Targeting p53 for Oncology Drug Discovery Bimal DasMahapatra RISE, 334 bdasmahapatra@drew.edu

Background BS with Chemistry major, MS & Ph. D in Biochemistry, University of Calcutta, India Post-Doc in Cellular & Molecular Biology & Virology, Med. College of Wisc. Milwaukee, and University of Wisconsin, Madison, WI. 24 years of experience in drug discovery research in Virology ( Coxsackie, HIV, CMV and HCV) and Oncology in Schering-Plough. HCV protease inhibitor ( Victrelis) Associated with start-up Biotech Cos ( Oncoceutics, p53 Therapeutics, PA ) involved in discovering and developing anticancer agents Join RISE, Sept. 2011 Approved , May 2011

Phase I, Phase II, Phase III The Drug Discovery Process Timeline – 12 to15 years Cost – $1 to 1.6 billion Target Selection Target Validation Assay Development Hits & Leads & Screening Lead Optimization Clinical Trials Phase I, Phase II, Phase III Development New Drug Application Market & Phase IV

What is cancer? Uncontrolled growth of abnormal cells Existing therapies & short comings Chemo & radiation therapies (Toxicity, mutagenic) Therapies targeting various oncogenes (Therapy resistance) Immunotherapy Side effect? p53 p53 repairs mutations or eliminates cells with damaged DNA. p53 pathway is compromised in all cancers

p53 blocks cancer progresion at multiple stages Evan & Vousden, Nature 411, 342, 2001

IT IS A TUMOR SUPPRESSOR Newsweek, December 23, 1996 It's a cell's most elegant defender, a gene called p53. It stops tumors before they grow. But if damaged, it is involved in cancer. -the mutant form of this gene whose inheritance virtually guarantees that a malignant tumor will grow Maintains genomic integrity (protect DNA from mutations), GUARDIN of GENOME Acts as a Master Regulator integrating numerous signals that control life and death of a cell

How Does P53 Work? A Responder To Various Stresses p53 proteasome DNA damage Altered telomeres Oncogenes Hypoxia Replication stress Metabolic selective pressure Disrupt p53 pathway Mutate p53 or p53 MDM2 MDM4 proteasome p53 Activation Tumor Cell Growth and Survival & micro RNA In normal cells p53 is kept inactive by it’s negative regulators, MDM2 and MDMX. These proteins bind to p53 inhibits transcriptional activation function and induce it’s degradation via proteasome . MDM2 ‘s expression is regulated by p53. When a cell is exposed to stresses like DNA damage, metabolic stress, oxygen deprivation or others, these proteins are phosphorylated and separated from p53. p53 accumulates and binds to DNA to regulate expression of many genes & micro RNA . It also binds to proteins to modulate their functions. Depending on the stress these proteins and micro rnas will result in repair of damaged DNA, growth arrest, metabolic homeostasis, senescence and cell death or apoptosis and many other functions ultimately preventing tumor cell formation, survival and proliferation. It is nearly impossible for a normal cell becoming cancerous unless p53 network is inhibited or compromised , and that is exactly why tumor cells are under pressure to inactivate p53 signaling pathways.

Inactivation of p53 and Human cancer Cancer Uncontrolled growth, genomic instability Cancer In over 50% of cancers, p53 is inactivated due to mutations. It is the most commonly mutated gene in human cancer. Environmental exposure and p53 mutations Carcinogen Source Mutation/ codons UV radiations Sun light CC→ TT (many codons) Benzopyrene Tobacco smoke, industrial waste G→T(156,157,245, 248,273) Aflatoxin Mouldy food G→T(249) Aristolochic acid Chinese herbs A→T Asbestos Construction materials (175,245, 278) Vinyl chloride Polyvinyl chloride GC→AT (179,249,255) In remaining cancers, p53 function is abrogated by: over expression of Mdm2 defects in signaling pathway viral proteins

Potential Research Projects Current efforts in restoring p53 activity for therapy development. Recent breakthrough in immunotherapy and challenges Personalized therapy - tailored for individual genetic background Ethical questions & controversies in cancer therapy Any other cancer related topics