The goal of my research program is to improve outcomes for patients with cancer. We validated the hypothesis that targeting cancer-causing genetic lesions will lead to less toxic and more effective cancer therapies. I began these studies with a well-defined gene target in a specific cancer and have moved to less well defined cancers. We have assisted in the U.S. Food and Drug Administration (FDA) approval of three drugs for patients with chronic myeloid leukemia (CML) and have identified nearly a dozen new activating mutations in a variety of other leukemias. For this work, we have established methods to comprehensively identify and validate activating mutations and endeavor to translate this knowledge into the clinic as rapidly as possible.
CML is a disorder marked by increased numbers of myeloid cells with full maturation. Historically, the average survival for patients was three to five years, with most progressing to a terminal acute leukemia. All patients with CML express the BCR-ABL tyrosine kinase, which is formed as a consequence of a (9;22) chromosomal translocation. BCR-ABL has been well established as the causative molecular abnormality of CML. My laboratory obtained compounds from Novartis Pharmaceutics and showed that an ABL kinase inhibitor, imatinib (formerly STI571, now known as Gleevec), effectively kills CML cells without harming normal cells in preclinical models. Based on this antileukemic activity, we designed a phase I clinical trial of imatinib for patients with CML who were resistant to or intolerant of other treatment options.
The phase I trial, conducted in collaboration with Charles Sawyers (HHMI, then at University of California, Los Angeles) and Moshe Talpaz (then at MD Anderson Cancer Center), demonstrated remarkable efficacy with only minor side effects. The five-year follow-up of newly diagnosed patients with CML treated with imatinib showed an overall survival of 89 percent (95 percent if only CML-attributable deaths are considered). Imatinib has also been shown to be effective in other BCR-ABL–positive leukemias, such as Ph-positive acute lymphoblastic leukemia (Ph+ALL), and in gastrointestinal stromal tumors (GISTs), which harbor activating mutations in KIT, another tyrosine kinase that my laboratory showed was inhibited by imatinib. Our early work with imatinib proved that the target, not the specific tumor type, is the critical factor for drug response.
Although many CML patients exhibit a durable response to imatinib, a proportion experience progressive disease. The relapse rate at five years is 17 percent, with relapses peaking in the second year and declining each year thereafter to less than 1 percent in the fifth year. In more than 65 percent of the cases studied, mutations scattered throughout the kinase domain of ABL have been identified as the causative reason for relapse. We have worked to identify compounds to inhibit these resistant mutations and identified a class of compounds capable of doing so. Similar compounds, including dasatinib and bosutinib, were advanced to clinical trials and are now FDA-approved for patients with resistance to imatinib. One mutation, T315I, was found to be resistant to all available drugs. In collaboration with ARIAD Pharmaceuticals, my lab characterized an inhibitor, AP24534 (ponatinib), that potently inhibits this BCR-ABLT315I mutant. Phase I trials of ponatinib demonstrated efficacy in BCR-ABL–positive leukemias with resistance to tyrosine kinase inhibitors, including those with T315I mutations, thereby providing a new line of therapy for patients with highly resistant disease.
Having established the paradigm that human cancer can be effectively treated with targeted molecular approaches, we are now extending our studies from CML, a disease with a well-established genetic basis, to other diseases with largely unknown pathogenetic underpinnings. We are currently identifying mutations that are important for the growth and survival of other hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and a variety of myeloproliferative neoplasms (MPNs). Based on recent DNA-sequencing efforts from our group and others, it has become apparent that the mutational landscape of these less well defined hematologic malignancies is highly variable. Tumor cells from individuals who have been diagnosed with identical leukemia subtypes can possess completely disparate sets of mutations, underscoring the difficulty in developing targeted therapies for other leukemias.
Using an integrated functional genomics approach, we are currently cataloguing therapeutically targetable genetic drivers of leukemogenesis. We have developed two functional assays that identify tyrosine kinases essential for, and kinase inhibitors that affect, the growth of patients’ isolated leukemic cells. Using deep-sequencing methodologies, we then define the spectrum of mutations found within each patient’s cells. Next, we integrate the potential targets identified through our two assays with a patient’s mutational profile, which allows us to prioritize the functionally important mutations most likely driving the growth of that individual patient’s cancer. Each mutation is made and tested for its ability to promote growth factor–independent growth of a hematopoietic cell line model.
Using this methodology, we are beginning to annotate all the driver mutations found in less well defined leukemias and match them with potentially effective therapeutic inhibitors. For example, we have identified mutations in CSF3R, the receptor for granulocyte colony simulating factor (GCSF) in patients with chronic neutrophilic leukemia (CNL) and atypical CML (aCML). Through our functional assays and further characterization of these mutations, we have determined that, depending on the location of the mutation, CSF3R mutant leukemic cells respond to either ruxilitinib or dasatinib. The integration of the mutational spectrum with the functional data allowed us to define a novel subset of hematologic malignancies based on CSF3R mutational status and rapidly identify actionable targeted therapy interventions for these patients.
Using this integrated functional genomics approach, we hope to unravel the complexity of leukemia pathogenesis and provide the critical information necessary to discover life-saving drugs for patients with other types of leukemia.
Grants from the National Cancer Institute, the Leukemia and Lymphoma Society, the T. J. Martell Foundation, the Doris Duke Charitable Foundation, and the Department of Defense provided partial support for this work.
As of January 18, 2013