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: 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.

Grant: 6534-18 | Translational Research Program (TRP):

Location:Yale University, New Haven, Connecticut 06520-8327

Year: 2017

Project Title: Exploiting Mutant IDH1/2-induced BRCAness With PARP Inhibitors As A Novel AML/MDS Therapy.

Project Summary:

We have identified a novel approach to treat certain types of leukemias that harbor a mutation in key genes that are involved in cellular metabolism. We found that these mutations create an altered chemical in the cell, which blocks the ability of tumor cells to repair broken DNA. This "achilles heel" can be exploited by treating such tumors with DNA damaging agents combined with DNA repair inhibitors. We have already demonstrated that this therapeutic approach is highly effective in brain tumors and other solid cancers which harbor mutations in these genes, and we now seek to determine whether the same is true in leukemias. Current strategies to treat tumors with these mutations are focused on suppressing the production of the altered metabolite. Our data suggest that this approach actually may not be ideal, as the metabolic vulnerability should be exploited rather than suppressed. The studies proposed here represent a highly translational, cross-disciplinary collaboration between researchers in hematology and oncology, radiation oncology, small molecule screening, and DNA repair basic science research. We expect that these studies will directly lead to a novel clinical trial in the future for leukemias with these mutations.

Grant: 6532-18 | Translational Research Program (TRP):

Location:The Regents of the University of California, San Francisco, San Francisco, California 94143

Year: 2017

Project Title: Inducing Effective Anti-leukemic Immunity With Novel AML Vaccines Expressing CD80/IL-15/IL-15R-alpha

Project Summary:

Patients with high-risk acute myelogenous leukemia (AML) have poor outcomes because current drug regimens fail to eradicate disease. Transplants of bone marrow or peripheral blood stem cells from matched related, or unrelated donors (allo-transplants) improve survival due to elimination of residual AML by immune cells present in donor cell populations. However, many patients are not eligible for allo-transplants, either because they lack suitable donors, or because they have pre-existing conditions making transplant too risky. Other therapies based on stimulating anti-leukemic immune responses have been tested, but achieving reproducible clinical efficacy has been elusive. In one approach, patients’ AML cells are collected before treatment, frozen, and later used as inactivated cell vaccines in order to stimulate immune responses specific to patients’ own tumor. However, to date, anti-leukemic immunity stimulated by unmodified AML cell vaccines has been inadequate. 

Our strategy to improve the efficacy of AML cell vaccines is to increase their immune stimulatory activity by viral mediated transfer of a unique combination of three genes. Viral constructs express 1) a protein required to initiate recognition by immune cells, CD80, 2) a hormone shown to stimulate unprecedented levels of anti-tumor immunity, IL-15, and 3) a carrier protein required for efficient production and secretion of IL-15 in leukemic cells, IL-15 receptor alpha (IL-15Ra). For proof of concept studies, vaccines were made by inactivating mouse AML cells with x-ray treatment to prevent introduction of live leukemia cells with skin injections. Serial vaccination with AML cells, in the absence of viral modification, was minimally effective in slowing progression of disease in leukemia-bearing mice. However, injection of mouse leukemia vaccines engineered to express IL-15/IL-15Ra/CD80, induced immune responses that permanently eradicated leukemia in 80% of vaccinated mice. 

We now propose to test the effects of engineered, patient-derived AML cell vaccines in stimulating effective anti-leukemic responses. The function of a newly constructed lentivirus expressing human IL-15, IL-15Ra, and CD80, has already been validated in selected patient AML samples. Our aims are to: 1) quantify the level and duration of transferred gene expression in human AML; 2) evaluate the responses of immune cells from normal and leukemic individuals after stimulation with IL-15/IL-15Ra/CD80-expressing human AML cell vaccines. Responses will be evaluated both in cell culture, and by transplanting responding immune cells and human AML cells into immune deficient mouse models; 3) test the specificity of immune responses stimulated by IL-15/IL-15Ra/CD80-expressing AML cell vaccines by comparing effects of stimulated immune cells on AML versus normal bone marrow cells. The additional data provided by these studies will support the design and application for funding of a Phase 1 vaccine trial. 

Grant: R6507-18 | Translational Research Program (TRP):

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

Year: 2017

Project Title: MYD88 And CXCR4 WHIM-like Mutations Offer A Targeted Treatment Approach For WM

Project Summary:

Ibrutinib is an active drug that is approved by the U.S. FDA and European Medicines Agency for the treatment of WM. WM patients who have a mutation in MYD88 (over 90% do) respond to ibrutinib, while those with mutations in CXCR4 show lower levels of response and delayed responses. Despite the overall high levels of response to ibrutinib among WM patients, the achievement of complete responses is lacking. We discovered as part of the LLS sponsored study that two important pathways exist by which mutated MYD88 can support growth and survival of WM cells. One pathway is mediated by BTK, a protein targeted by ibrutinib. The other pathway involves a family of proteins known as the IRAK proteins. We discovered as part of this work that the IRAK1 protein was particularly important in relaying survival signals, and that it remains turned on in tumor cells taken from patients with WM, whereas BTK is shutoff. This finding encouraged us to develop potent and selective inhibitors that target IRAK1. One compound that we developed (JH-X-119-01) potently blocked IRAK1, and was very selective for IRAK1. We showed that this compound could synergize with ibrutinib and kill more MYD88 mutated tumor cells, including WM cells and those derived from patients with aggressive lymphomas (ABC type), than Ibrutinib alone. While the activity of this compound is excellent in cell models it does not possess all the requisite parameters for evaluating its efficacy in preclinical murine models.  We therefore propose to execute a medicinal chemistry campaign to achieve compounds simultaneously optimized for potency and drug like properties such as resistance to being degraded by liver enzymes and being able to be absorbed across the gut for therapy of MYD88 mutated diseases, including WM, ABC DLBCL, and primary brain lymphomas. During the course of our studies, we also pursued identifying other targets that are in the pathway that allow MYD88 mutated cells to grow. One target known as HCK was discovered that plays a master role as a regulator of many growth and survival pathways including BTK. We performed proof-of-concept studies with a toolbox compound, a compound that blocks HCK but is not suitable for use as a drug in humans, and showed this drug was very active in MYD88 mutated diseases. We propose to do medicinal chemistry to optimize this molecule for use in humans. During our studies, we also discovered that CXCR4 mutations found in 30-40% of WM patients cause resistance to ibrutinib. We worked out the signaling responsible for this resistance, and also found that blockers of CXCR4 reverse drug resistance. We developed a clinical trial that will open in the Spring 2017, and combine a CXCR4 blocker (ulocuplumab) with ibrutinib in WM patients who have the CXCR4 mutation. We will use advanced genetic technologies to see how CXCR4 mutated cells behave when a CXCR4 blocking agent is combined with ibrutinib.

Grant: 1346-18 | Career Development Program (CDP):

Location:University of Cincinnati, Cincinnati, Ohio 45221-0222

Year: 2017

Project Title: The Oncogenic Role And Underlying Mechanism Of TET1 In Acute Myeloid Leukemia

Project Summary:

Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematopoietic malignancies. Thus, it is urgent to better understand the mechanisms underlying the pathogenesis of AML, and on the basis of such understanding, to develop novel therapies with higher efficacy and minimal side effects to treat AML. The properties of cancer are often determined by the proteins that are expressed from information provided by the genes in the cell. Expression of information from genes is regulated in part by chemical modifications of the DNA in the gene, in a process called “epigenetic regulation.” One such modification is called methylation.  A family of proteins involved in epigenetic regulation are the 3 TET proteins, which ultimately affect the methylation status of critical genes. TET proteins are traditionally thought to be negative regulators of tumor growth. However, in contrast to this tumor suppressive role, we recently reported that TET1 is highly expressed in certain subtypes of AML, suggesting an opposite role for TET1, the promotion of tumor growth. 

We are currently studying the mechanisms by which TET1 promotes tumorigenesis and how we might use this information to develop a novel approach to treat AML. Some central questions are to understand how tumors develop, how they are maintained after they develop, and how the leukemia stem cells provide a reservoir for continued tumor development in a patient. Therefore, we seek to understand the role of TET1 in both the development and maintenance of the AML types that overexpress TET1, and the role of TET1 in the leukemic stem cells. In addition, we are studying the critical target genes that are affected by TET1, which will provide further insight into the role of TET1 in AML. Lastly, we are examining ways to therapeutically target TET1 using mouse models of AML. The success of our studies will provide novel insights into our understanding of the critical role of TET1 in AML and may also lead to the development of novel and more effective therapeutic approaches to treat the AML.

Grant: 5462-18 | Career Development Program (CDP):

Location:Yale University, New Haven, Connecticut 06520-8327

Year: 2017

Project Title: A Protein Degradation Approach For The Treatment Of Acute Myeloid Leukemia

Project Summary:

Many cancers result from a genetic mutation causing an “always on” protein. Current treatments are based on the deactivation of the proteins by blocking that protein’s active site. Herein I propose an alternative approach in which proteins are permanently degraded rather than temporarily deactivated, which may prove to be a more favourable form of therapy. To do this, I will take advantage of the cell’s own natural ability to degrade its own proteins when they are in excess or no longer needed. I will design and prepare compounds which recruit the native protein degradation machinery to the target proteins by creating a bridge between protein degradation components and the target protein. This approaches uses a two-headed molecule called a Proteolysis Targeting Chimera (PROTAC).

The potential advantages of protein degradation over protein inhibition are three fold:

     1. Constant and complete deactivation of proteins is necessary for a treatment to be successful. Protein inhibition, as happens with standard targeted drugs, is often a reversible process, allowing previously inhibited proteins to again be functional. Protein degradation, as happens with PROTACs, is irreversible, therefore resulting in complete deactivation.

     2. PROTACs have shown the potential to be catalytic, meaning one PROTAC molecule could destroy more than one protein molecule, preventing cells from simply producing more protein to overcome the deactivation of the existing population.

     3. An issue arising from current treatments is the development of resistance after treatment for a relatively short period of time. The proposed PROTAC compounds may be able to circumnavigate such resistance mechanisms.

I propose to prepare PROTACs containing recognition elements for target proteins involved in blood cancers. Specifically, I am focusing on FLT3, which is a protein important in about 1/3 of all AMLs. I will assess PROTACs for the ability to degrade target proteins in cell-based models. The resulting compounds will then be optimised before progression into animal models. It is conceivable that by employing protein degradation, it may be possible to completely remove all disease causing protein. The ultimate goal is to produce a drug that may be useful for the treatment of AML containing FLT3 mutations. Importantly, PROTAC technology has applicability in a number of different cancers.

Grant: 1344-18 | Career Development Program (CDP):

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

Year: 2017

Project Title: The Biological And Therapeutic Consequences Of SF3B1 Mutations In Myelodysplastic Syndromes

Project Summary:

Myelodysplastic syndromes (MDS) are a group of blood disorders characterized by impaired differentiation of hematopoietic stem cells into functional blood cells. MDS frequently has a poor prognosis and is associated with a high risk of transformation into acute myeloid leukemia. There are few treatment options for MDS, largely because the underlying molecular changes that drove MDS were not known until recently. 

Recent genome sequencing studies revealed that MDS and related diseases are associated with specific mutations (genetic changes) in hematopoietic stem cells. These mutations most commonly affect genes that control a molecular process termed "RNA splicing." RNA splicing is critical to the process by which genetic information in DNA is "read" to make proteins. We now know that MDS-associated mutations that affect RNA splicing cause mistakes during the transfer of genetic information from DNA to protein. However, we do not yet know precisely which mistakes ultimately give rise to MDS. 

We plan to use both experimental and computational methods to determine how mutations that affect RNA splicing give rise to MDS. Understanding the specific molecular changes that occur in MDS cells carrying these mutations will enable us to identify potential new therapeutic opportunities for treating MDS. Because the same mutations affecting RNA splicing are found in other blood diseases as well, such as chronic lymphocytic leukemia, we hope that our discoveries will improve the treatment of many different blood diseases.

Grant: 5465-18 | Career Development Program (CDP):

Location:The Regents of the University of California, San Francisco, San Francisco, California 94143

Year: 2017

Project Title: Inhibiting The Palmitoylation/Depalmitoylation Cycle As A Selective Therapeutic Strategy In NRAS Mutant Leukemia.

Project Summary:

Acute myeloid leukemia (AML) is an aggressive blood cancer that affects children and adults. Recent advances for sequencing the DNA of leukemia cells have greatly advanced our understanding of the genetic causes of AML; however, this new knowledge has not yet resulted in better treatments. 

One of the most common mutations found in AML alters a type of RAS gene called NRAS. The protein made by NRAS works like an “on” and “off” switch that instructs cells to grow in response to growth factors. RAS gene mutations found in AML and other cancers lock these switches in the “on” position, which drives abnormal growth. Recent studies of AML cells have shown that NRAS gene mutations are absent when patients are in remission and frequently reappear when the leukemia relapses. Therefore, NRAS mutations are likely very important for the growth of AML cells, and inhibiting abnormally active N-Ras proteins (proteins created by the NRAS gene) may be of great benefit for patients. Unfortunately, developing drugs that can directly turn abnormal N-Ras proteins “off” is extremely difficult. 

We are testing a new approach for inhibiting mutant N-Ras by exploiting a potential “Achilles heel” in the protein. It is likely that N-Ras must be located at the cell surface to stimulate growth. This localization depends on two chemical modifications that are regulated by different enzymes: the addition of a lipid group (palmitoylation) and its subsequent removal (depalmitoylation). We think that inhibiting this cycle will kill AML cells with NRAS mutations but will not affect normal cells. We will test this using a mouse model in which we engineered a mutation of the NRAS gene so it cannot be palmitoylated. Next, we will investigate chemical inhibitors of the enzyme that depalmitoylate the N-Ras protein as a possible treatment for AMLs with NRAS mutations. Finally, we will try to define the enzymes responsible for N-Ras palmitoylation, with the long-term goal of blocking this reaction as an alternative to inhibiting depalmitoylation. Altogether, I anticipate that my project will advance our understanding of NRAS mutant AML and will identify novel strategies to treat this aggressive blood cancer.

Grant: 3380-18 | Career Development Program (CDP):

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

Year: 2017

Project Title: Interrogating The Sf3b1 Mutated/Atm Deleted Mouse As A Novel Faithful Model Of Chronic Lymphocytic Leukemia

Project Summary:

Human genomic analyses have defined the complex genetic heterogeneity of chronic lymphocytic leukemia (CLL) as the most common indolent B-cell malignancy. These studies have revealed that selection of certain genetic alterations occurs throughout disease progression and correlates with therapy failure. Despite the remarkable efficacy of a number of recently introduced therapies, CLL remains incurable, and resistance to these novel drugs is challenging the clinical management of CLL patients.

Genetically engineered mouse models represent a promising approach to studying the functional impact of novel cancer-associated gene alterations and are useful to developing preclinical platforms for testing the efficacy of novel drug combinations. The main challenge with CLL modeling is the lack of animal models that faithfully recapitulate the genetic changes discovered in patients. Through novel genetic engineering strategies, we therefore seek to introduce mutations typical of human CLL in mice and to characterize disease features in these novel models, including, but not limited to, aberrancies in B cells (the cell of origin of this leukemia), and T lymphocytes (the cells which generally control immune responses but are notably dysfunctional in CLL patients, thus favoring disease progression).

We recently observed CLL development in animals bearing two of the most common gene alterations found in patients, that is mutations in the genes Sf3b1 and Atm, whose functionality is critical for CLL survival and responsiveness to therapy. We took advantage of this model to create a transplantable platform, whereby leukemias harvested from a donor animal can be expanded into recipients, which are then treated with different drugs (and/or their combinations). The first class of compounds that we will test is splicing modulators, which are drugs capable of interfering with alternative splicing – the main process regulated by Sf3b1 Alternative splicing is a core cellular process involved in the regulation of gene function. Preliminary studies have already shown efficacy of splicing modulators when tested alone or combined with FDA-approved agents for the treatment of CLL.

The overall goal of my studies is to establish robust preclinical platforms to test new therapies and to facilitate the optimization of treatment strategies tailored to the genetic makeup of individual CLL patients, with the aim of obtaining deeper clinical remissions and potentially allowing treatment discontinuation in these patients.