Grant: 6545-18 | Translational Research Program (TRP):
Location:Brigham and Women’s Hospital, Boston, Massachusetts 02241-3149
Project Title: Targeting Notch In B Cell Lymphoma/leukemiaProject 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
Project Title: Targeting Stromal Cell-derived Gremlin1 To Control Multiple Myeloma Disease DevelopmentProject 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
Project Title: Novel Strategies For The Therapy Of Genomic High Risk CLLProject 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
Project Title: RUNX1 Mutations That Confer Exquisite Sensitivity To GlucocorticoidsProject 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: 5471-18 | Career Development Program (CDP):
Location:Harvard Medical School, Boston, Massachusetts 02241-5649
Project Title: Studying The Function Of Co-activator MAML1 In Notch-associated T-cell Acute Lymphoblastic LeukemiaProject Summary:
Normal cell growth and differentiation relies on a small number of signaling pathways that direct the gene expression patterns unique to each cell type. One pathway particularly important in cell-cell communication is the Notch pathway, which normally relies on direct contact between a signal-sending cell and a signal-receiving cell. After the signal is activated, a portion of the Notch protein enters the cell nucleus and forms a complex with two other proteins, called RBPJ and MAML1, to regulate the expression of genes that control cell growth and cell fate decisions. Aberrant activation of the Notch pathway by mutations, however, leads to the development of T cell acute lymphoblastic leukemia (T-ALL). In fact, Notch1 mutations are found in more than half of all human T-ALL cases. The goal of my project is to understand how the MAML1 gene cooperates with Notch to induce the production of Notch-responsive genes. In one line of study, I will use a Notch inhibitor to toggle the Notch pathway between “on” and “off” states, and determine what protein partners MAML1 chooses in the “Notch active” state and how these partnerships affect its function. I will also analyze the temporal sequence of events that take place in the nucleus after Notch is switched on in leukemic cells, focusing on the role of MAML1 in the induction of target gene expression. These studies will help us understand how Notch and MAML1 cooperate to stimulate aberrant gene expression in leukemic cells and may lead to new strategies for therapeutic development in T-ALL.
Grant: 1348-18 | Career Development Program (CDP):
Location:Northwestern University, Evanston, Illinois 60208
Project Title: The Role Of Plek2 In The Pathogenesis Of Myeloproliferative NeoplasmsProject 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
Project Title: Enhancing Adoptive Immunotherapy Of AML With Engineered T Cells By Expressing Immunomodulatory Fusion Proteins That Overcome Inhibitory SignalsProject 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: 3374-18 | Career Development Program (CDP):
Location:Brigham and Women’s Hospital, Boston, Massachusetts 02241-3149
Project Title: Functional Characterization Of The Mutant Calreticulin-MPL Interaction In Myeloproliferative NeoplasmsProject Summary:
Myeloproliferative neoplasms (MPN) are a group of rare blood cancers that occur when the body produces too many white blood cells, red blood bloods, or platelets. Though the overall prognosis for MPN tends to be favorable, more advanced forms of these diseases can lead to severe anemia, increased risk of blood clots, and transformation to leukemia. MPN were first described in 1951 by hematologist William Dameshek, but the underlying genetic cause of these diseases remained a mystery for over 50 years. In 2005, four different research groups simultaneously discovered that approximately 63% of MPN patients harbor mutations in the gene JAK2. This was a tremendous breakthrough in the MPN field and led to the development of the FDA-approved drug ruxolitinib (Jakafi), a compound that inhibits JAK2 activity, for the treatment of MPN. Despite this advance however, the causal genetic abnormalities in the remaining 40% of non-mutated JAK2 MPN patients remained unknown for nearly a decade thereafter. In 2013, two different groups performed sequencing experiments on blood cells from non-mutated JAK2 MPN patients, and found that the majority of these patients harbor mutations in the gene calreticulin (CALR). The CALR gene encodes a “housekeeping” protein that resides in the endoplasmic reticulum (ER) and ensures quality control of protein folding in the cell. We currently have an incomplete understanding of the mechanism by which CALR mutations transform normal blood cells to cause MPN.
Unlike normal CALR, mutant CALR is found near the cell surface. Our recent research has shown that the mutations enable an interaction with a cell surface receptor protein called MPL. We have further shown that this interaction leads to an activation of the JAK2 pathway. A central hypothesis from this research is that mutant CALR binds to proteins that it does not normally bind to, and some of these proteins may be essential for the oncogenic activity of CALR. Building on this work, we will utilize state-of-the-art technology to determine the proteins mutant CALR binds to in the cell that are not bound by normal, non-mutated CALR. Through this work, we hope to gain a comprehensive understanding of the protein partners with which mutant CALR interacts in the cell to drive disease development, which would ultimately inform new targets for therapeutic intervention. Ultimately, we hope that our work will lead to improved therapeutic strategies for MPN patients, particularly those who do not respond well to ruxolitinib and other existing treatments.
Grant: 5461-18 | Career Development Program (CDP):
Location:The Trustees of Columbia University in the City of New York, Columbia University Medical Center, New York, New York 10027
Project Title: The Role Of NOTCH1 Controlled Micropeptides In T-ALLProject Summary:
Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer and a leading cause of disease-driven death in children. Understanding the causes and mechanisms of leukemia is essential in order to develop specific highly active and less toxic treatments. One of the most common drivers of leukemia growth and survival is the NOTCH1 gene. NOTCH1 is frequently mutated in leukemia, and these mutations cause increased NOTCH1 activity, which in turn triggers a cellular program driving uncontrolled cell proliferation. Our understanding of the specifics of how NOTCH1 promotes leukemia transformation remains rudimentary.
Though most of our knowledge of T-ALL comes from the genetic dissection of known protein-coding genes, it is likely that other components of the genome contribute to T-ALL as well. A recently discovered component of the genome gives rise to very small proteins, called micropeptides that likely have profound effects on gene expression. Our research aims to investigate the role of this new family of gene-encoding proteins as potential key drivers of leukemia growth. Our central hypothesis is that among the multiple proteins controlled by NOTCH1, micropeptides are of particular importance for leukemia growth and survival. While large proteins function as molecular machines, micropeptides function as keys or switches that bind to and turn these molecular machines “on” and “off”. We are using the latest genomic technologies and refined computational approaches to identify the complete repertoire of NOTCH1-controlled micropeptides operating in leukemia. We will then evaluate the specific role and mechanisms by which these short proteins contribute to leukemia cell growth. Dissecting the mechanism of action of these key leukemia-driving micropeptides may identify novel targets for the treatment of ALL.
Grant: 6527-18 | Translational Research Program (TRP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Assessment Of Epigenetic Reprogramming Of The T Cell Response To CTLA-4 Blockade In AMLProject Summary:
The prognosis for patients with relapsed or refractory acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) whose disease comes back is poor, and innovative new therapeutic approaches are urgently needed. We conducted and published results from a clinical trial for patients whose blood cancer came back after bone marrow transplantation with ipilimumab, which is an antibody drug that uses the immune system to kill cancer cells. A small number of patients, including those with relapsed AML, had durable clinical responses. This clinical activity prompted us to develop a new proposal to evaluate whether or not we could safely boost response by adding a hypomethylating agent, decitabine, to ipilimumab treatment. Decitabine is a drug commonly used in the treatment of MDS/AML that is well-tolerated with modest clinical activity. Decitabine has the ability to affect the expression of genes. We now have a new approved clinical trial to assess the safety and clinical activity of the novel combination of decitabine plus ipilimumab in patients with relapsed or refractory AML/MDS who are post-transplant and who are transplant naïve. Using peripheral blood and bone marrow samples collected throughout treatment on study, we will evaluate the hypothesis that decitabine treatment might sensitize leukemia cells to ipilimumab by altering the immune response within the sites of leukemia infiltrates. Together with local expert collaborators we will perform a comprehensive analysis using patient samples collected from the clinical trial to evaluate for transcriptional (gene expression) and epigenetic (changes in a chromosome that alters gene activity and expression) changes within the immune cells present at leukemia sites including bone marrow and other tissues. We will then study which immune cells subpopulations are present and whether or not they have functional activity. We will correlate these laboratory findings with clinical activity to decitabine and ipilimumab to help us to understand treatment response or resistance. Knowledge gained from this investigation will help us to improve the design of future immunotherapy-based regimens with curative potential for patients.