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Research Interests

Understanding cell contact inhibitionWhile normal cells possess mechanisms that suppress cell proliferation when conditions are inappropriate, tumor cells can circumvent these mechanisms. One such regulatory mechanism is triggered by a stimulus known as “cell contact inhibition”, when cells reach a critical number and density. This “contact-inhibition” often becomes dysregulated during tumorigenesis. Over the past several years we have focused on how ”contact-inhibition” triggers anti-proliferative/growth control signals. A central player in the process is a protein called Merlin, which is the product of the NF2 (neurofibromatosis type 2) tumor suppressor gene. Recent studies have indicated the NF2 allele is

functionally inactivated in a broad range of tumors and has been shown to function as a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hpo/Yap pathway. We recently identified the Angiomotins, members of the Motin protein family, as Merlin-interacting proteins that localize to tight and adherens junctions. And have determined that Merlin’s ability to regulate multiple downstream signaling pathways is mediated through the Angiomotins. We are working to determine how the Angiomotins function and whether the targeting these effectors might prove beneficial in the treatment of NF2.

Understanding the molecular basis of Neurofibromatosis Type 2 and identifying therapeutic targets NF2 is a dominantly inherited autosomal disease caused by loss of the NF2 tumor suppressor gene. The NF2 gene codes for Merlin, a protein that predominantly localizes to the cell membrane. However, the mechanism/s through which Merlin exerted its function/s are incompletely understood. Moreover, there is an urgent need to develop therapeutic options for NF2 patients. Our work over the years identified Merlin as a regulator of a number of signaling pathways and potential therapeutic targets, including the p21-activated kinases (PAKs) and focal adhesion kinase (FAK). Through collaborations with organic/medicinal chemists and structural biologists and we employed structure-informed design approaches to identify and develop new classes of highly selective PAK inhibitors. Recent studies from our group identified the FDA approved drug crizotinib, as a potential therapeutic for NF2-assoicated schwannoma and determined the mechanism of action for this drug. We continue to study the molecular basis of NF2 and are currently focusing on another class of enzymes which play critical roles in NF2 tumor growth and assessing the consequences of therapeutic intervention in animal models of NF2.

Our work on NF2 identified and validated a number of therapeutic targets including the p21-activated kinases (PAKs). In addition, we identified and determined the mechanism of action for Crizotinib, an FDA approved drug, as a potential drug treatment for NF2 associated schwannoma. This work led to the initiation of a phase-IIb clinical trial for NF2. More recently, we characterized the role of Hippo/Yap signaling in NF2 and identified previously unknown effectors in this pathway, the Angiomotins. The studies have elucidated a mechanism through which Merlin regulates multiple signaling pathways from cell junctions. In addition, we characterized the role of Hippo/Yap signaling in NF2 and identified an obligate function for Yap in NF2, through transcriptional regulation of genes that promote survival of NF2-null Schwann cells mediated by a COX2/EGFR signaling axis. These studies also demonstrated in vivo that COX2 inhibitors could suppress tumor growth of NF2 schwannomas. Recent work from our group has also identified novel functions for YAP, as a transcriptional repressor of key cell cycle regulators.

Identifying vulnerabilities in Ras-driven tumorigenesisThe RAS genes are the most mutated oncogenes in cancer and as such present ideals target for therapeutic inhibition. This however has proven to be a formidable challenge and efforts have therefore focused on studying the signaling pathways regulated by RAS and identifying other effectors that are required for RAS-induced transformation, with the hope that these would present vulnerabilities to Ras-driven tumorigenesis. Over the past several years our group focused on identifying such targets and understanding their function. These studies led to identification of the small G-protein Rac1 and the Notch1 receptor as required for KRAS function in lung tumorigenesis. More recently, our group has developed and implemented novel High Throughput Screening (HTS) approaches to identify small molecules that are synthetic lethal to oncogenic KRAS. These approaches employ 3-dimensional formats that are thought to more closely reflect the conditions experienced by tumor cells in vivo. These efforts were successful in identifying synthetic lethal molecules that would not have been discovered employing traditional 2D culturing methods. We are currently using this approach in conjunction with a host of isogenic cell pairs to identify small molecules that are selectively lethal against cells carrying oncogenic mutations. We are incorporating a host of chemoproteomic tools such as functionalized fragment libraries to identify the targets of these small molecules and determine how they function.

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