Hallmarks of cancer

1. GENETIC INSTABILITY
AND
PARP INHIBITORS; OLAPARIB.
MD AMIR HOSSAIN
ID:1778011158
Masters student
China Pharmaceutical University, China

2. INTRODUCTION
 Cell maintains their genome integrity and promotes
faithful genome propagation In normal condition.
• It does so by
– Coordinated DNA replication
– DNA-damage sensing and repair
– Cell-cycle checkpoints
Most checkpoint factors are evolutionarily conserved and
many are tumor suppressors(P53)

3. GENETIC INSTABILITY
 Genetic instability refers to a range of genetic alterations from point
mutations to chromosome rearrangements.
 A range of genetic alterations from point mutations to chromosome
rearrangements.
-Aguilera and Gonzales,2008
 A variety of DNA alterations, encompassing single nucleotide to whole
chromosome changes.
- Pikor et al., 2013
 Types : Can be divided into classes according to the type of events
 Nucleotide Instability
 Microsatellite Instability
 Chromosomal Instability
 Examples: BRCA1 or BRCA2 mutations

4. CAUSES OF GENETIC INSTABILITY
 Replication dysfunction
 S phase checkpoint Dysfunction
 Remodeling
 Cell physiology and metabolism
 Aging

5. PARPs and DNA Damage Repair
 Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage
repair.
 PARP-1 activation is one of the earliest responses to DNA damage in human
cells.
 PARP acts as a “flag” that drives the assembly of DNA-repair complex at sites
of DNA damage, mainly promoting BER and single strand break repair (SSBR)
pathways

6. PARP INHIBITORS
 PARP inhibitors are a group of pharmacological inhibitors of the enzyme Poly
ADP-ribose polymerases (PARP). They are developed for multiple indications;
the most important is the treatment of cancer.
 PARPs succeed in the treatment of BRCA1 and BRCA2 mutation-associated
breast and ovarian cancers.
 E.g.:Olaparib (AZD2281), Veliparib (ABT-888), and Niraparib (formerly MK-
4827) etc.

7. OLAPARIB
 It is a potent PARP inhibitor
 Trade name Lynparza. It developed by KuDOS
Pharmaceuticals and later by AstraZeneca
 In December 2014, olaparib was approved for use
as a single agent by the EMA and the FDA
 has promising antitumor activity in patients with
metastatic breast cancer and a germline BRCA
mutation.
>BRCA 1
>BRCA 2

8. Mechanism of action
 Olaparib is an inhibitor of poly (ADP-ribose) polymerase
(PARP) enzymes, including PARP1, PARP2, and PARP3.
 That results inhibition the replication cancer cell and
death of cancer cell.
OLAPARIB

9. INDICATIONs
 For the maintenance treatment of adult patients
with recurrent epithelial ovarian, fallopian tube
or primary peritoneal cancer·
 For the treatment of adult patients with
deleterious or suspected deleterious germline
BRCA-mutated advanced ovarian cancer who have
been treated with three or more prior lines of
chemotherapy.

10. DOSAGE AND ADMINISTRATION
 Tablets: 150 mg, 100 mg.
 Recommended tablet dose is 300 mg taken orally
twice daily with or without food.
 Continue treatment until disease progression or
unacceptable toxicity

11. ADVERSE REACTIONS
Most common adverse reactions:
 ≥ 20% in clinical trials were anemia, nausea, fatigue
, headache, dyspepsia, decreased appetite,
constipation and stomatitis.
 ≥25% were decrease in hemoglobin, decrease in
lymphocytes, decrease in leukocytes, decrease in
platelets.

12. DRUG INTERACTIONS
 CYP3A Inducers: concomitant use with strong or
moderate CYP3A inducers, decrease efficacy.

13. REFERENCES
 Pikor,L. Thu,K. Vucic,E. Lam,W.(2013) ‘The detection and
implication of genome instability in cancer’.Cancer
Metastasis,32:341-352.
 Luca Livraghi and Judy E. Garber(2015) ‘PARP inhibitors
in the management of breast cancer: current data and
future prospects’ BMC Medicine201513:188
 Aguilera,A. and Garcia-Muse,T.(2013) ‘ Causes of Genome
Instability’.Annual Review of Genetics,47:19-50.

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