PARP Inhibitors: A Novel Class Of Anti-Cancer Drugs

PARP Inhibitors

Cancer researchers have long sought new therapeutic strategies to attack cancer cells while sparing normal cells. One promising avenue is targeting DNA repair pathways that are crucial for cancer cell survival but dispensable in healthy cells. PARP (poly polymerase) inhibitors are a class of anti-cancer drugs that do precisely this - they exploit DNA repair defects in cancer cells to selectively kill them. In this article, we will explore the mechanisms of action of PARP inhibitors and their emerging role in the treatment of various cancers.

Understanding the Role of PARP in DNA Repair

Our cells are constantly exposed to environmental and endogenous factors that can damage our DNA. Unrepaired DNA damage can potentially lead to mutations and cancer. Cells have evolved multiple DNA repair pathways such as homologous recombination (HR), non-homologous end joining (NHEJ) and base excision repair (BER) to maintain genomic integrity. PARP enzymes, particularly PARP1 and PARP2, play a key role in the BER pathway which repairs single-strand DNA breaks. When activated by DNA damage, PARP enzymes help recruit other DNA repair proteins to the site of damage by polyADP-ribosylating them.

Exploiting DNA Repair Defects in Cancer Cells

Many cancers have mutations in BRCA1 and BRCA2 genes which are important for the HR DNA repair pathway. BRCA-mutated cancers thus have defective HR. Researchers realized that inhibiting the backup BER pathway with PARP inhibitors would be synthetic lethal to these BRCA-mutated cancer cells as they would lack both key DNA repair pathways. Preclinical studies showed PARP inhibitors were indeed highly effective against BRCA-mutated cancer cell lines and tumors. This novel strategy of exploiting DNA repair deficiencies in cancer cells formed the rationale for clinical development of PARP inhibitors.

PARP Inhibitors in Ovarian Cancer Treatment

Ovarian cancer has one of the highest rates of BRCA mutations among cancers. Several Phase I, II and III clinical trials found PARP inhibitors like olaparib, rucaparib and niraparib significantly improved outcomes in women with recurrent platinum-sensitive ovarian cancer who had germline or somatic BRCA mutations. In 2017, olaparib became the first PARP inhibitor approved by the FDA for treatment of recurrent ovarian cancer with a BRCA mutation. Other PARP inhibitors have since gained similar approvals based on improvement in progression-free survival in late line ovarian cancer settings. PARP inhibitors are also being studied in combination with chemotherapy for frontline treatment of BRCA-mutated ovarian cancer to improve long-term outcomes.

Expanding Use in Breast and Prostate Cancers

Encouraged by success in ovarian cancer, PARP Inhibitors are being explored in other BRCA-associated cancers. In metastatic breast cancers with BRCA1/2 mutations, olaparib and talazoparib have shown response rates of around 60% as monotherapy in late line settings. Based on promising Phase III data, talazoparib recently received FDA approval for treatment of germline BRCA-mutated, HER2-negative metastatic breast cancer. PARP inhibitors are also showing activity against other DNA repair defective breast cancer subtypes driven by mutations in genes like ATM, PALB2 etc. Prostate cancer with BRCA2 mutations may also benefit from PARP inhibitors based on early evidence. Multiple ongoing studies are evaluating various PARP inhibitors alone or in combination for advanced prostate cancer.

Moving Beyond BRCA Mutations

Researchers are investigating if the PARP inhibition strategy can be expanded beyond just BRCA-mutated cancers. Many sporadic cancers can acquire BRCAness or HR deficiency phenotype via epigenetic or non-BRCA pathway alterations. Such BRCA-like or HR-deficient cancers may also be vulnerable to PARP inhibitors. Preliminary studies found some response even in DNA repair proficient or BRCA wild type cancers, pointing to alternative sensitivity mechanisms. Studies aim to identify biomarkers beyond BRCA status that correlate with PARP inhibitor sensitivity. Combining PARP inhibitors with other targeted therapies or chemotherapy is another avenue to widen their utility across more cancer types.

Future Prospects and Challenges

PARP inhibitors have revolutionized treatment of advanced BRCA-mutated cancers in a short span and offer promise of durable responses and long-term survival benefits. Ongoing research is defining their optimal use across lines of therapy in combination with other agents. But resistance does emerge with prolonged use, necessitating rational combinations to delay or overcome resistance. Additional biomarkers are needed to predict response beyond BRCA status. Expanding use to other HR deficient tumors and identifying optimal predictive biomarkers hold the key to realize the full potential of this novel anti-cancer strategy. As PARP inhibitors continue establishing their role, they signify our growing ability to rationally exploit specific vulnerabilities in cancer cells.

PARP inhibitors have emerged as an excellent example of personalized cancer therapy by targeting DNA repair deficiencies. Their success in BRCA-mutated cancers opens promising new avenues of exploiting other genome maintenance defects across diverse tumor types. Better biomarkers and rational combinations hold the potential to make PARP inhibition a mainstream treatment approach against many cancers in the future.

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