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: 1348-18 | Career Development Program (CDP):

Location:Northwestern University, Evanston, Illinois 60208

Year: 2017

Project Title: The Role Of Plek2 In The Pathogenesis Of Myeloproliferative Neoplasms

Project Summary:

Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases with overproduction of mature blood cells and increased risk of evolving to acute leukemia. A specific mutation on one of the blood cell surface proteins called Jak2 is the leading cause of this group of diseases. The discovery of this mutation led to the development of inhibitors specifically targeting Jak2. However, these inhibitors are not curative. In addition, MPN patients treated with these inhibitors often develop drug resistance and significant side effects due to the indispensable roles of this blood surface protein in normal blood production. We have been studying new approaches to treating MPNs, especially focusing on the proteins that are important for the development of MPN disease but not essential for normal blood cells. We identified one of these proteins, Plek2, which a part of normal red blood cell development but may also be involved in the disease state in some MPNs. Our studies using mouse models and tumor cell lines demonstrated that Plek2 is critical for the MPN disease development and is a mediator of Jak2 signaling. In addition,mice that lose Plek2 do not exhibit obvious side effects. These novel discoveries made Plek2 an attractive drug target for the treatment of MPNs. The overall goal of my research is to better understand how Plek2 reverts the disease progression in MPNs using mouse models and bone marrow cells from MPN patients. We will analyze how Plek2 mediates Jak2 signaling as well as how Plek2 may be involved in other MPN mutations, such as CALR and MPL. Successful completion of this project will lay the foundation for targeting Plek2 as a novel therapeutic approach for the clinical management of MPNs.

Grant: 3375-18 | Career Development Program (CDP):

Location:Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024

Year: 2017

Project Title: Enhancing Adoptive Immunotherapy Of AML With Engineered T Cells By Expressing Immunomodulatory Fusion Proteins That Overcome Inhibitory Signals

Project Summary:

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has the worst survival rate of all leukemias, with only 26% of AML patients surviving 5 years. Since our immune cells can have the ability to eradicate tumors, immunotherapeutic approaches are being developed as treatment options with the goals of providing better efficacy and fewer side effects. One form of immunotherapy is adoptive immunotherapy, which provides an opportunity to genetically modify T cells to recognize and destroy tumors and generate a population of memory cells that can serve as a “living drug.” We identified a T cell receptor (TCR) that recognizes and tightly binds WT1 – a well-validated protein that promotes the cancerous activity of tumors – and observed clinical activity in patients with T cells modified to express this TCR. However, tumor cells can express inhibitory proteins that block activation of the T cells that recognize the tumor and thereby avoid immune-mediated eradication. To overcome this inhibition and further enhance efficacy, we engineered immunomodulatory fusion proteins (IFPs)that combine a tumor-specific inhibitory receptor with a costimulatory signaling domain, essentially to replace a “brake” with an “accelerator” for the immune response. By this method, we have effectively targeted several inhibitory proteins, demonstrated that we can significantly improve T cell therapy in a mouse model of AML, and acquired initial evidence of function in human T cells. To obtain data needed to translate our findings into the clinic, we plan to assess safety and potential toxicity to normal tissues in mouse models with T cells expressing different IFPs targeting AML cells expressing the relevant proteins. We will also assess efficacy with human IFPs in human T cells targeting AML cells in mouse models. Our long-term goals are to validate this approach in clinical trials, advancing a novel, safe and effective T cell immunotherapy that ultimately will improve AML patient outcomes.

Grant: 8012-18 | Screen to Lead Program (SLP):

Location:H. Lee Moffitt Cancer Center & Research Institute, Atlanta, Georgia 30374-2801

Year: 2017

Project Title: Rationally Designed Dual BRD4-Kinase Inhibitors For The Treatment Of Myeloid Cancer

Project Summary:

Current anti-cancer targeted drugs often fail due to ineffectiveness or drug resistance, suggesting alternative strategies are needed to develop effective therapies. We recently determined that certain drugs bind to and inhibit two different classes of proteins that play important roles in cancer. These two classes are called kinases and BET proteins, which have completely different functions in the cell. The general approach in drug discovery has been to optimize a single drug to target a single protein. Our identification of the dual inhibitory activity of BET-kinase inhibitors provides an opportunity to optimize inhibiting both targets with a single drug. To this end, we have developed drugs that exhibit improved kinase and BET inhibitor activity. The ability of these compounds to target multiple regulators of cancer may provide superior effectiveness against blood cancers that are known to require both targets of the drug. For example, one of the dual inhibitors targets the JAK2 kinase, which is a major driver of myeloid cancers. JAK2 kinase inhibitors, which have been designed to solely target kinase activity, have not been successful in patients due to ineffectiveness and drug resistance. As these cancer cells also require BET protein function, our dual inhibitors may improve effectiveness and prevent drug resistance, a concept support by our initial studies. This proposal is written to support our optimization and development of our lead compounds for blood cancers.

Grant: 5474-18 | Career Development Program (CDP):

Location:The University of Chicago, Chicago, Illinois 60637

Year: 2017

Project Title: Transcriptional And Epigenetic Roles For β-catenin In The Genomic Instability And Oncogenic Transformation Of T-cell Leukemia/lymphoma

Project Summary:

Cancer arises from changes in DNA, and these changes can come in various forms. In the case of leukemia and lymphoma, most have genomic instability, meaning the normal organization of DNA (the genome) is disrupted due to improper repairing of DNA breaks. DNA is organized into structures known as chromosomes, and changes to normal chromosomal structure is evidence of genomic instability in a cell. Chromosomal defects mark approximately 80% of T-cell leukemia and often involve the moving of cancer-causing genes to other chromosomes (translocation) into positions that switch them “on.” This instability of the genome is a continuous process and allows for selection of ever more aggressive and therapy-resistant tumor cells. Our protein of interest, beta-catenin, has very tightly controlled, low expression levels in normal cells; however, uncontrolled beta-catenin expression has been linked to genomic instability in cancer through mechanisms that remain unclear.

Previous work from our lab showed that uncontrolled beta-catenin expression causes mice to develop T-cell leukemia. These leukemias have genomic instability and chromosomal defects similar to those seen in T-ALL patients. The pattern of DNA breaks suggests that the excess beta-catenin impairs mechanisms (known as checkpoints) that ensure that DNA is replicated and repaired correctly. In fact, these mice have lower than normal expression levels of genes required for DNA checkpoints and repair. Based on observations of this model, I hypothesize that beta-catenin affects multiple levels of gene regulation to impair DNA checkpoints and repair. Beta-catenin controls transcriptional mechanisms of gene expression, which switch genes “on” or “off,” as well as epigenetic mechanisms, which change the shape of DNA to allow various kinds of gene regulators to interact. Using state-of-the-art genomic technologies, I will examine DNA checkpoint and repair mechanisms to understand both transcriptional and epigenetic changes that happen in cells with uncontrolled beta-catenin. I will also examine cells from leukemia patients to apply what I see in my mouse model to human disease.

Chromosomal defects are a driving force in cancer and reflect a fundamental failure of the checkpoints that maintain genome integrity. My goal is to increase our understanding of how beta-catenin controls these intricate cellular processes. My studies aim to identify novel strategies for the treatment of this complex blood cancer.

Grant: 6545-18 | Translational Research Program (TRP):

Location:Brigham and Women’s Hospital, Boston, Massachusetts 02241-3149

Year: 2017

Project Title: Targeting Notch In B Cell Lymphoma/leukemia

Project Summary:

Remarkable progress has been made in the treatment of CLL and other B cell tumors such as mantle cell lymphoma, but to date none of these treatments result in cures, and new therapies are needed. Our group has a longstanding interest in targeting the Notch pathway as a cancer treatment strategy. Recently, mutations in Notch genes have emerged as being among the most important causes of CLL and other B cell tumors. These mutations result in Notch “hyperactivity” and are associated with more aggressive disease; thus, patients with tumors with Notch mutations are particularly in need of new therapies. Our proposed work is focused on the idea that even in tumor cells with Notch mutations, Notch activation depends on neighboring cells that express proteins called ligands that turn on Notch. The precise identity of these ligands is not known, but drug companies have developed therapeutic antibodies that specifically inhibit several known Notch ligands, including those that we think are responsible for Notch activation in B cell tumors. Our proposed studies aim to identify the ligand that is causing Notch activation in B cell tumors, to determine the reason that Notch causes B cell tumors to behave more aggressively, and to prove that Notch inhibitors, alone and in combination with other drugs currently used to treat CLL and other B cell tumors, are effective in killing tumor cells. Taken together, these studies will set the stage for new clinical trials of Notch inhibitors in patients with B cell tumors. 

Grant: 6547-18 | Translational Research Program (TRP):

Location:The University of Adelaide, Adelaide, South Australia 5000

Year: 2017

Project Title: Targeting Stromal Cell-derived Gremlin1 To Control Multiple Myeloma Disease Development

Project Summary:

Multiple myeloma (MM) is a bone marrow (BM) cancer of antibody producing plasma cells (PC). MM PCs are thought to spread throughout the BM in a manner similar to the way in which solid tumours spread. However, which cells and/or factors within the BM are important in helping PCs establish and grow, remains largely unknown. Using newly developed microscopic and genetic marking techniques: we have shown that there are very few sites within the BM that are capable of supporting the growth of PC tumours. In fact, we have found that the majority of the PCs that migrate to, and “land” in the BM remain “dormant” and fail to grow. These findings suggest that in order to grow, MM PCs must encounter an environment that has the right type of cells and factors, which support their growth. We believe that a rare type of cell, called an osteochondroreticular stem cell (OCR-SC), which we recently discovered, plays an essential role in “switching on” the growth of MM PC. OCR-SCs are unique in their ability to make a protein called Gremlin 1 (Grem1), which has been shown in other types of cancer, to stimulate tumour growth. Our early studies show that Grem1 can potently stimulate MM PC growth and that very high levels of Grem1 are found in areas of the BM that are occupied by tumour. We have assembled a team of experienced researchers with unique skills and established relationships with industry to enable us to investigate whether inhibiting Grem1 activity can provide a way to limit the growth of MM PC and prevent MM disease development.

1. We will use a technique known as laser scanning cytometry (LSC) and BM samples from patients with a asymptomatic forms of MM known as monoclonal gammopathy of unknown significance (MGUS) or smouldering MM (SMM) and samples from patients with MM, to determine whether Grem1-expressing cells are found in areas of active tumour growth, and not in areas in which the PC remain dormant. Similarly, we will use LSC to examine the bones from mice in which we have induced a MM-like disease to show that Grem1-expressing OCR-SCs are a key component of the “activating” areas of BM which support MM PC growth.

2. We will use genetically altered mice, in which Grem1 has been removed from OCR-SCs, to show without doubt, that Grem1 is required for the growth and development of MM. In addition, we will inject an antibody that blocks the function of Grem1 into mice with MM, to see if this will lead to MM PC tumour death or dormancy. These studies will be the first important steps to see if Grem1 is a good therapeutic target to stop disease development in MM patients.

3. We will measure the levels of Grem1 in the blood in a large number of samples that we have collected from patients with MGUS, SMM or MM. This will allow us to determine if Grem1 levels are associated with the amount of disease a patient has, or whether Grem1 levels predict the risk of a patient with benign disease developing advanced disease. 

Grant: 6538-18 | Translational Research Program (TRP):

Location:The Ohio State University, Columbus, Ohio 43210

Year: 2017

Project Title: Novel Strategies For The Therapy Of Genomic High Risk CLL

Project Summary:

Cancers such as chronic lymphocytic leukemia (CLL) are characterized by a slow accumulation of a specialized kind of white blood cell called a B-lymphocyte. It starts in the bone marrow and spills over to accumulate in the blood, lymph node, liver and spleen. The reason CLL is problematic is that the leukemic B-cells are non- functional and live for a long time either because they have proteins that help them survive for a long time or lose proteins that normally would cause them to die.

CLL undergoes changes in its genes.  For instance, it often loses a very important gene called p53. p53 is called the guardian of the genome and is necessary to kill the CLL cells after treatment with drugs. Every cell of the body has two copies of this gene. In CLL, one copy of p53 is lost due to deletions and the other copy sometimes gets altered by mutations. The mutated p53 supports the survival of the CLL cells and help the disease become resistant to treatment.  Both deletions and mutations of p53 have been found to decrease survival in patients whose CLL cells carry these abnormalities.

Mutated p53 depends on HSP90, a protein that binds to mutated p53 and helps it carry out its cancer supporting function. One of the key functions of mutated p53 is to block the cell death inducing action of normal p53 and in addition activate other genes that support CLL cell survival. We plan to use drugs that stop the action of HSP90 (HSP90i). Blocking HSP90 will prevent it from stabilizing mutated p53 and cause it to be destroyed, which in turn, will kill CLL cells that carry deletions or mutations of p53. Therefore, HSP90i treatment may represent a new treatment that can treat  this poor prognosis group of CLL patients (del17p/mutant p53) either alone or in combination with drugs such as ibrutinib that are currently in use used to treat the disease.

Grant: 6553-18 | Translational Research Program (TRP):

Location:IRIC - Institut de Recherche en Immunovirologie et en Cancerologie, Montreal, Quebec H3C 3J7

Year: 2017

Project Title: RUNX1 Mutations That Confer Exquisite Sensitivity To Glucocorticoids

Project Summary:

Acute myeloid leukemia (AML) is a disease caused by several genetic alterations, including mutations in the RUNX1 gene. The presence of RUNX1 mutations in AML cells is generally associated with bad prognosis for these AML patients, and RUNX1 mutations are also the cause of Family platelet disorder, which predisposes these patients to AML development. In order to discover novel cures for patients suffering from RUNX1-mutated AML, we identified glucocorticoids as effective drugs that kill AML cells carrying RUNX1 mutations. In this proposal, we plan to perform experiments to better understand how these molecules kill these AML cells and test the ability of GCs to cure mice that we will engineer to develop AMLs harboring RUNX1 mutations, in the hope of bringing this discovery to the clinic to improve treatment of patients suffering from RUNX1- mutated AML. 

Grant: 1345-18 | Career Development Program (CDP):

Location:The University of Utah, Salt Lake City, Utah 84112-9003

Year: 2017

Project Title: MicroRNAs In Myeloid Leukemia Development And Resistance To Chemotherapy

Project Summary:

Mutations in genes that control cell growth and survival are commonly found in leukemia. In the case of acute myeloid leukemia (AML) there is often a mutation in a gene called FLT3 that causes it to be activated all the time and promote disease. However, there are many aspects of how this mutated gene is able to promote AML that remain unclear, making it challenging to design and develop new therapies against this devastating condition. My lab studies a newly discovered class of molecules, called microRNAs, which are altered in diseases such as leukemia. In the case of AML with FLT3 mutations, one particular microRNA, called miR-155, is inappropriately elevated and thought to contribute to disease characteristics, including resistance to chemotherapy. Indeed, our preliminary results indicate that when miR-155 is reduced, many symptoms of leukemia that are caused by FLT3 are alleviated in mice and human AML cells growing in a dish. This suggests that miR-155 might work with FLT3 mutations to drive some types of AML in the clinic. We propose to study this relationship in greater detail to understand how these molecules collaborate to cause disease, unveil the mechanisms that are controlled by these genes at the molecular level, and determine if inhibition of miR-155, or other candidate microRNAs, can reduce AML disease in pre-clinical mouse models. Together, this work will provide novel insights into the contribution of microRNAs to different aspects of AML with FLT3 mutations, and hopefully inform the development of next generation microRNA therapeutics that can be used to treat this devastating disease.

Grant: 5468-18 | Career Development Program (CDP):

Location:New York University School of Medicine, Boston, Massachusetts 02241-415026

Year: 2017

Project Title: Understanding The Function Of 3D Chromatin Topology In Myeloid Disease

Project Summary:

Greater understanding of the fundamental mechanisms promoting the development of acute myeloid leukemia (AML) may help researchers develop new treatment approaches targeting these mechanisms. Chromosomes (collections of DNA and their associated proteins) are heritable and dynamic carriers of genetic information. Chromosomes are constantly looping, and these structural changes shape the gene expression pattern of a cell. This 3D genome landscape, known as genome topology, provides the physical structure required to inform the identity and function of a cell. The key players in establishing genome topology include the cohesin complex, a group of proteins that physically wraps around DNA to establish looping events, as well as the CTCF protein, which acts to bind DNA and establish the boundary of genome topological domains. Though genomic topological changes are normal in a healthy cell, alterations in genome topology likely play a role in cancer development.

Interestingly, regulators of genome topology are commonly mutated in various diseases, including cancers such as AML. AML is a common adult leukemia characterized by excessive proliferation of abnormal immature white blood cells. AML patients continue to have a dismal survival rate. Notably, mutations in the cohesin complex are an early step in AML formation, suggesting that controlling DNA looping and overall genome topology is a critical function to prevent cancer. However, there are limited insights into how maintaining the topological integrity of the genome halts AML formation. Our research focuses on understanding how regulators of the genome’s 3D structure protect healthy blood stem cells from forming leukemia. Using cutting edge technology, such as inducible RNA interference and CRISPR/Cas9, we will shed new light into the earliest steps in leukemia formation. Ultimately, mechanistic insights uncovered by these approaches have the potential to inform new treatment strategies targeting the root genetic causes of leukemia development.