Patients with relapsed blood cancers after allogeneic stem cell transplant are often treated with donor lymphocyte infusion (DLI), a type of immunotherapy that boosts the anti-tumor response and aims to induce cancer remission. The success of DLI varies from patient to patient. Dr. Bachireddy aims to investigate the determinants of DLI success and failure by studying the leukemic and immune cells during response to immunotherapy. Careful study of successful anti-tumor immune responses may reveal insights into tumor-immune interactions that may be relevant to predicting patient response to novel immunotherapies in other tumors.

A major cause of relapse after therapy is the persistence of measurable residual disease (MRD) cells—cancer cells that remain after treatment and eventually spread. Due to technical and logistical challenges in accessing and analyzing MRD cells, the molecular and cellular pathways that enable MRD progression remain poorly understood. Dr. Bachireddy will use innovative molecular tools to analyze tissue samples from blood cancer patients at a single-cell level to unlock insights into MRD progression. Using cutting-edge machine learning approaches, he will identify immunosuppressive mechanisms that may be targeted to halt MRD progression. Beyond these blood cancers, he aims to reveal organizing principles of MRD progression that are relevant across human cancers.

One of the persistent challenges in treating high-risk pediatric leukemia, particularly in cases of acute megakaryoblastic leukemia (AMKL), is the high incidence of relapse due to resistance to standard treatments such as chemotherapy and bone marrow transplantation. T cell therapy has shown potential in treating various types of leukemia, offering the prospect of overcoming mechanisms that tumor cells employ to evade traditional therapies. However, a significant challenge in T cell therapy for AMKL lies in identifying T cells that are able to recognize and target leukemia cells specifically. Dr. Balood’s research is dedicated to advancing T cell therapy for AMKL. He plans to test and identify T cell clones that specifically recognize and eliminate leukemia cells with the goal of translating these findings into an effective T cell therapy with minimal toxicity in leukemia patients. Dr. Balood received his PhD from University of Montreal School of Medicine, Montreal, his MS from Tarbiat Modares University School of Medicine, Tehran, and his BS from Shahid Chamran University of Ahvaz, Ahvaz.

Dr. Bhansali is studying how epigenetic processes—specifically the three-dimensional folding of DNA—promote the development, growth, and survival of cancers. His research focuses on T-cell acute lymphoblastic leukemia (T-ALL), an aggressive blood cancer affecting both children and adults for which traditional chemotherapy remains the mainstay of treatment. LDB1 is a protein involved in the process of DNA folding that partners with another protein called LMO2, which is highly expressed in up to 75% of T-ALL. Dr. Bhansali hypothesizes that LDB1/LMO2 rewire the normal gene expression machinery in our blood cells in a way that activates cancer-promoting genes to cause leukemia. Targeting this process may shed light on new treatment avenues and ways to overcome resistance to treatment.

Acute myeloid leukemia (AML) is an aggressive blood cancer that affects children and adults. One particularly difficult-to-treat subtype of AML that represents about 10% of all cases is characterized by a mutation in the KMT2A gene. Menin inhibitors (MI), a novel targeted therapy, have shown promise against this subtype in early clinical trials. Studies have also shown that compounds that degrade a protein called Ikaros can dramatically enhance the efficacy of MI. In seeking to uncover why MI and Ikaros protein degraders work well together, Dr. Bourgeois and his colleagues have found that both drugs target gene expression programs that are critical for the survival of KMT2A-mutant AML cells. Dr. Bourgeois is now working to better understand which genes can be targeted to further enhance the efficacy of Ikaros protein degraders in KMT2A-mutant AML. This work will shed light on the essential gene expression programs required for KMT2A-mutant AML cell survival, and ideally help guide drug development that specifically targets this subtype.

Myelodysplasia and acute myeloid leukemia are blood cancers with a poor prognosis. At the root of these malignancies are cells harboring mutant forms of proteins with dysfunctional activity which results in abnormal cell behavior and drives disease progression. The focus of my project is the development of new therapeutics that precisely identify cells with mutant forms of the proteins and, by harnessing their aberrant biological activity, causes those cells to self-destruct. These selective therapeutics will be able to kill cancer cells but leave the healthy cells intact proving more effective and having less side-effects than the chemotherapies currently in use.

About 70% of pediatric leukemias and up to 10% of adult leukemias are caused by a genetic disruption in which the mixed lineage leukemia (MLL) 1 gene breaks off and attaches to a different chromosome. This event, known as a chromosomal translocation, gives rise to a distinct subset of leukemias called MLL-rearranged acute myeloid leukemia (AML). Studies have shown that a protein called KMT2D plays a critical role in the development of MLL-rearranged AML. However, the potential of KMT2D as a novel therapeutic target remains underexplored. Dr. Cruz [The Mark Foundation for Cancer Research Physician-Scientist] will use molecular biology, epigenetic, and biochemistry approaches to describe the precise molecular mechanism by which KMT2D regulates gene expression in MLL-rearranged AML. Her work will provide insight into potentially targetable proteins for this aggressive blood cancer.

Dr. Eisen [David Ryland Fellow] studies how a class of enzymes known as the Tec kinases help to activate the immune response. Two of these kinases, Itk and Btk, are remarkably similar in sequence composition and structure but play distinct roles in immune cells. Dr. Eisen is using high-throughput methods to understand the differences between these enzymes. This work will also aid in the overall molecular understanding of Btk, which is a therapeutic target of B-cell lymphoma and is inhibited by the chemotherapeutic ibrutinib.

About 70% of pediatric leukemias and 10% of adult leukemias are caused by a genetic disruption in which the mixed lineage leukemia (MLL) 1 gene breaks off and attaches to a different chromosome. This event, known as a chromosomal translocation, gives rise to a distinct subset of leukemias called MLL-rearranged acute myeloid and lymphoblastic leukemias (AML or ALL). Novel treatments for these cancers represent a major unmet medical need. However, the development of therapeutics is hampered by a lack of basic understanding of how the MLL translocations disrupt the function of affected cancer cells. Dr. Farnung will use biophysical and structural biology approaches to visualize how MLL translocations function at the atomic level and influence the important process of gene transcription. His work will elucidate the precise molecular mechanisms that drive acute leukemias and provide a platform for the development of novel therapeutic strategies against these cancers.

Many cancer diagnostic and treatment strategies use markers on the cell surface to find and kill cancer cells in a sea of healthy tissue. Dr. Flynn's research aims to expand our knowledge of what molecules are found on the surface of cancer cells. He will focus on acute myeloid leukemia (AML), as there is a major unmet clinical need for new curative treatments. Specifically, he aims to define RNA as a new cell surface molecule that could have unique structures on AML cells. With this knowledge he will develop antibodies to selectively detect cancer cells and enable tumor killing. Because tumors from other parts the body also express RNA on their surface, this strategy is expected to be broadly applicable to other cancer types.