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SELECTBIO Conferences Prognostic, Predictive, and POC: Biomarkers from Research to Clinic

Donald Durden's Biography

Donald Durden, Pediatric Researcher, University Of California School Of Medicine

Dr. Durden’s research is directed at defining the alterations in pediatric tumors which will define sensitivity or resistance to specific targeted therapeutic agents. The characterization of pediatric malignancies using genomic and multiple “omic” analyses is a major focus of the Durden laboratory. As Vice Chair for Research in the Department of Pediatrics, Associate Director for Pediatric Oncology at MCC and Director of UCSD Rady Children’s Tumor Biorepository and Director of UCSD Rady Children’s Center for Personalized Pediatric Oncologic Therapeutics Program he will oversee and execute the genomic, epigenetic, proteomic, etc. characterization of Pediatric Tumor Tissue and Molecular Tumor Boards to individualize therapies based on an analysis of signaling pathways activated. The Durden laboratory is funded by the NCI to study the role of PTEN-PI-3 kinase-AKT signaling axis in adult and pediatric oncogenesis. The Durden laboratory reported the first evidence that PI-3 kinase inhibitors have antitumor activity in vivo (Cancer Research, 2002). This observation lead to an issued patent (6,668,002 in 1999) and launched a concerted effort by the Durden laboratory in collaboration with SignalRx pharmaceuticals (founded by Dr. Durden) to develop a pan PI-3 kinase inhibitor for human Phase I trials. Dr. Durden developed, patented and executed the development of one of the first PI-3 kinase inhibitors (SF1126) (Cancer Research, 2008) to enter human clinical trials. He continues to aggressively study the PTEN-PI-3 kinase signaling pathway in the tumor and stromal compartment in an effort to develop strategies which will stratify therapy to improve efficacy of this class of agent. His current interests include: 1) Role of PTEN and PI-3 kinase in tumorigenesis 2) Role of signaling pathways downstream of PTEN/PI3K in tumor microenvironment that control tumor progression and metastasis 3) Drug discovery efforts to develop more potent PI-3K and MEK or dual PI-3K/MEK inhibitors for cancer therapeutics. Major finding over the past funding period include: 1) Discovery of the role of PTEN in medulloblastomagenesis (PLoS One, 2011) 2) Completion of the Phase I clinical trial of pan PI-3K inhibitor, SF1126 (Eur. J. Cancer, 2012) and 3) Report the role of PI-3K inhibitor, SF1126 in Neuroblastoma therapeutics (CCP, 2010). He has published extensively in macrophage/myeloid signaling and recently discovered a signaling pathway in the macrophage stromal tumor compartment that is required for the metastatic phenotype (PLoS One 2014)(MCR, In press, 2014). More recently, he has initiated studies to evaluate the signaling pathways (PTEN/PI-3K) in cancer stem cells which propagate pediatric neuronal brain tumors and impart resistance to therapy. He founded SignalRx pharmaceuticals, Inc. to develop an expanded portfolio of potent isoform specific and PI-3 kinase inhibitors as well as dual PI-3 kinase/BET brd4 epigenetic inhibitors (over 10 patents issued on these novel compositions of matter) and PTEN inhibitors for clinical translation into human disease. The Phase I clinical trial of SF1126 was reported in 2012. Finally, he will soon open one of the first “bucket” trials in pediatric and adult solid tumors using SF1126 as pan PI-3 kinase inhibitor in patients with PIK3CA activating mutations or PTEN loss. He continues to be involved in drug discovery, drug development, clinical trial design and implementation focused around this signaling pathway and the molecular characterization of tumor tissue in individual patients.

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Novel Stromal Biomarkers for Anticancer Therapeutics; Macrophage M1 to M2 Transition; a Dual Epigenetic/PI-3 Kinase Inhibitory Platform

Friday, 16 January 2015 at 15:00

Add to Calendar ▼2015-01-16 15:00:002015-01-16 16:00:00Europe/LondonNovel Stromal Biomarkers for Anticancer Therapeutics; Macrophage M1 to M2 Transition; a Dual Epigenetic/PI-3 Kinase Inhibitory PlatformPrognostic, Predictive, and POC: Biomarkers from Research to Clinic in San Diego, California, USASan Diego, California,

Macrophages, a major leukocyte population present in tumors, play an essential role in promoting tumor growth by affecting angiogenesis, immune suppression, invasion and metastasis. Despite considerable research efforts, the signal transduction events within macrophages which encode the complex cascade of events required for tumor growth and polarization of macrophages are poorly understood. Our previous findings demonstrate that a4ß1 and avß3 integrin directed cell migration on specific extracellular matrices (ECM) requires a specific kinase-GTPase pair, Syk-Rac2. This pathway was shown to regulate the ECM dependent postnatal angiogenic response with no defect in vascular development. Herein, we have linked this ECM dependent signaling pathway in macrophages to the regulation of M2 macrophage differentiation and to the regulation of tumor growth, invasion and metastasis. Using mouse genetic models, we provide direct evidence that a macrophage specific, a4ß1 integrin dependent Syk-Rac2 signaling axis acts in concert with the p110 isoform (PTEN-PI-3 kinase pathway) to control HIF1a levels, tumor growth and metastasis. We report a novel proteasome/E3 ligase dependent mechanism by which PI-3 kinase regulates HIF1a levels under hypoxic conditions in the stromal compartment. Moreover, treatment with Syk or PI-3 kinase inhibitors demonstrate potent activity in multiple metastatic models. The results define a novel molecular mechanism for the regulation of HIF1a and a macrophage autonomous signaling pathway that is required for alterations in the ECM and the provisional integrin to regulate tumor metastasis and suggest treatment for metastatic disease targeting this pathway in the M2 macrophage compartment. Moreover, we describe a novel chemistry platform scaffold at SignalRx Pharmaceuticals, Inc. from which we have developed a number of potent dual PI-3 kinase/BET brd4 bromodomain inhibitors for cancer therapeutics.

Add to Calendar ▼2015-01-15 00:00:002015-01-16 00:00:00Europe/LondonPrognostic, Predictive, and POC: Biomarkers from Research to ClinicPrognostic, Predictive, and POC: Biomarkers from Research to Clinic in San Diego, California, USASan Diego, California,