Note for: Advances and perspectives of PARP inhibitors
Note for: Advances and perspectives of PARP inhibitors
Doi: 10.1186/s40164-019-0154-9
Overview:
-
Continuous DNA replication in cancer cells leads
to higher demand of DNA repair components
-
Growing evidence -- > broader population of
patients -- > benefit from PARPi beside one who has BRCA1/2 mutated tumors
-
Potential patients for PARPi
o
Defective in replication stress
o
HR deficiency
-
Summarizing
o
Advanced of PARPi in clinical application
o
PARPi based combination strategies in
preclinical and clinical studies
Cancer characteristic
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Generation of mutations
-
Neoantigens
-
Genome integrity
To survive
-
Maintain specific DNA damage repair pathways to
control DNA damage events
-
Thus, targeting DNA repair pathways -- > ideal
targets for cancer treatment
Rational
-
Different of HR status between cancer (HR-defective)
and normal cells
o
Initiate PARP -- > cell replicate -- > DSB
-- > cancer cells repair DNA through NHEJ -- > toxic
o
Initiate PARP -- > cell replicate -- > DSB
-- > normal cells repair DNA majorly through HR -- > survive
Background of PARP
-
PARP1 -- > more related to DNA damage repair
-- > generate PAR after DNA damage event
-
6 main domains
o
Three zinc finger domains
o
One BRCA1 c-terminus domain (auto-modification
domain)
o
WGR- rich domain
o
One catalytic domain
§
One helical domain (HD)
§
One ADP-ribosyltransferase catalytic domain
(ART)
During undamaged DNA
o
HD inhibits binding between PARP1 + beta-NAD
During SSB (single strand break)
o
PARP1 recognize the SSB through Zn-finger domains
o
Auto-inhibitory function of HD -- > stop
(through conformational change)
o
Catalytic function of ART activates
o
Promoting the recruitment of DNA repair
effectors and chromatin remodeling
o
Auto-PARylation on PAPR1 -- > cause dissociation
of PARP1 from DNA chains -- > restore auto-inhibitory status of PARP1
Clinical development of PARP inhibitors
-
The mode of mechanism in term of killing cancer
cells is not clear
-
It proposes that trapping PARP on damaged DNA --
> induce apoptosis in cancer cells rather than inhibiting the catalytic site
-- > this comes from the observation of talazoparib which show the most cytotoxicity
potency with the highest ability to trap PAPR1 with DNA
FDA-approved PARP inhibitors
-
Olaparib
o
First PAPRi entering clinical practice
o
Used with gBRCA1/2m ovarian cancer
o
Used for maintenance treatment for patients who
are sensitive to platinum-based therapy
-
Rucaparib
o
Same as olaparib -- > used as maintenance treatment
for patients who are sensitive to platinum-based therapy
-
Niraparib
o
Maintenance treatment of Pt-sensitive epithelial
ovarian, fallopian tube, or primary peritoneal cancer patients
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Talazoparib
o
Among PARPis -- > this one has the most PAPR1
trapping and cytotoxic potency
PAPR inhibitors in clinical trials
-
Veliparib has not been approved by FDA for
cancer treatment
-
Combination therapy with Pt-based drug
Beyond BRCA1/2 mutated cancer
HR deficient cancer
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Looking the mutation in genes which give rise
the same phenotype as of gBRCA1/2m
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Thus, PARPi could be used
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Those genes are related to HR
o RAD51
o
ATM
o
ATR
o
PALB2
o
Fanconi anemia gene family
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Identification of HR deficiency in cancer cells
-- > complex work
-
Better to find “measurable way to indicate the
HR activity” -- > thus, PAPRi could be initiated, for example,
o
Large scale chromosomal rearrangements
o
Loss of heterozygosity
Replication stress
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SCLC -- > HR proficiency but sensitive to
PARPi -- > later, it founds out that this cancer type is attributed to high
replication stress -- > drive by 1.mutation of tumor suppressor gene 2. Amplification
of oncogenes
PARPi-involved combination
therapy
-
Acting as sensitizers for chemotherapies, immunotherapies,
and targeted therapies -- > limiting DNA damage repair
o
PARPi + genotoxic chemotherapy
o
PARPi + immune checkpoint inhibitor
§
PARPi generate more neoantigen (more damage,
more mutations), thus, increase the immunogenicity of cancers
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