Biological Chemistry and Molecular Pharmacology
Research in our lab focuses on understanding the diverse signaling networks regulating essential cellular processes in normal and cancer cells. We use a multifaceted approach in which genetic models, molecular biology and pharmacological tools converge on pre-clinical models to investigate and decipher the molecular mechanisms underlying cancer initiation, progression, recurrence and metastasis, with the ultimate goal of developing safe and effective therapies for treating cancer patients. By integrating these technologies and pharmacological approaches, our lab has pioneered a new paradigm for understanding signal transduction, thus changing the way we think about important problems in applying targeted therapies to cancer.
Targeting PI3K isoforms in signaling and cancer
Over the past decade, we have developed several unique and valuable tools for the analysis of the Phosphatidylinositol 3-Kinase (PI3K) pathway in cancer. We were the first to determine the distinct roles of the two ubiquitously expressed isoforms of PI3K, p110α and p110β, in both normal physiology and the pathogenesis of cancer. In collaboration with Dr. Roberts, we defined p110α as the key PI3K isoform that mediates RTK or Ras signaling and drives oncogenic HER2/Neu- or mutant-Ras induced tumorigenesis. We found that, while p110β plays a less prominent role in oncogene and RTK signaling, it is uniquely important in GPCR signaling. More importantly, we show that many types of PTEN-deficient tumors depend on p110β. In collaboration with Dr. Gray’s group, we reported the first functional characterization of a p110β-selective inhibitor, KIN193, and provided the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals. Our study suggests that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient cancers. Currently, clinical trials with p110β-selective inhibitors are underway in patients with advanced PTEN-deficient solid tumors (NCT01458067). PTEN-deficiency is known to play a causative role in tumorigenesis and cancer progression, and is one of the most frequent events in metastasis, we have begun to investigate the molecular and signaling bases of p110β-dependent role of PTEN-deficiency in these processes.
Targeting therapeutic resistance: Insights from GEMMs of human cancer
Therapeutic resistance is a major obstacle in the clinic. Utilizing our novel GEMM of breast cancer driven by inducible PIK3CAH1047R, coupled with pharmacological approaches, we identified a number of significant resistance mechanisms to PI3K-targeted therapy, such as spontaneous focal amplification of Met and Myc, recurrent mutations in Ras and β-catenin, and compensatory activation of the MAPK pathway. Our most recent and exciting finding on this front is the identification of Cyclin D1-CDK4 mediated resistance to HER2-targeted therapy, which we discovered using our new GEMM of breast cancer driven by overexpression of wild-type human HER2 in conjunction with chemical inhibitors. More importantly, our results led to the design of a randomized phase II trial examining CDK4/6 inhibitor plus trastuzumab as a regimen for patients with metastatic, refractory HER2+ breast cancer.
Targeting brain metastases of breast cancer: Insights from orthotopic PDX models
Much of our effort is focused on translating laboratory discoveries into real treatment options with meaningful clinical outcomes. To accelerate this process, our lab has led the efforts at DFCI to establish and characterize novel breast cancer patient-derived xenograft (PDX) models, with an emphasis on brain metastases, an emerging clinical challenge. To date, mouse models of metastatic disease and of brain cancer have been sorely lacking. Thus, our orthotopic PDXs of brain metastases represent pioneering mouse models that will not only allow translation of our basic research directly into clinical benefits for near-term patients, but also have a significant impact on future treatment of and research on metastatic breast cancer.
Targeting kinase signaling in cancer: Systems biology and pharmacology approaches
Building on our expertise in kinase signaling in cancer, we developed first-in-kind kinome-wide kinase libraries and initiated the systematic study of kinases in oncogenic transformation, which has facilitated the identification of a number of novel oncogenes and cancer targets. The most exciting recent findings from my lab are the identification of MELK (Maternal Embryonic Leucine-zipper Kinase) and CDK7 as novel cancer kinase targets that are essential in triple-negative breast cancer, but dispensable in normal cells through in vivo tumorigenesis screens. These findings provide us with a unique opportunity to investigate the differences between normal and cancer cells, and to exploit these differences for the development of novel therapies.
Research in our lab focuses on understanding the diverse signaling networks regulating essential cellular processes in normal and cancer cells.
For the most up to date list of publications, please use this link.