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: 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.

RESEARCH PLAN:
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.

Grant: 1351-18 | Career Development Program (CDP):

Location:The Ohio State University, Columbus, Ohio 43210

Year: 2017

Project Title: Understanding And Overcoming Resistance To Bruton Tyrosine Kinase Inhibitors In Chronic Lymphocytic Leukemia

Project Summary:

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and until recently was treated with therapies toxic to the patient. Our clinical and research team at The Ohio State University Comprehensive Cancer Center helped provide critical information which led to the FDA approval of ibrutinib, a less toxic targeted therapy. Ibrutinib inhibits the BTK protein, which is a protein that CLL uses for its own pathological survival. Ibrutinib shows remarkable clinical activity that is more durable than any therapy ever studied in CLL. Unlike some CLL treatments, ibrutinib can be given to all age groups, making it a more widespread therapy. Ibrutinib’s success should form the basis for its inclusion in even more effective combination therapies that may someday lead to a cure. Historical experience indicates that effective new therapeutics for CLL will also have a major role in treatment of non-Hodgkin lymphoma and autoimmune diseases.

While ibrutinib is effective for many patients, some develop resistance to this treatment. My research team seeks to determine predictive genomic factors that result in BTK inhibitor therapy resistance. We discovered that some patients acquire mutations that then confer resistance to ibrutinib. The large group of patients treated with ibrutinib, including our collection of samples from patients with resistance mutations, represents an invaluable resource to pursue pre-clinical and clinical work to identify more effective CLL treatments. Exploring the mutations and their associated signaling pathways (which we will continue to discover) will help us understand ways to overcome treatment-related resistance by either early recognition or, potentially, novel therapeutic approaches. 

Our experiments use primary CLL cells from patients whom are seen by our clinical team.  We are also using the most appropriate laboratory-based model available for understanding preclinical drug development and CLL biology. Our experimental approach will directly address the Leukemia & Lymphoma Society’s mission to cure blood cancer by discovering new potentially curative treatment strategies for CLL.

Grant: 3374-18 | Career Development Program (CDP):

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

Year: 2017

Project Title: Functional Characterization Of The Mutant Calreticulin-MPL Interaction In Myeloproliferative Neoplasms

Project 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

Year: 2017

Project Title: The Role Of NOTCH1 Controlled Micropeptides In T-ALL

Project 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

Year: 2017

Project Title: Assessment Of Epigenetic Reprogramming Of The T Cell Response To CTLA-4 Blockade In AML

Project 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.