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Posts Tagged ‘Phosphoinositide 3-kinase’


Reporter: Aviva Lev-Ari, PhD, RN

 

Kinase Inhibitors

Seventh Annual

Novel Strategies for Kinase Inhibitors

Exploring New Therapeutic Areas

September 24-25, 2013  | Boston, MA

Dr. Jeffrey Settleman, Senior Director of Discovery Oncology at Genentech, to Present “The Role of Growth Factors in Resistance to Anti-Cancer Kinase Inhibitors” at Novel Strategies for Kinase Inhibitors Conference

The Role of Growth Factors in Resistance to Anti-Cancer Kinase Inhibitors

Selective kinase inhibitors have been clinically validated as an important class of oncology drugs. While mutational activation of the targeted pathway largely defines the patient population most likely to benefit from treatment, there is considerable variability among patients with respect to the magnitude and duration of benefit, implicating intrinsic resistance mechanisms. We find evidence of a potentially broad role for stromally-produced growth factors in clinical response to kinase inhibition. > Read More in NatureDr. Settleman’s research is focused on cancer cell biology and therapeutics. He is particularly interested in personalized cancer medicine and mechanisms of drug resistance. Since 2010, Dr. Settleman has been at Genentech, where he is currently the Senior Director of Discovery Oncology, overseeing efforts to identify and validate targets for oncology drug discovery and to discover predictive biomarkers for new cancer therapies. Before Genentech, Dr. Settleman was Director of the Center for Molecular Therapeutics and the Scientific Director of the Massachusetts General Hospital Cancer Center. He joined the Harvard School of Medicine faculty in 1992 and was named the Laurel Schwartz Professor of Oncology at Harvard Medical School in 2008. Dr. Settleman completed his postdoctoral fellowship at the Whitehead Institute for Biomedical Research at M.I.T. in Dr. Robert Weinberg’s laboratory. He earned his Ph.D. in genetics from Yale University in 1989.

 

Learn More   |   View Brochure   |   Register  (Deadline to Save Up to $250 is August 16)

Recommended Short Courses*

– New Class of Kinase Inhibitors: Covalent Modifiers

– Advancing Tools & Technologies for Fragment-Based Design

* separate registration required for short courses

Conference-at-a-Glance

Beyond Cancer

Second Generation Janus Kinase Inhibitors

Jordan S. Fridman, Ph.D., Senior Director, Pharmacology, Incyte Corp.

BTK Inhibitors in Inflammation and Autoimmunity

John Douhan III, Ph.D., Senior Principal Scientist, Immunoscience, Pfizer

ARRY-382, a Selective cFMS Inhibitor for the Treatment of Osteolytic Bone Diseases

Dale Wright, Ph.D., Research Investigator, Senior Project Leader, Pharmacology, Array BioPharma, Inc.

Targeting B-Cell Receptor Signaling with PI3Kdelta Inhibitors for Treatment of Inflammatory Diseases and B-cell Malignancies

Kamal Puri, Ph.D., Associate Director, Research, Gilead Sciences, Inc.

> Sponsored presentation (opportunities available)

Deregulated Cdk5-Targeted Inhibitor for Neuro-inflammation

Harish C. Pant, Ph.D., Chief; Laboratory of Cytoskeleton Protein Regulation, National Institute of Neurological Disease and Stroke/NIH

Orally Available, CNS Penetrant MLK Inhibitors for Treatment of Neurodegenerative Diseases

Val Goodfellow, Ph.D., CEO, Califia Bio, Inc.

Allosteric Kinase Inhibitors

JNK Inhibitor Discovery at Celgene – Tanzisertib and Beyond

Yoshitaka Satoh, Ph.D., Senior Principal Scientist, Medicinal Chemistry, Celgene

Highly Selective Allosteric FMS Kinase Inhibitors

Bryan Smith, Ph.D., Director, Biology, Deciphera Pharmaceuticals LLC

P529, An Allosteric Modifier of the TORC1 and TORC2 Complexes of the PI3K/Akt/mTOR Pathway

David Sherris, Ph.D., President and CEO, Paloma Pharmaceuticals, Inc.

Allosterically Targeting Polo-Like Kinase 1 for Selective Cancer Cell Killing

Kyung Lee, Ph.D., Senior Investigator, Section Head, Laboratory of Metabolism, National Cancer Institute

Interactive Breakout Discussion Groups

In a Class By Themselves: Discovery and Characterization of Allosteric  Modulators of Protein Kinases

Moderator: John Watson, Ph.D., Senior Research Investigator, Bristol-Myers Squibb, Lead Discovery, Evaluation, Profiling and Compound Management

Challenges Working with Non-competitive Kinase Inhibitors

Moderator: John Robinson, Ph.D., Senior Scientist, Medicinal Chemistry, Array BioPharma, Inc.

Repurposing Kinase Inhibitors

Moderator: Jordan S. Fridman, Ph.D., Senior Director, Pharmacology, Incyte Corp.

Overcoming Cancer Drug Resistance and Selective Kinase Inhibitors

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Featured Speaker: The Role of Growth Factors in Resistance to Anti-Cancer Kinase Inhibitors

Jeffrey Settleman, Ph.D., Senior Director, Discovery Oncology, Genentech

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Featured Speaker: Stromal Factors that are Targets for Pi-3 Kinase Inhibitor Therapeutics in the Control of Metastasis

Donald Durden, M.D., Ph.D., Professor, Department of Pediatrics; Director Pediatric Oncology Research, University of California, San Diego and CEO, SignalRx Pharmaceuticals

mTOR Inhibitor Torin-1 for Effective Targeting of Resistant Human Colon Cancer Stem Cells

Maria Giovanna Francipane, Ph.D., Post Doctoral Research Scholar, Pathology, University of Pittsburgh

Development of c-MET Kinase Inhibitors for Cancer Therapy and Drug Resistance

Xiangdong Liu, Ph.D., Drug Discovery Group, Incyte Corporation

Exploiting a Serendipitous Binding Opportunity in the Development of Highly Selective Rho Kinase Inhibitors

Erick Young, Ph.D., Distinguished Research Fellow, Medicinal Chemistry and Research Administration, Boehringer Ingelheim Pharma

PLENARY KEYNOTE PRESENTATIONS

Towards a Patient-Based Drug Discovery

Stuart L. Schreiber, Ph.D., Director, Chemical Biology and Founding Member, Broad Institute of Harvard and MIT; Howard Hughes Medical Institute Investigator; Morris Loeb Professor of Chemistry and Chemical Biology, Harvard University

Enteroendocrine Drug Discovery for Treatment of Metabolic Diseases

Paul L. Feldman, Ph.D., Senior Vice President, GlaxoSmithKline

> For sponsorship & exhibit information, including sponsored podium presentations, please contact Jon Stroup at 781-972-5483.

> Stay on and Attend Cardio-Metabolic Drug Targets

 

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Novel Strategies for Kinase Inhibitors is part of Discovery on Target, the preeminent event on novel drug targets, which features more than 600 attendees, 150 scientific presentations, 12 conferences, and 10 short courses.

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AKT Signaling Variable Effects

 

Reporter: Larry H Bernstein, MD, FCAP

 

Heterogeneous kinetics of AKT signaling in individual cells are accounted for by variable protein concentration

Meyer R, D’Alessandro LA, Kar S, Kramer B, She B, Kaschek D, et al.
Front. Physio. 2012; 3:451.     http://dx.doi.org/10.3389/fphys.2012.00451

In most solid cancers, cells harboring oncogenic mutations represent only a sub-fraction of the entire population. Within this sub-fraction the expression level of mutated proteins can vary significantly due to

  • cellular variability limiting the efficiency of targeted therapy.

To address the causes of the heterogeneity, we performed a systematic analysis of one of the most frequently mutated pathways in cancer cells, the phosphatidylinositol 3 kinase (PI3K) signaling pathway. Among others PI3K signaling is activated by the hepatocyte growth factor (HGF) that regulates

  • proliferation of hepatocytes during liver regeneration but
  • also fosters tumor cell proliferation.

HGF-mediated responses of PI3K signaling were monitored both at the single cell and cell population level in primary mouse hepatocytes and in the hepatoma cell line Hepa1_6. Interestingly, we observed that the HGF-mediated AKT responses at the level of individual cells is rather heterogeneous. However, the overall average behavior of the single cells strongly resembled the dynamics of AKT activation

  • determined at the cell population level.

To gain insights into the molecular cause for the observed heterogeneous behavior of individual cells, we employed

  • dynamic mathematical modeling in a stochastic framework.

Our analysis demonstrated that intrinsic noise was not sufficient to explain the observed kinetic behavior, but rather

  • the importance of extrinsic noise has to be considered.

Thus, distinct from gene expression in the examined signaling pathway fluctuations of the reaction rates has only a minor impact whereas

  • variability in the concentration of the various signaling components even in a clonal cell population is a key determinant for the kinetic behavior.
English: Structure of the HGF protein. Based o...

English: Structure of the HGF protein. Based on PyMOL rendering of PDB 1bht. (Photo credit: Wikipedia)

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