1. Targeting p53 for Oncology Drug Discovery
Bimal DasMahapatra
RISE, 334

2. 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

3. 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

4. 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

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

6. 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

7. 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.

8. 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

9. 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