Research we fund

My research investigates the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis. Contrary to conventional studies analyzing cell mixtures, my research uniquely probes the specific cells underlying leukemia development. We expect to identify the key cellular and molecular events that drive leukemia onset and relapse. These findings will help improve diagnosis and can serve as new therapeutic targets for treating leukemia.

Project Term: July 1, 2019 - June 30, 2024

We want to understand how leukemia inhibits blood production as this is one of the main causes of death in leukemia patients. We use new microscopy techniques developed by our group to image—for the first time—all types of blood cells and how they are eradicated by leukemia cells. Identification of the mechanisms through which leukemia inhibits blood production will be the foundation for new studies to develop drugs to maintain normal blood levels and prevent death in leukemia patients.

Project Term: October 1, 2021 - September 30, 2026

Coming soon.

Project Term: July 1, 2021 - June 30, 2026

It has been demonstrated that most cases of AML are associated with mutations in multiple genes. Dr. Majeti's studies will provide novel insights into the genetic events and other factors such as the microenvironment that affect in the development of myeloid malignancies, particularly AML. This study will have significant implications for the prevention and treatment of myeloid malignancies, particularly AML.

Project Term: July 1, 2020 - June 30, 2023

AML is characterized by founder mutations in epigenetic regulators that perturb alpha-ketoglutarate flux to block differentiation and rewire metabolism exposing new druggable vulnerabilities. By integrating bioenergetics and 5hmC profiling in primary cells, we have discovered unexpected 2-hydroxyglutarate-independent vulnerabilities for TET2, IDH1, IDH2, WT1, and CEBPA mutations. Here, we propose mutation-directed drug development for AML through targeting of the alpha-ketoglutarate pathway.

Project Term: October 1, 2020 - September 30, 2023

We seek to reduce the adverse cardiac effects of chemotherapy in pediatric AML patients. We are assessing markers of heart function and injury to compare two clinical strategies for prevention of chemotherapy-induced heart injury. We are also developing a tool using these markers of heart function to characterize a child’s risk for cardiac dysfunction, which is critical to guiding safe chemotherapy delivery. By reducing the toxicity of therapy on the heart we hope to optimize delivery of effective chemotherapy and contribute to long-term leukemia cure without the burden of life-threatening heart disease during survivorship.

Project Term: July 1, 2019 - June 30, 2024

In this proposal we seek a mechanistic understanding how mutations in ATP6V1B2 in FL activate autophagic flux and also maintain mTOR in an active state. Given that 25-30% of FL harbor mutations in various v-ATPase subunits and regulators (ATP6V1B2, APT6AP1, VMA21) we will extend our studies to these genes. We will clarify how and under what circumstances activated autophagy can be targeted in FL, why it works, and what the best molecular targets and drugs are.

Project Term: July 1, 2019 - June 30, 2022

Blood-forming stem cells are routinely transplanted into patients to treat blood cancers. We discovered that multiple members of the GASP (G-protein coupled receptor Associated Sorting Proteins) family inhibit the function of blood-forming stem cells during transplantation. Our goal is to determine exactly how GASP family members inhibit these critical cells in order to inform our efforts to improve the efficiency of blood stem cell transplantation.

Project Term: July 1, 2018 - June 30, 2023

My studies are in primary myelofibrosis, a blood cancer characterized by a buildup of fibrous tissue that impairs the bone marrow’s ability to produce normal blood cells. I am studying alterations in large cells in the bone marrow called megakaryocytes and exploring how changes in the bone marrow microenvironment contribute to disease progression. By knowing more about this process, we can uncover new ways to treat the disease before it progresses to a more severe phase.

Project Term: January 1, 2021 - December 31, 2023

Dr. Soheil Meshinchi is taking a personalized medicine approach to identify immunotherapies for specific subsets of pediatric acute myeloid leukemia (AML). Pediatric AML remains a devastating disease with only a 60% survival rate. Survivors often have long-term quality of life issues related to the toxic chemotherapy used to treat their disease. A better knowledge of the molecular basis of pediatric AML will help identify targets for therapeutic intervention. Some of these targets may be mutants of normal genes, while others may be overexpression of normal genes, which would provide a therapeutic window in which targeting the overexpressed gene product may preferentially kill tumor cells. Dr. Meshinchi has surveyed the gene expression spectrum of pediatric AML and has identified several targets which are overexpressed in pediatric AML. One protein, CD74, is highly expressed in a subset of AMLs. Another target is CD70, which is highly expressed in about half of all pediatric AML cases that include a fusion of the MLL protein. Patients with MLL fusions have a worse outcome. Lastly, some infant AML patients have another kind of fusion protein paired with overexpression of the FOLR1 protein. All three proteins that Dr. Meshinchi has identified as being highly expressed in subsets of pediatric AML have much lower expression in healthy cells. Therefore, targeting these proteins is a logical choice. These three proteins are all expressed on the surface of the cell, making them accessible to targeting by special therapeutic antibodies called “antibody drug conjugates” (ADCs). ADCs have a toxic payload attached to them. When the antibody binds to its target on the cell surface, the cell takes in the ADC releasing the toxic payload, which then kills the cell. This immunotherapy approach is a highly specific, personalized approach for treating cancer. ADCs to each of the protein targets identified by Dr. Meshinchi are being clinically evaluated in other diseases, providing the opportunity to potentially repurpose those drugs for pediatric AML. Therefore, Dr. Meshinchi proposes to evaluate these ADCs in laboratory models of pediatric AML. Should any of these drugs show promise in these laboratory models, Dr. Meshinchi will propose clinical trials in pediatric patients through LLS’s Pediatric Acute Leukemia (PedAL) Master Clinical Trial. If any of the targets do not have an effective drug in the laboratory models, Dr. Meshinchi will create new ADCs using proven expertise currently available in his laboratory. Therefore, these studies present the possibility of new, targeted immunotherapy for specific subsets of pediatric AML patients, either rapidly through drug repurposing, or through the development of new ADCs. The goal is to improve the survival and quality of life for these vulnerable blood cancer patients.

Project Term: October 1, 2020 - September 30, 2022

Coming soon.

Project Term: July 1, 2021 - June 30, 2026

Advances in understanding and management of AML in children has been stagnant for decades. Observed improvements in survival are more directly linked to improvements in supportive care or risk identification rather than advances in therapeutics. Excitement around FDA approval of two new IDH1/2 inhibitors did not reach the pediatric oncology community given paucity or absence of such mutations in children. This also highlights the stark differences between AML in older adults and that in younger patients. Thus, “trickle down therapeutics” where therapies that are developed in older adults are used effectively in children is a flawed concept. Discoveries and therapeutic development in younger patients must be prioritized if meaningful advances are to be made in curing AML in younger patients. Given that AML in children is not a priority for the pharmaceutical companies, alternate mechanisms for advancing therapeutics in children and young adults should be implemented.

Project Term: October 1, 2021 - September 30, 2026