Biomedical Engineering Reference
In-Depth Information
15.7.5
Niraparib (MK 4827)
Niraparib is an oral PARP 1 and 2 inhibitor with preclinical data
showing single agent anti-tumor activity against BRCA mutant
cell lines in culture and xenograft models. It is currently being
tested in phase 1 clinical trials as a single agent, in advanced solid
tumors, ovarian tumors and prostate tumors, and as combination
therapy in patients with advanced solid tumors in combination
with carboplatin, carboplatin with paclitaxel, and carboplatin with
liposomal doxorubicin [95].
A phase I trial of niraparib as a single agent had shown a half-
life of approximately 40 hours. PARP inhibition was shown in PBMC
of patients treated with doses higher than 110 mg. The MTD was
determined to be 300 mg daily. The DLT was thrombocytopenia. In
the expansion cohort comprising patients with high-grade serous
ovarian cancer treated at the MTD, six ovarian cancer patients
achieved PR; five of the six patients had
germline mutations
[96]. This is the second PARP inhibitor to show activity as a single
agent in patients carrying the
BRCA
BRCA
mutation.
15.8
Acquired Resistance to PARP Inhibitors
As stated above, one defining characteristic of
mutated
tumor cells is that they are sensitive to platinum agents [97]. However,
acquired resistance to cisplatin was shown by secondary intragenic
mutations in BRCA2 that restore the wild-type BRCA2 reading frame
[98]. Secondary mutations that restore BRCA1/2 were associated
with resistance to platinum chemotherapy and may predict resistance
to PARP inhibitors in hereditary ovarian carcinomas with germline
BRCA1/2 mutations [99]. Other mechanisms of platinum resistance
aside from restoration of HR function may not result in PAPR
inhibitor resistance. For cells that have been converted to wild-type
based on a second mutation, it is possible that sensitization to PARP
inhibitors may be maintained if another part of the HR pathway was
blocked. Because proteasome inhibitors inhibit FANCD2, phospho-
ATM, NBS1, BRCA1, FANCD2, and RAD51, which are all necessary in
HR, proteasome inhibitors might reinstitute “BRCAness” [98, 100].
BRCA1
and
2
