Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein–protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants.

1. THE GUARDIAN ANGEL
OF GENOME P53 IN
CANCER TREATMENT
BY
J.RAVINDER RAJU

3. DISCOVERY OF P53
 In 1970 six investigators independently
reported.
 Named as “ Death star, guardian of
genome,good and bad cop,master
watchman & molecule of the year”
(1993,science magazine )
 Studies involving two approaches:
I)virologic approach
II)serologic approach

6. .
 Mutated/inactivated in >50% cancers
 P53 located on chromosome 17p
 P53-”Caretaker” system
 Functions like brakes ,keep cell numbers down either by:
1)cell cycle arrest
2)promoting apoptosis

7. Structure and functions

8. Regulation of p53

10.  More than 26,000 somatic mutation data of p53
in the IARC.
 Frequency of p53 mutations varies from ~10 to
70%
 Germ line mutations of p53 cause Li-fraumeni
syndrome
 Most p53 mutations in cancer within DNA
binding domain

11. P53 based cancer therapies:
Adenovirus based therapy ONYX 015:
 Adenoviruses rely on their host cells to
replicate
“ONYX 015” –modified adenovirus
Deletion of E1B gene
E1B proteins involved in production of cyclin E
for replication
E1B function is not required in cancer cells
In cancer cells deregulation of cyclin E
observed

12. P53 based cancer therapies:
P51 gene therapy:
 1st p53 gene therapy reported in 1996
Retroviral vector containing wild type p53
gene
Under the control of actin promoter to treat
NSCLC
Viruses are engineered to lack early proteins
Few clinical trails reached phase III
Recently p53 gene therapy has been
developing in china

13. P53 stabilization:
MDM2 - E3 ubiqutin ligase which controls p53
degradation
Many tumors over express MDM2,without p53
mutations
 For eg: nutlins acts as antagonists of MDM2-
P53 interaction
M-219 is another molecule that stabilize p53

15. FUTURE OF P53:
Although there have been 10,000
publications much is still unknown
Still don’t under stand the micro
environmental conditions that favor
the selection of cells with p53
mutations
 Why the expression of wt p53
results in apoptosis in some cells,
growth arrest in others