Grant: 5437-16 | Career Development Program (CDP):
Location:Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
Project Title: CHARACTERIZATION OF THE TRANSCRIPTIONAL REWIRING FOR LEUKEMIA RESISTANCE TO TARGETING THE MUTANT METABOLIC ENZYME IDH2R140QProject Summary:
Acute myeloid leukemia (AML) is one of the most common types of blood cancer affecting adults, and its incidence is expected to increase as the population ages. As an acute leukemia, AML progresses rapidly and is typically fatal within few months if left untreated. Five-year survival varies from 15–70%, and relapse rate is between 30% and 78%, depending on subtype. The mutant variant of the metabolic enzyme isocitrate dehydrogenase 2 (IDH2R140Q) has a critical role in AML. Even though inhibitors for this mutant enzyme are available, leukemia cells develop drug resistance. This study aims to understand how leukemia cells switch from sensitive to resistant when targeting IDH2R140Q. We will characterize the behavior of leukemia cells in a mouse that is affected by AML. In particular, we will switch on and off the expression of the mutant enzyme at different stages of the disease and we will look for the presence of specific marker that are absent in sensitive cells. For example, we will directly monitor gene expression and track key regulators of gene expression like messenger RNA (mRNAs) and very small RNAs (microRNAs). We will validate our findings on samples from responsive and relapsed patients’ cohorts in clinical trials for IDH2R140Q targeted therapy. This study will be a breakthrough on genetic criteria that stratify patient cohorts for treatments with IDH inhibitors and achieve effective therapeutic regimes.
Grant: 9002-16 | Transforming CURES Initiative (TCI):
Location:Cedars-Sinai Medical Center, Los Angeles, California 90048
Project Title: ZRSR2 Mutations: MDS And Evolution To AMLProject Summary:
Myelodysplastic syndrome (MDS) is a heterogeneous group of disorders in which blood cell production is ineffective, partly because they die prematurely. Using powerful sequencing techniques, we and others recently identified in MDS samples frequent reoccurring mutations in genes involved in a RNA processing known as RNA-splicing. These mutations are highly specific to MDS, and represent a previously undiscovered pathway for MDS development. ZRSR2 is one of the splicing-factor genes frequently mutated in MDS, and these patients have a high rate of progression to acute myeloid leukemia (AML). We analyzed bone marrow samples harboring ZRSR2 mutations and found that these samples displayed aberrant RNA splicing in a subgroup of 600 genes, some of which are involved in cell proliferation and differentiation. Our aim is to determine the contribution of ZRSR2 mutations to MDS and progression to AML. We are using sophisticated molecular biology approaches and have AML/MDS cell lines and human MDS samples with ZRSR2 mutations. In addition, we developed hematopoietic specific Zrsr2 knockout mice, as well as human and murine cell lines with ZRSR2 mutation in order to model ZRSR2 alterations in MDS. Using ZRSR2 as a focus, we will uncover the role of aberrant splicing in the pathogenesis of MDS and set the stage for the design of specific and potent therapeutic strategies.
Grant: 6491-16 | Translational Research Program (TRP):
Location:Joan & Sanford I. Weill Medical College of Cornell University, New York, New York 10022
Project Title: Targeting Signaling-mediated Transcription In T-cell LymphomaProject Summary:
The majority of T-cell lymphomas are not cured with conventional chemotherapy, in part because most regiments were originally designed for B-cell lymphomas, a different disease. There is a need for new agents that are developed more specifically for T-cell lymphomas. Treatments designed considering the particular biology of T-cell lymphomas would have more chances of being effective in patients. Our group was able to grow T-cell lymphoma cells directly from patients in artificial lymph nodes (organoids) mimicking the environment in which these lymphoma cells grow in patients. Using this methodology we identified proteins that the lymphoma cells expose to the outside. Lymphoma cells use these proteins to capture signals from the environment. These signals tell to the lymphoma cells to reproduce by awakening a set of genes. We also identified that a protein called CDK7 mediates between the signal and the gene activation.
By blocking CDK7 using a compound called THZ1, T-cell lymphoma cells stop their proliferation and die. T-cell lymphoma, unlike other lymphomas and tumors, are addicted to CDK7, therefore THZ1 is more specifically killing T-cell lymphomas. In the research proposed here we would like to understand how to better use this treatment for T-cell lymphoma patients. Since not all T-cell lymphomas are the same, with our studies we will determine what makes a particular type of T-cell lymphoma more likely to respond to THZ1 by analyzing all the genes that change with the treatment. We would like to improve the chances of THZ1 to be effective for most patients, so in this proposal we will also determine what combination of new drugs inhibiting proteins that signal from the environment help THZ1 in killing more T-cell lymphoma cells. Because these proteins are different between several types of T-cell lymphomas, the drugs that target them will also be different. These combinations will therefore be tailored to fit different types of T-cell lymphomas, making the treatment more personalized.
Grant: 6493-16 | Translational Research Program (TRP):
Location:The Johns Hopkins University School of Medicine, Chicago, Illinois 60693
Project Title: GDF15-SOX2 Signaling And Self-renewal In Multiple MyelomaProject Summary:
The recent decade has brought dramatic advances in the treatment of multiple myeloma (MM) with the introduction of several novel therapies. These new drugs have dramatically improved the ability to greatly reduce tumor burden in newly diagnosed MM patients, but even in the case of complete tumor eradication, virtually all patients will eventually relapse. Our laboratory has been interested in developing treatments that can prevent cancer relapse and previously identified a small and unique population of tumor cells termed cancer stem cells (CSCs). CSCs differ from most MM tumor cells since they are capable of extensive grow and the ability to produce more tumor cells. Therefore, we believe that eliminating these cells will prevent tumor regrowth and relapse. Following the discovery of MM CSCs, we have strived to identify factors that regulate their growth, and have recently found that a signaling molecule called Growth Differentiation Factor 15 (GDF15) dramatically increases both the number of MM CSCs and their ability to produce more tumor cells by turning on SOX2, a factor that controls the expression of specific genes in normal stem cells. In this proposal we will examine how GDF15 and SOX2 regulate MM CSCs and will develop novel therapies to that should decrease relapse rates to extend and improve the lives of patients with MM.
Grant: 5436-16 | Career Development Program (CDP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Genome Stability And The Evolution Of Optimal Spindle Size And FunctionProject Summary:
In many cancers, including blood cancers, cells acquire another set of genetic material during tumorigenesis. It is critical to investigate the differences between these cells and normal ones. Previous studies from our laboratory showed that there is a higher frequency of chromosome separation errors in yeast cells carrying another set of genetic material, and it may be attributed to distorted spindle geometry observed in these cells. I will use two series of experiments to test how spindle geometry affects chromosome separation in these cells. First, I will use live-cell imaging and automated analysis of these images to investigate the location and orientation of chromosomes and the kinetics of microtubules that capture chromosomes. These experiments will define critical parameters for successful chromosome separation. In the second series of experiments, I will induce evolution in test tubes and select for cells with improved cell division. I will identify genetic alterations and adaptive mechanisms that help restore spindle functions. Taken together, the proposed study will define fundamental differences between normal and cancer cells, and identify mechanisms that may be critical for cancer cell survival.
Grant: 6487-16 | Translational Research Program (TRP):
Location:University of Maryland at Baltimore, Baltimore, Maryland 21203-6428
Project Title: Using PARP Inhibitors To Enhance The Cytotoxic Effects Of DNA Demethylating Agents In AMLProject Summary:
Acute myeloid leukemia (AML) frequently occurs in older patients who are unlikely to tolerate or respond to treatment with intensive chemotherapy. These patients are currently treated with the DNA demethylating drugs (DNMTis) azacitidine or decitabine, but more than half do not respond. Therefore, effective combinations of other drugs with DNMTis are being explored. Normal cells die when their DNA is damaged, but AML cells have developed abnormal DNA repair mechanisms that enable them to survive the effects of DNA damage. This suggests that drugs aimed at crippling the abnormal DNA repair pathways in AML cells may kill these cells. Poly (ADP-ribose) polymerase (PARP) is a key protein in abnormal DNA repair in AML cells. Our laboratory has shown that AML cells are very sensitive to a combination of very low doses of a DNMTi and a PARP inhibitor (PARPi). We believe that the two drugs cooperate to cause the death of AML cells. Moreover, AML cells with mutations in the FLT3 gene (FLT3/ITD), a subtype that responds poorly to current treatments, is particularly sensitive to this novel drug combination therapy. These results have been confirmed in a mouse model of AML. Notably, these data have led us to develop a clinical trial to test the combination of the DNMTi SGI-110 and the PARPi BMN 673.
In Aim 1 of this grant application, we will study samples from AML patients treated in the clinical trial to determine whether the molecular changes we have identified correlate with clinical responses to the drug combination therapy.
In Aim 2, we will determine whether the abnormal molecular changes in patients with FLT3/ITD mutations contribute to the mechanism(s) leading to death of AML cells treated with drug combination.
In Aim 3, we will determine whether the combination of PARPis and DNMTis acts on AML stem/progenitor cells to eradicate AML disease.
Grant: 6486-16 | Translational Research Program (TRP):
Location:The University of Texas MD Anderson Cancer Center, Houston, Texas 77210-4266
Project Title: Targeting Apoptosis In ALL With Venetoclax And Cytotoxic ChemotherapyProject Summary:
While well over 90% of children diagnosed with acute lymphoblastic leukemia can now expect to be cured of their disease, the prognosis in adults is not as good. Roughly half of adult patients diagnosed with ALL will succumb to the disease. Thus, there is an important unmet need to improve therapy in adult ALL. We propose to perform initial clinical testing of the safety and effectiveness of an exciting new drug, venetoclax (ABT-199, AbbVie), that has the potential to cause malignant ALL cells to essentially commit suicide.
Inside each of our cells is a cell suicide program called apoptosis. If a cell sustains enough damage, it senses this and commits suicide by apoptosis. In most cells in our bodies, the program of apoptosis is relatively dormant, so that it requires a lot to make normal cells commit suicide. However, in certain cancers like ALL, the apoptosis program is quite active and agents that activate apoptosis can very effectively induce the malignant cells to commit suicide. In some cases of ALL, there is a protein, called BCL-2, which opposes apoptosis, and keeps the ALL cells from committing to apoptosis. In such cells, a selective inhibitor of BCL-2 is likely to be effective.
Venetoclax is an oral drug from AbbVie Pharmaceuticals that selectively inhibits BCL-2. It has shown excellent efficacy in clinical trials of chronic lymphocytic leukemia, a disease of abnormal white blood cells similar, but not identical, to ALL. In clinical trials of venetoclax, over 80% of patients who were resistant to prior therapies had a good response to the drug. 25% had a complete response, so that no remaining disease was detectable by conventional means. Moreover, there were few toxicities. In addition, venetoclax has showed activity in different types of lymphoma as well as acute myelogenous leukemia.
Several laboratories, including those of Drs. Konopleva and Letai, have shown that ALL is dependent on BCL-2 and sensitive to venetoclax. Similar results provoked the clinical trials in CLL and AML where venetoclax has shown such promising activity. The purpose of this proposal is to test our ability to extend the benefits of venetoclax to ALL. We propose to perform initial clinical testing of the effectiveness of an exciting new drug, venetoclax (ABT-199, AbbVie). We propose to use this agent in elderly patients in combination with a conventional low intensity chemotherapy regimen to test the safety of the combination but also to get preliminary estimates of its effectiveness. In addition, Dr. Letai has developed an exciting biomarker that has previously demonstrated the ability to predict which cases of leukemia are most sensitive to venetoclax in other clinical trials. We will be using BH3 profiling in parallel with this study to see if we can predict which patients get most benefit. If successful we will be able to use BH3 profiling to direct venetoclax therapy to those who will benefit most in future clinical trials.
Grant: 5445-16 | Career Development Program (CDP):
Location:University of California, San Francisco, San Francisco, California 94143
Project Title: Identifying Ubiquitin Ligase Substrates Important For Progression Of Multiple MyelomaProject Summary:
In recent years, patient survival of multiple myeloma has been greatly enhanced by the introduction of two classes of pharmaceuticals, bortezomib and the IMiDs, including pomalidomide and lenalidomide. Both of these drug classes inhibit a cellular pathway called the ubiquitin-proteasome system (UPS). The Toczyski laboratory has developed a technology that can be used to explore the function of components of this pathway. In this proposal, I plan to use this technology on two groups of enzymes. First, I will use it on a protein (called CRBN) already known to be important for multiple myeloma progression and which is the target of the IMiDs. This will allow us to better understand how this protein works and will inform our ability to generate new drugs against it. Second, I will use it to explore the function of related proteins in multiple myeloma cells. Together, these studies will provide valuable information for combating this disease.
Grant: 6482-16 | Translational Research Program (TRP):
Location:Brigham and Women’s Hospital, Boston, Massachusetts 02241-3149
Project Title: Development Of SALL4 Inhibitory Drug(s) In Treating AMLProject Summary:
A total of 18,860 new cases and 10,460 deaths from acute myeloid leukemia (AML) are estimated in the United States in 2014. This is a disease in which standard chemotherapy has not changed in over 25 years, and survival remains extremely poor.
Our proposal is to treat leukemia by targeting a transcription factor SALL4. SALL4 is a gene that is expressed in embryonic stem cells, down-regulated during development, and absent in most adult tissues. Importantly, SALL4 is aberrantly re-expressed in various cancer cells, including most AML. We have recently reported that the transcription factor SALL4 plays a key role in promoting self-renewal of leukemic stem cells (LSC). We have identified a peptide that can block SALL4 function in leukemogenesis. We further propose that with the design of small molecules that mimic the peptide to inhibit SALL4, we can better target leukemia.
To pursue this direction, Leukemia and Lymphoma Society (LLS) has recently funded us a 320K-compound screen project under the screen to lead (SLP) program. We have successfully identified and validated several small molecule chemical scaffolds that could be potential SALL4 inhibitors. These compounds represent novel non-peptide/peptoid scaffolds. We further propose to collaborate with chemists and to use these hits we identified through the SLP program as starting points for medicinal modifications and development of more potent, selective, and efficacious lead small molecules as novel therapies against leukemias.
Over all, accomplishment of our proposed project will help us to identify new lead compounds for therapeutic use in a disease in which survival remains extremely poor. In addition, our ground-breaking novel approach in targeting SALL4 in AML will serve as a paradigm for targeting SALL4 in other tumors since SALL4 is also aberrantly expressed in various solid tumors, thus, provide a new direction in targeted cancer therapy.
Grant: 6489-16 | Translational Research Program (TRP):
Location:Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024
Project Title: Optimizing Bispecific Antibody Therapy For Acute LeukemiaProject Summary:
Acute leukemias are difficult-to-treat cancers of white blood cells from which many patients will eventually die despite aggressive treatments. There is thus a critical need for new drugs to treat these tumors. For more than 30 years, proteins (so-called “antibodies”) that specifically recognize and grip on to leukemic cells have been developed with the hope of providing an effective yet relatively non-toxic treatment option for these diseases. So far, however, antibodies have shown relatively limited activity in the clinic against acute leukemias. One strategy that is pursued to make antibodies more effective is to modify them in a manner that they become “bispecific”, that is they recognize leukemia cells and the patient’s own immune cells (typically T-cells, a type of lymphocyte) at the same time, thereby bringing these 2 cell types in close contact to one another. The T-cell can then selectively kill the attached cancer cell. Highly promising results were recently reported with a small bispecific antibody called “blinatumomab” in some patients with acute lymphoblastic leukemia (ALL) who failed conventional chemotherapy. However, because of the small size of this antibody, it is eliminated efficiently by the kidneys; therefore, continuous intravenous administration via infusion pump is required for several weeks to maintain adequate blood levels. Also, about half of the patients do not experience good benefit from this antibody. The reasons why some but not all patients respond to these small bispecific antibodies are currently not fully understood, but our preliminary indicate that stimuli sent via T-cell co-receptors might play a role. Recognizing the limitations of presently exploited bispecific antibodies, the goal of our collaborative research project is to develop novel, highly active bispecific antibodies for the treatment of acute myeloid leukemia (AML) and ALL that have longer half-lives and can thus be given in a simpler fashion than current antibodies. We hope that our studies will identify lead candidate molecules that could be brought to the clinic toward the end of the 3-year award period. We will also study in detail how exactly small bispecific antibodies lead to the killing of acute leukemia cells, and study potential resistance mechanisms that may limit the usefulness of bispecific antibody. By understanding the factors that predict response, our research will then allow us to identify the most appropriate patients to be treated with these antibodies. Our findings will also lead to the development of combination treatments that may overcome resistance, thereby expanding the patient subsets that could benefit from these agents. Together, by optimizing bispecific antibodies, we anticipate that our investigations may significantly improve the treatment options for patients with acute leukemia.