SU2C Scientific Research Teams
Ross L. Levine, MDScientific Research Team:
Ross L. Levine, MD
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, and there are few therapeutic options to prevent resistance. We have chosen acute myeloid leukemia (AML) and kinase-dependent non-small cell lung cancer (NSCLC) to investigate the dynamics of therapeutic response and resistance for several important reasons. First, in both cases 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, in the case of AML, 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. We propose to perform genomic and transcriptional/epigenomic studies of serially obtained clinical isolates from NSCLC and AML patients before therapy, at the time of maximal response, and at therapeutic relapse. This sampling approach, coupled with state-of-the-art genomic, transcriptional, and functional studies, will allow a view of the cancer dynamics in response to therapeutic perturbations that has not previously been done on primary patient samples. Our team has worked to develop a series of studies that will address important questions relating to genetic/epigenetic evolution as a mechanism of drug resistance, and the interplay between the immune system and the cancer genome/epigenome in response to cancer therapies. We have assembled a multidisciplinary team that will use preclinical models and in depth interrogation of patient biopsies to investigate the evolution of cancers as they develop resistance to cancer therapies, and to develop complex, integrated models of resistance that can serve as the basis for therapeutic studies.