B2 in FL activate autophagic flux and also maintain mTOR in an active state. Given that 25-30% of FL harbor mutations in various v-ATPase subunits and regulators (ATP6V1B2, APT6AP1, VMA21) we will extend our studies to these genes. We will clarify how and under what circumstances activated autophagy can be targeted in FL, why it works, and what the best molecular targets and drugs are.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Soheil Meshinchi, PhD, MD
Fred Hutchinson Cancer Research Center
Seattle, WashingtonNovel 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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Gareth Morgan, PhD, MD, FRCPath, FRCP
New York University School of Medicine
New York, New YorkStructural chromosomal rearrangements and the multi-step progression of multiple myeloma
Two newly identified structural DNA changes, termed chromothripsis and chromoplexy, result in the formation of new chromosomal structures where multiple genes can be deregulated simultaneously. These events involve the relocation of super-enhancers to the sites of oncogenes, which provides a strong drive for cancer progression, an association with high-risk status, adverse prognosis, and punctuated evolution.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Charles Mullighan, MD
St. Jude Children's Research Hospital
Memphis, TennesseeImproving therapy for CRLF2-rearranged Ph-like acute lymphoblastic leukemia
CRLF2-rearranged ALL is the most common subset of Ph-like ALL, has a very poor prognosis and lacks effective therapy. This project will use two novel approaches to improve treatment. The first is developing proteolysis-targeting chimeras to degrade JAK2 and inhibit constitutive JAK-STAT signaling. In the second approach, we will use CRISPR/Cas9 activating and inhibitory genomic screens to identify cellular dependencies, vulnerabilities and synthetic lethal opportunities for therapy.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Ryotaro Nakamura, MD
Beckman Research Institute of the City of Hope
Duarte, CaliforniaCMV-CD19 bi-specific CAR T cells with CMV vaccine as post-transplantation immunotherapy for ALL
We propose to develop an innovative adaptive cellular immunotherapy (ACIT) utilizing Chimeric Antigen Receptor (CAR)-engineered T cells, which respond to both CD19+ cells and cytomegalovirus (CMV) antigen, namely CMV-CD19 bi-specific T cells, followed by CMV vaccine to further expand the T cells in vivo. We aim to address the unmet need to improve high relapse rate in patients with ALL undergoing hematopoietic cell transplantation (HCT) from a matched or mismatched unrelated/related donors.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Sattva Neelapu, MD
The University of Texas MD Anderson Cancer Center
Houston, TexasCD79b as a novel target for CAR T-cell therapy in B-cell malignancies
Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 induces durable remissions in a significant proportion of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (NHL). However, relapse or progression occurs in ~60% of patients with majority of them experiencing CD19 loss in their tumors. Here, we will characterize the mechanism of CD19 loss in NHLs and develop CD79b CAR T-cell therapy as a novel approach to overcome CAR T resistance due to CD19 loss.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Robert Kridel, PhD, MD
University Health Network
Toronto, OntarioDelineation of the molecular heterogeneity underlying treatment failure in follicular lymphoma
A proportion of follicular lymphoma patients will experience early treatment failure and premature death. We will delineate the molecular features that underlie treatment failure from a recent randomized trial (BIONIC) & Canadian cohort via 3 aims: 1) confirm the prognostic significance of prior reported biomarkers (eg, m7-FLIPI, etc); 2) establish the genetic taxonomy of FL via integrated genomic analyses and consensus clustering; and 3) determine the prognostic value of circulating tumor DNA.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Stephen Oh, PhD, MD
Washington University in St. Louis
St. Louis, MissouriLeveraging 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 ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Bruno Paiva, PhD
Universidad de Navarra
PamplonaSystematic multiomic profiling of tumor and immune cells for non invasive detection of early myeloma
Multiple myeloma remains largely incurable and there is consensus that the pathway to cure cancer involves treating patients earlier. Thus, there is an unmet need to develop methods for early detection of pre-malignant disease and to help tailoring treatment for patients with smoldering myeloma. We aim to develop new methods for minimally invasive characterization of patients with smoldering myeloma in order to treat disease causation instead of symptomatology and increase curability rates.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Michael Keller, MD
Children's Research Institute
Washington, District of ColumbiaT-cell immunotherapy for prevention of COVID-19 following bone marrow transplantation
SARS-Cov-2 infections may be prolonged in cancer patients and may enable intrahost development of virulent viral variants. Adoptive immunotherapy with virus-specific T-cells has been an effective treatment for refractory viral infections in immunocompromised patients following HSCT. We propose to study the functionality of coronavirus-specific T-cells (CSTs) from healthy donors, and utilize CSTs as preventative therapy for patients undergoing bone marrow transplant in a phase I study.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2021 End Date: June 30, 2024
Lev Kats, PhD
The University of Melbourne
Parkville, VictoriaTargeting DCAF1 as a novel treatment strategy for therapy resistant multiple myeloma
We have identified the multi-domain protein DCAF1 as a genetic dependency in multiple myeloma and developed a series of potent on-target DCAF1 inhibitors that have a unique mode of action compared with existing therapies. In this proposal we will continue the detailed molecular characterization of our lead compound Vpr8. In parallel, using Vpr8 as the scaffold, we will develop a new series of PROTAC drugs that engage the ubiquitin ligase activity of DCAF1-containing E3 complexes.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Piers Patten, PhD
King's College London
LondonUnderstanding SARS-Cov-2 evolution in haemato-oncology patients
Through phenotypic and functional studies of immune cells, proteomic mapping of immune responses and genomic studies of variant strains, this project will assess the evolution of natural SARS-CoV-2 infection and COVID-19 vaccine responses in hemato-oncology patients. Integration of immunological profiles and genomic outcomes with clinical characteristics will inform future best patient management, especially for those patients at risk of prolonged infection with long term viral shedding.
Program: Translational Research ProgramProject Term: Start Date: September 1, 2021 End Date: August 31, 2024
John Pimanda, PhD
The University of New South Wales (UNSW)
, New South WalesOptimising 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 ProgramProject Term: Start Date: January 1, 2021 End Date: December 31, 2023
Sean Post, PhD
The University of Texas MD Anderson Cancer Center
Houston, TexasUnderstanding the mechanisms and developing novel therapies for a high-risk DLBCL population
The most aggressive forms of DLBCL are marked by alterations that result in MYC and BCL2/6 activation. In cases without genetic alterations at these loci, the mechanisms underpinning their overexpression remains largely unknown. Herein, we will examine how a putative driver of DLBCL (hnRNP K) impacts disease progression through its direct regulation of these critical oncogenes and evaluate treatment responses using clinical samples and animal models for this high-risk DLBCL patient population.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2018 End Date: June 30, 2021
Peng Ji, PhD, MD
Northwestern University
Chicago, IllinoisTargeting Plek2 for the treatment of myeloproliferative neoplasms
Current therapy for MPNs remains suboptimal with ongoing risks for thrombosis. Newer drug such as JAK inhibitor has toxicity and is not curative. New targeted therapy with less side effects is urgently needed in the field. This project focuses on the inhibitors of Plek2, a novel target of MPNs. We have identified lead compounds of Plek2 through screening and medicinal chemistry. We propose to further study the mechanisms of action of the inhibitors and perform in vivo studies using MPN models.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Michael Rout, PhD
Rockefeller University
New York, New YorkEngineering nanobodies for lymphoma immunotherapeutics
This project will generate optimized single-chain antibodies (nanobodies) against HVEM and BTLA, two cell receptors that are misregulated in ~75% of follicular lymphomas. We will select for nanobodies that inhibit lymphoma tumor growth through restoration of HVEM or BTLA activity. We will further engineer lymphoma-targeted CAR-T cells, which have shown anti-tumor activity in other malignancies, to secrete these anti-HVEM or anti-BTLA nanobodies, in an alternative combination therapy approach.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Kathleen Sakamoto, PhD, MD
Stanford University
Palo Alto, CaliforniaNiclosamide 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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Mala Shanmugam, PhD
Emory University
Atlanta, GeorgiaDeciphering the metabolic basis for t(11;14) multiple myeloma venetoclax sensitivity
The BCL-2 antagonist venetoclax is highly cytotoxic in a subset of t(11;14) multiple myeloma (MM). In investigating the metabolic basis for the sensitivity of t(11;14) MM to venetoclax, we determined that sensitive cells exhibit significantly reduced succinate ubiquinone reductase (SQR) activity. In addition, inhibition of SQR sensitizes resistant MM to venetoclax. Our proposal seeks to investigate SQR as a diagnostic and therapeutic target to broaden the application of this potent BH3 mimetic.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2018 End Date: June 30, 2021
Kevin Shannon, MD
The Regents of the University of California, San Francisco
San Francisco, CaliforniaCo-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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Jolanta Grembecka, PhD
Regents of the University of Michigan
Ann Arbor, MichiganASH1L 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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
David Fruman, PhD
University of California, Irvine
Irvine, CaliforniaPreclinical optimization of statin/BH3 mimetic combinations in multiple myeloma
This project will evaluate a novel two-drug combination to improve killing of multiple myeloma (MM) cells. First, we will test the hypothesis that statins increase killing of MM cells by BH3 mimetics including venetoclax and the MCL-1 inhibitor AMG 176. Second, we will identify biomarkers that predict response. This project will have significant positive impact on two fields: repurposing statins for blood cancer, and application of BH3 mimetics to improve health and survival of MM patients.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Gianpietro Dotti, MD
The University of North Carolina at Chapel Hill
Chapel Hill, North CarolinaTargeting 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 ProgramProject Term: Start Date: July 1, 2021 End Date: June 30, 2024
Courtney DiNardo, MD
The University of Texas MD Anderson Cancer Center
Houston, TexasTargeted 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 ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Timothy Ley, MD
Washington University School of Medicine in St. Louis
St. Louis, MissouriImproving 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 ProgramProject Term: Start Date: April 1, 2021 End Date: March 31, 2023
Alexey Danilov, PhD, MD
Beckman Research Institute of the City of Hope
Duarte, CaliforniaEnhancing efficacy of cyclin-dependent kinase inhibitors in diffuse large B-cell lymphoma
Nearly half of patients with diffuse large B-cell lymphoma (DLBCL), ultimately fail current therapies and die from their disease. Selective targeting of cyclin-dependent kinase 9 (CDK9) is a promising strategy, as evidenced by potent anti-tumor effects in preclinical models of DLBCL. Yet tumors evade therapy by developing resistance. This proposal seeks to both elucidate and circumvent the oncogenic events underlying this resistance in order to offer novel therapeutic approaches to treat DLBCL.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2023
Brian Dalton, PhD, MD
Johns Hopkins University
Baltimore, MarylandTherapeutic 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 ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Riccardo Dalla-Favera, MD
Columbia University Medical Center
New York, New YorkTargeting the NAD salvage pathway in GCB-DLBCL
Novel therapies are needed for ~40% of Diffuse Large B-Cell Lymphoma (DLBCL) patients who do not respond to the standard immune-chemotherapy regimen. Repurposing for DLBCL FDA-approved drugs and other targeted compounds in clinical development may offer a fast-track route to the clinic. Toward this end, we identified inhibitors of the enzyme NAMPT as active against a subset of DLBCL. The goal of this proposal is to thoroughly develop the pre-clinical rationale for NAMPT inhibition against DLBCL.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Dan Vogl, MD
The Trustees of the University of Pennsylvania, Medical Center
Philadelphia, PennsylvaniaTargeting the myeloma bone marrow microenvironment through S100A9 inhibition with tasquinimod
We propose laboratory and clinical studies to understand the mechanisms of anti-myeloma activity of tasquinimod, a small molecule inhibitor of S100A9. This proposal is part of an ongoing collaboration between Dr. Yulia Nefedova, whose laboratory studies the myeloma bone marrow microenvironment and its immunosuppressive effects, and Dr. Dan Vogl, whose clinical and translational research program focuses on novel therapies for relapsed and refractory myeloma.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Aditi Shastri, MD
Albert Einstein College of Medicine
New York, New YorkAntisense 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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Tomasz Skorski, PhD, MD, DSc
Temple University
Philadelphia, PennsylvaniaGenetic roadmaps to synthetic lethality in myeloproliferative neoplasms (MPNs)
Myeloproliferative neoplasms (MPNs) carry JAK2(V617F), MPL(W515L) and mutations in calreticulin (CALRmut) often accompanied by mutations in TET2, ASXL1, DNMT3A, EZH2, and other genes. We will develop a strategy based on gene mutation profiling to identify MPNs displaying specific defects in DNA repair. These defects will be then explored by specific DNA repair inhibitors to eliminate quiescent and proliferating MPN stem and progenitor cells without affecting normal cells and tissues.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2021 End Date: June 30, 2024
Tomasz Skorski, PhD, MD, DSc
Temple University
Philadelphia, PennsylvaniaPrecision 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 ProgramProject Term: Start Date: July 1, 2018 End Date: June 30, 2021
Srividya Swaminathan, PhD
Beckman Research Institute of the City of Hope
Duarte, CaliforniaDevelopment of natural killer (NK) cell-based therapies to treat MYC-high pediatric lymphoid cancers
Refractory pediatric B- and T- lymphoid cancers exhibit hyperactivation of MYC and its downstream pathways. Experimentally, MYC inactivation sustains tumor regression. However, MYC’s requirement in normal B/T-cells has hampered the development of MYC inhibitors. Recently, we showed that MYC-High B/T-Lymphoid Neoplasms (B/T-MLN) evade Natural Killer (NK) cell surveillance. Hence, we propose to develop targeted off-the-shelf NK therapies as an alternative to MYC inhibition for treating B/T-MLN.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2021 End Date: June 30, 2024
Ashwin Unnikrishnan, PhD
The University of New South Wales (UNSW)
, New South WalesBeyond azacitidine: investigating new therapeutic strategies for the treatment of MDS
This proposal aims to understand the molecular mechanisms underlying response to AZA therapy in MDS, as a basis for developing more effective therapies. A ribonucleotide, AZA’s effects on RNA remain unknown. Here, we will investigate the impact of in vivo AZA therapy on RNA alternative splicing and DNA demethylation in MDS patients. Secondly, we will investigate whether AZA treatment exposes neoepitopes in the dysplastic cells of patients, which could be exploited for cancer immunotherapy in MDS
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Katherine Borden, PhD
IRIC - Institute for Research in Immunology and Cancer
Montreal, QuebecThe 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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2021
Catherine Bollard, MD
Children's Research Institute
Washington, District of ColumbiaT 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 ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Matteo Bellone, MD
Fondazione Centro San Raffaele
LombardiaGut microbiota modulation to prevent progression of smoldering multiple myeloma to active disease
Blocking the progression of smoldering multiple myeloma (SMM) to active MM is an unmet clinical need. In primary mouse models of MM, we aim at demonstrating that modulation of the gut microbiota by vaccination against the commensal Prevotella heparinolytica and/or colonization by P. melaninogenica, also in combination with anti-PD-L1 antibodies, inhibit the progression of asymptomatic MM to full-blown disease. Our findings are expected to provide the ground for clinical trials in SMM patients.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2021 End Date: June 30, 2024
Wendy Béguelin, PhD
Weill Cornell Medicine
New York, New YorkPreventing follicular lymphoma progression and transformation through precision therapy
Follicular lymphomas (FL) depend on stromal cells for survival and proliferation and evade T-cell immune surveillance. Although indolent, most FLs eventually undergo either progression or transformation to an aggressive lymphoma. Effective treatments to prevent this remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for FL that overcome defective immune surveillance, prevent FLs from receiving stromal support and prevent disease progression.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Loren Walensky, PhD, MD
Dana-Farber Cancer Institute
Boston, MassachusettsPrecision 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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Brian Walker, PhD
Indiana University
Indianapolis, IndianaThe impact of non-coding somatic mutations on the prognosis and progression of multiple myeloma
Past studies of protein-coding regions have extensively characterized the genome of multiple myeloma (MM), but there has been little information on the prognostic impact of non-coding variants that may affect gene expression and regulation. Using a well-defined set of patient samples at different stages of disease progression we will define non-coding mutational hotspots in MM that contribute to progression and poor prognosis, identifying novel targets for alternative treatment strategies.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Venkata Lokesh Battula, PhD
The University of Texas MD Anderson Cancer Center
Houston, TexasTargeting 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 ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022
Ryan Wilcox, PhD, MD
Regents of the University of Michigan
Ann Arbor, MichiganXPO-1 as a novel therapeutic target in GATA-3 expressing mature T-cell lymphomas
GATA-3 identifies high-risk subtypes of mature T-cell lymphomas (MTCL), as its target genes, which we have systematically identified, have significant cell-autonomous and non-cell-autonomous (by regulating constituents of the tumor microenvironment) roles in these MTCL. As our preliminary data suggests that XPO-1 inhibition is a novel, and largely unexplored, therapeutic strategy in these MTCL, we will examine its cell-autonomous (Aim #1) and non-cell-autonomous (Aim #2) role in GATA-3+ MTCL.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2024
Kirsten Williams, MD
Emory University
Atlanta, GeorgiaInitiation 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 ProgramProject Term: Start Date: July 1, 2018 End Date: June 30, 2022
Roberta Zappasodi, PhD
Weill Cornell Medicine
New York, New YorkRestoring lymphoma immunosurveillance by combined EZH2 inhibition and immunotherapy
The project builds on evidence that mutations leading to persistent EZH2 activation drive germinal center B-cell lymphomagenesis by disrupting T-cell surveillance, and will test the hypothesis that EZH2 inhibition synergizes with immune checkpoint blockade and/or co-stimulation to eradicate these diseases. These results will provide the rationale for clinical development of precision-medicine immune-epigenetic combination therapies for lymphomas where these mechanisms are specifically altered.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: June 30, 2024
Carl Allen, PhD, MD
Baylor College of Medicine
Houston, TexasTesting targeted therapy in LCH
We propose to the hypothesis that patients with LCH who fail initial chemotherapy will respond to a targeted strategy of blocking MAPK signaling through MEK inhibition. This trial is a Phase 2 study to evaluate the safety and efficacy of cobimetinib in patients with refractory LCH. Exploratory aims will evaluate response of lesions with specific mutations, ability of peripheral blood mononuclear cells to determine disease burden, and development of somatic mutations in patients who relapse.
Program: Translational Research ProgramProject Term: Start Date: October 1, 2021 End Date: September 30, 2023
Alec Zhang, PhD
The University of Texas Southwestern Medical Center
Dallas, TexasDevelopment of LILRB1-based immunotherapy for multiple myeloma treatment
LILRB1 is a human immune inhibitory receptor expressed on a variety of immune cells. Based on preliminary data, we hypothesize that blocking LILRB1 signaling in immune effector cells of myeloma patients will lead to increased anti-cancer activities of immune cells. We will identify subsets of myeloma patients with higher LILRB1 expression on immune cells, and determine whether anti-LILRB1 antagonizing antibodies can improve the function of immune cells for multiple myeloma treatment.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2021 End Date: June 30, 2024
Baochun Zhang, PhD, MD
Dana-Farber Cancer Institute
Boston, MassachusettsA multiantigen-targeting cytotoxic CD4+ T cell approach for treating B cell malignancies
B cell malignancies comprise a large number of different types of lymphomas and leukemia, which collectively represent the sixth leading cause of cancer death in the US. These cancer cells are potential targets of the host immune system’s CD4+ T cells, however, the latter normally lack the ability to kill such cancer cells. In this project, we develop a novel approach to rapidly produce CD4+ T cells capable of killing B cell cancers, and advance this approach towards clinical trials.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2019 End Date: June 30, 2022