Funded in Collaboration with Stand Up To Cancer (SU2C)
Preclinical and clinical studies have informed the development of increasingly effective cancer therapies that can lead to dramatic clinical responses. However, in the majority of cases, patients subsequently develop therapeutic resistance. Although recent studies by our labs and by others have elucidated mechanisms of resistance, the complex series of genetic and epigenetic events that drive therapeutic resistance have not been well delineated, there are few therapeutic options to prevent resistance. We have chosen acute myeloid leukemia (AML) to investigate the dynamics of therapeutic response and resistance for several important reasons. First, there is abundant evidence that targeted therapies (tyrosine kinase inhibitors) can induce substantive clinical responses, including complete remissions, in patients with genotypically defined disease subsets. Moreover, combination chemotherapy can induce a high rate of complete response similar to that observed with molecularly targeted therapies. Second, our team proposes to perform genomic and transcriptional/epigenomic studies of serially obtained clinical isolates from patients before therapy, at the time of maximal response, and at therapeutic relapse. Our clinical sites have established a robust infrastructure to obtain clinical samples at the different time points. This sampling approach, coupled with state-of-the-art genomic, transcriptional, and functional studies, will address questions that are central to the fields of cancer biology, modeling, and cancer therapeutics, and – most importantly will allow us to test models of the evolution of drug resistance and novel therapeutic approaches that can then be rapidly translated to the clinical context.