New Investigator Research Grant Program

Genetic mutation is the key underlying mechanism in the development of cancer. Among the spectrum of mutations driving malignancy, mutation in the TP53 gene is the most important event leading to therapy resistance. TP53 is often referred to as the “guardian of the genome,” as it acts to stop the proliferation of cells that have mutated or have acquired damaged DNA. Hence the loss of TP53 function is strongly associated with poor patient response to therapy including chemotherapy and targeted therapy. Acute myeloid leukemia (AML), the most common acute leukemia in adults, is an aggressive blood cancer characterized by an outgrowth of immature blast cells, which then crowd out normal blood cells in bone marrow and blood. The major drugs used to treat AML cause the cancer cells to commit suicide via a pathway called “apoptosis.” However, the subgroup of AML patients with TP53 mutations have a significantly poorer prognosis for all forms of therapy. Thus, there is a pressing need to identify new agents that can improve the response of leukemia patients with TP53 mutations. By building on our preliminary studies and the development of laboratory models that can recapitulate the biology of AML cells with mutated TP53, we plan to further dissect why mutations in TP53 makes AML cells so difficult to treat. We will apply this understanding to identify novel treatments that can be tested in clinical trials to improve therapeutic responses in AML patients with TP53 mutations.