Grant Finder

LLS investigators are outstanding scientists at the forefront of leukemia, lymphoma and myeloma research at centers throughout the world. Search to see the many research projects that LLS is currently funding.

Grant: 6498-16 | Translational Research Program (TRP):

Location:Vrije Universiteit Brussel, Brussels, 1090

Year: 2015

Project Title: Immunotherapy Targeting Neo-epitopes In Multiple Myeloma

Project Summary:

Multiple myeloma (MM) is caused by the proliferation of malignant monoclonal plasma cells in the bone marrow. It is the second most frequent neoplasm of the blood and bone marrow. Since the introduction of new drugs and the availability of stem-cell therapy, the survival rate of MM patients has increased faster than that of any form of cancer. However, due to the occurrence of drug resistance, MM remains incurable. Therefore, there is a need for novel therapies.

The aim of this project is to introduce a new immunotherapy for multiple myeloma. Immunotherapy is a relatively new treatment modality for cancer patients and is based on the observation that tumor cells express “tumor associated antigens”, which can be recognized by the T lymphocytes of the patients. Activated T cells that recognize a tumor-associated antigen on a tumor cell have the capacity to kill this tumor cell (“killer T cells”).

It is well known that the genetic information present in cancer cells contains many mutations: the genetic code of cancer cells differs from the genetic code of healthy cells from the same patient. Some of these mutated genes can encode for antigens (“neo-antigens”), which are thus specifically expressed on cancer cells, but not on healthy cells. These neo-antigens are patient-specific as the mutations that occur in cancer cells differ between patients. It would be of particular interest to stimulate T cells that recognize neo-antigens expressed by myeloma cells through immunotherapy.

In our project, we will isolate tumor cells from multiple myeloma patients and examine the genetic code of the tumor cells for the presence of mutations that could result in the expression of neo-antigens. We will evaluate the feasibility to raise T cell responses specific for the identified neo-antigens. If our results are promising, we will offer the opportunity to myeloma patients to participate in a clinical trial where we will provide a personalized vaccine developed to specifically enhance immune responses directed against the neo-epitopes expressed by the myeloma cells.

Grant: 6497-16 | Translational Research Program (TRP):

Location:Duke University Medical Center, Durham, North Carolina 27708

Year: 2015

Project Title: The Notch2-BCR Axis: Targeting Drivers Of B Cell Fate In Chronic GVHD

Project Summary:

An estimated 60-80% of long-term survivors of HCT will develop chronic graft versus host disease (cGVHD), and death results in up to one third of the long-term post-HCT survivors. Treatments and prevention strategies for cGVHD are urgently needed. Chronic GVHD is clinically akin to acquired autoimmune diseases, representing unacceptable toxicity for patients who are otherwise cured of their cancer. By studying primary patient samples, our laboratory has identified cell signaling pathways that are hyper-activated in particular types of cGVHD patient cells. These immune cells, called B cells, represent particularly interesting therapeutic targets because they are known to contribute to cGVHD pathology in relevant murine models of this disease, and importantly, elimination of B cells in patients with anti-CD20 antibody, rituximab, does not result in cancer relapse after HCT. Studies in our lab have uncovered the mechanisms behind the limitation of global B cell depletion with rituximab. We found that factors present in the post-transplant setting prime aberrant B cells for activation and survival. While we and others are currently pursuing development of small molecule inhibitors of signaling pathways important for B cell survival and activation, we are finding that these inhibitors also target other cells. The lack of specificity for cGVHD B cells of these agents will potentially result in unwanted toxicity or in tumor relapse. We have therefore continued to pursue other molecular pathways that potentially drive pathological B cell production but that do not affect other organ systems. Very recently, we have discovered the importance of a pathway that warrants further study. This pathway, called the Notch2 pathway, is known to be critical for development of certain B cell subsets that we have identified in patients with cGVHD. We now have preliminary data showing that cell surface Notch2 expression on cGVHD B cells is increased. Cell surface Notch2 represents a viable therapeutic target of a novel monoclonal antibody available to our group for further study. Published and preliminary data as well as the availability of a novel therapeutic agent position my group, along with expert collaborators, to examine the Notch2 B cell signaling pathways in primary cells from HCT patients and using a murine model of cGVHD. Despite years of research, chronic graft versus host disease (cGVHD) remains common, debilitating and deadly. Our immediate goal herein is to develop a novel targeted agent for patients undergoing HCT hypothesizing that we will abrogate clinically significant cGVHD while maintaining anti-tumor responses.

Grant: 3356-16 | Career Development Program (CDP):

Location:Sloan Kettering Institute for Cancer Research, New York, New York 10087

Year: 2015

Project Title: Investigating Physiologic L-2-hydroxyglutarate Production And Its Relevance To Normal Hematopoiesis And Leukemogenesis

Project Summary:

Leukemia-associated mutations in the enzymes isocitrate dehydrogenase 1 and 2 result in production of the ‘oncometabolite’ D-2-hydroxyglutarate (D-2HG), which poisons machinery required for normal gene expression and locks leukemia cells in an immature stem cell-like state. 2HG is a chiral molecule that can exist in mirror-image D- or L- conformations, but biologic sources and activities of L-2HG remain poorly understood. We discovered that under conditions of oxygen limitation (a.k.a. hypoxia), cells potently and selectively produce L-2HG via a novel metabolic pathway. Hypoxia-induced L-2HG inhibits gene expression machinery and promotes stem cell-like marks. Normal blood stem cells and leukemia stem cells reside in hypoxic regions of the bone marrow. Thus, we hypothesize that L-2HG might represent a molecular mechanism whereby the hypoxic niche promotes and maintains the immature state of normal blood stem cells and leukemia stem cells. To test this hypothesis, we propose the following aims: (1) use cell culture systems to more fully elucidate the effects of L-2HG on gene expression machinery, (2) employ mouse models to determine if L-2HG influences the development of normal blood cells or leukemia, (3) utilize patient samples to investigate a potential role of L-2HG in human leukemia. Investigating the role of L-2HG in normal blood cells and leukemia will help build a scientific framework to aid development of novel anti-cancer therapeutics that target metabolic enzymes.

Grant: 3357-16 | Career Development Program (CDP):

Location:Shanghai Institute of Immunology, , Shanghai

Year: 2015

Project Title: VBcl2 Is Essential For Persistent Infection And Pathogenesis Of Kaposi's Sarcoma-associated Herpesvirus (KSHV)

Project Summary:

Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is associated with the pathogenesis of Kaposi’s sarcoma (KS), body cavity-based lymphoma (BCBL) or pleural effusion lymphoma (PEL), and some cases of Multicentric Castleman’s disease (MCD) and post transplant lymphoproliferative diseases (PTLD). One critical virulence factor involved in KSHV persistence and oncogenicity is the viral homolog of the Bcl2 protein (referred to as vBcl2). Alongside its well-characterized anti-cell death activity, our preliminary studies have established that vBcl2 effectively suppresses the anti-viral autophagy pathway (‘self-eating’, lysosome-dependent degradation and recycling of the intracellular components) by directly targeting the key autophagy effector protein Beclin-1. Based on these, we hypothesize that inhibition of autophagy by vBcl2 constitutes a novel mechanism by which KSHV evades host immunity and confers persistent infection and pathogenesis (Aim 1), and host autophagy limits KSHV persistent infection in humanized mouse model in vivo (Aim 2). Achieving the above aims will define the molecular mechanism by which KSHV vBcl2 regulates host autophagy pathway and KSHV infection. It not only addresses a fundamental biological question, but also can facilitate the development of new preventive and/or therapeutic approaches.

Grant: 4317-16 | Career Development Program (CDP):

Location:Erasmus University Rotterdam, Rotterdam, 3015 GE

Year: 2015

Project Title: Targeting Epigenetic Therapy To Specific Acute Myeloid Leukemia (AML) Patient Cohorts For Maximal Clinical Efficacy

Project Summary:

With current treatment, acute myeloid leukemia (AML) is fatal for most patients, caused either directly by the disease itself or by complications induced by chemotherapy or stem cell transplantation. Consequently, there is an urgent need for new drugs that are more specific and less toxic. In this project, we will study the efficacy of new classes of drugs, which we call “epigenetic compounds”. These drugs are specifically designed to target abnormalities in patients with leukemia that are not contained in the genetic information of the leukemia cells, but rather in the way the leukemia cells read the information from their genes. Recent work by us and others has shown that such epigenetic therapy holds great promise. However, AML appears to be a very heterogeneous disease, and with current knowledge it is not yet possible to predict which patients benefit from particular compounds. We will directly test these drugs in bone marrow samples obtained from human AML patients. We will test which patients with AML benefit most from treatment with particular drugs. In addition, we will investigate what the mechanism of action of the drugs is. This will allow for the subsequent testing of such drugs in clinical trials, potentially in combination with other compounds.

Grant: 9004-16 | Transforming CURES Initiative (TCI):

Location:Boston Children's Hospital, Boston, Massachusetts 02241-4413

Year: 2015

Project Title: Modeling MDS And Leukemia Predisposition For Novel Therapeutics.

Project Summary:

Monosomy 7 refers to deletions of chromosome 7 or deletion of a specific region of chromosome 7 (7q). Monosomy 7 is associated with poor survival using standard chemotherapy treatments. Monosomy 7 is a common characteristic of MDS/AML arising in patients who were previously treated with chemotherapy for other malignancies or in patients with a genetic predisposition to cancer. The paucity of model systems to study monosomy 7 has impeded the development of new therapies for this devastating disorder. Current evidence indicates that additional genetic mutations are required for monosomy 7 to progress to leukemia. Therefore, we developed induced pluripotent stem cells (iPSC) from patients with a leukemia predisposition syndrome, Shwachman-Diamond syndrome (SDS), and introduced a deletion of 7q. Monosomy 7 in SDS patients is associated with a high risk of progression to leukemia. The advantage of iPSC is that they can develop into blood cells. Since we already have these cells in hand, we are poised to investigate the effect of monosomy 7 on blood cell production and identify monosomy 7-associated molecular alterations to understand how monosomy 7 promotes leukemia. We will also treat iPSC with different agents to find treatments that preferentially eradicate monosomy 7 cells relative to control non-monosomy 7 cells. Promising agents will be further tested on monosomy 7 MDS/AML bone marrow samples from non-SDS patients. Our aim is to develop new treatment strategies.

Grant: 6495-16 | Translational Research Program (TRP):

Location:Università degli Studi di Torino- Dipartimento di Biotecnologie e Scienze per la Salute, Torino, 10126

Year: 2015

Project Title: Clonal Evolution Analysis And Heterogeneity Of Mutational Profiles In Multiple Myeloma (MM) Patients Receiving Immunomodulatory Drugs (IMiDs)

Project Summary:

Multiple Myeloma (MM) is a malignant monoclonal plasma cell disorder whose pathogenesis is only partially understood. Although the use of conventional treatments, few, if any, patients with MM are cured. The recent introduction of novel drugs overcome cell resistance to conventional treatments and has improved responses and outcome of MM patients. Importantly, there is a class of novel agents that target cells involved in immune response (immunomodulatory drugs [IMiDs]), which are profoundly active in MM. Several studies have reported that the combination of pomalidomide (a new generation IMID) and dexamethasone in patients who have progressed after multiple treatment options has important benefits in term of outcome. However, most of MM patients considered to have an ”high risk” disease develop resistance over time.
New and sensitive techniques, such as next generation sequencing (NGS), allow the study of intrinsic and biological characteristics of several cancers and its monitoring over time providing insights into molecular mechanism of disease behaviour and novel therapeutic targets.
We are planning to perform a biological sub-study in the context of a clinical trial, which will involve MM patients at relapse during lenalidomide (an IMID agent). Then, these patients will receive pomalidomide in association with other drugs (dexamethasone alone or cyclophosofamide and dexamethasone) but importantly some will be treated at early relapse (without clinical symptoms) while some at late relapse (in presence of organ damage) to compare the best strategy.
The overall goal of this project is to investigate genomic characteristics of MM cells and to correlate biological profile with clinical outcome into a translational method combining deep sequencing of tumor samples at the serial stages of disease progression and evaluating clones change over time. Furthermore we will analyze sensitivity and resistance mechanisms of these two IMIDs in MM cells with the identification of new candidates genes which may impact in prognostic stratification, therapeutic approaches and assessment of disease response to treatment.

 

Grant: 6494-16 | Translational Research Program (TRP):

Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215

Year: 2015

Project Title: Prognostic And Therapeutic Targeting Of AP Endonuclease In Multiple Myeloma

Project Summary:

A prominent feature of multiple myeloma (MM) and other cancers is a significant genomic instability which leads to further genetic changes in cancer cell. This is believed to ultimately result in progression of disease, development of drug resistance and metastatic disease in other cancers. Using multiple approaches including sophisticated gene sequencing studies we have described global mutational changes in myeloma and defined genomic heterogeneity and its evolution overtime. We have now identified that a genome repair pathway called homologous recombination (HR), is dysregulated in MM; and inhibition of
HR activity reduces, whereas its induction leads to increased genetic instability. We have further identified that APE1, as a gene that is dysregulatd in myeloma and is involved in the regulation of HR pathway in MM. Moreover, we observe that MM patients with very high APE1 expression have a poor survival and reducing its activity may reduce the rate of mutation. Based on these information we now propose to identify the role of APE1 in MM. We will evaluate the role of elevated AP endonuclease activity as a marker of prognosis using our validated assay, in 700 uniformly-treated MM patient samples collected at the time of diagnosis from patients enrolled in the IFM/DFCI clinical study and correlate it with response, TTP,

and survival (Sp. Aim 1); investigate genomic impact of elevated APE1 in MM and normal cells (Sp Aim 2); and develop and test a small molecule inhibitor of APE1 in MM and normal cells (Sp. Aim 3). We will evaluate these potential drugs for impact on Genome stability, growth, ability to invade/migrate and develop drug resistance, using in vitro assays, and impact on tumor growth in murine model of MM. These studies will improve our understanding of genomic progression, facilitate development of prognostic tests, and identify novel therapeutics to prevent evolution and development of drug resistance in MM.

Grant: 5440-16 | Career Development Program (CDP):

Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215

Year: 2015

Project Title: Role Of Sumoylation In The Fanconi Anemia Pathway

Project Summary:

Fanconi anemia (FA) is a genetic disorder characterized by anemia, bone marrow failure (BMF), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Sixteen FA proteins act in a repair pathway originally elucidated in the D’Andrea laboratory, and perturbation of this pathway causes defects characteristic of FA. Despite its rare occurrence, identifying the molecular defects underlying FA can guide our understanding and treatment of its associated diseases (BMF, MDS and AML) in the general population. A key feature of the FA repair pathway is an eight subunit core complex whose activity is critical for removal of crosslinks from DNA. New studies from the D’Andrea laboratory have uncovered a link between the degradation of a subunit of this complex and its modification by a protein called SUMO. Disruption of this regulation in humans confers FA, highlighting its clinical relevance. Interestingly, other subunits of the complex are also modified by SUMO, suggesting broader roles for this modification in FA pathway regulation. To define these, we will use a two-pronged approach: at the enzyme level, we will assess the contribution of candidate enzymes that degrade sumoylated proteins in the FA pathway; at the substrate level, we will characterize the function of sumoylation of FA proteins. Together, these studies will shed light on the molecular mechanisms safeguarding the genome and suggest therapeutic strategies for FA and its associated diseases, such as AML and MDS.

Grant: 3363-16 | Career Development Program (CDP):

Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215

Year: 2015

Project Title: Mechanistic Basis Of Cohesin-mediated Leukemogenesis

Project Summary:

We have made tremendous progress in describing the genetic basis of human leukemias with the advent of new technologies, such as next generation sequencing (NGS). However, we currently do not understand how most of the genes implicated in leukemia development actually cause leukemia, and how to best target them with new therapies. In this project, we will focus on acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and specifically answer the question why patients who carry a single abnormal copy of one of the cohesin genes, such as STAG2 and SMC3, develop leukemia. We will use AML and MDS cells from patients who carry normal versus abnormal copies of these cohesin genes to answer this question. Treatment options for patients with MDS and AML are limited, and better understanding of the mechanisms by which leukemia causing genes, such as cohesins, contribute to leukemia development in patients will inform the design of urgently needed new treatments. The impact of this work might also extend to patients with other blood cancers, including chronic myelomonocytic leukemia (CMML) and chronic myeloid leukemia (CML), which are also frequently found to have abnormal copies of one of the cohesin genes.