Parp Inhibitor: A Promising New Approach to Cancer Treatment Homing in on Tumor-Specific Targets

Parp Inhibitor

Poly (ADP-ribose) polymerases or PARPs are a family of enzymes that play an important role in DNA repair. When DNA is damaged, PARPs work to attach ADP-ribose units to various acceptor proteins involved in DNA repair. This process is called poly-ADP ribosylation and helps recruit DNA repair proteins to the damage site. PARP1 and PARP2 are the main enzymes targeted by Polymerase inhibitors.

By inhibiting the activity of PARPs, especially PARP1 and PARP2, Polymerase inhibitors block the DNA repair mechanism known as base excision repair (BER). BER is one of the primary pathways cells use to repair single-strand DNA breaks which occur frequently due to endogenous and exogenous DNA damaging agents. Without functioning BER, single-strand DNA damage is left unrepaired and can eventually lead to double-strand DNA breaks during DNA replication.

Double-strand breaks are extremely toxic to cells and must be repaired through homologous recombination repair (HRR). Cancer cells that are deficient in HRR, such as those with BRCA1/2 mutations found in some breast and ovarian cancers, are unable to repair this type of DNA damage. The accumulation of double-strand breaks leads to cell cycle arrest and eventual cell death, a form of synthetic lethality. This unique mechanism of synergy between PARP Inhibitors and HRR deficiency is the basis for the use of Polymerase inhibitors as a targeted cancer therapeutic approach.

Clinical Applications of Parp Inhibitor

Ovarian Cancer

Polymerase inhibitors have shown remarkable clinical activity in women with ovarian cancer associated with BRCA1/2 mutations. These mutations account for approximately 15-25% of hereditary ovarian cancers. Early phase clinical trials found response rates around 80% with Polymerase inhibitors like olaparib and niraparib as maintenance therapy after chemotherapy in BRCA-mutated ovarian cancer.

Phase 3 trials further demonstrated a statistically significant improvement in progression-free survival with Polymerase inhibitors compared to placebo in this population. In 2017, olaparib became the first Polymerase inhibitor approved by the FDA for BRCA-mutated ovarian cancer maintenance based on these results. More recent approvals of niraparib and rucaparib have widened treatment options.

Breast Cancer

PARP inhibition also shows promise in BRCA-mutated breast cancer, which makes up approximately 5-10% of cases. While response rates have generally been lower than in ovarian cancer, dual PARP/PI3K inhibition may overcome resistance. Olaparib gained FDA approval in 2018 for BRCA-mutated, HER2-negative metastatic breast cancer previously treated with chemotherapy based on a phase 3 trial showing improved progression-free survival versus standard therapy.

Other Solid Tumors

Beyond BRCA-mutated cancers, Polymerase inhibitors are being explored in various solid tumors. For example, early clinical studies found that 10-15% of men with metastatic castration-resistant prostate cancer had tumor responses when given olaparib. Ongoing research aims to identify biomarkers beyond BRCA status that can predict sensitivity to PARP inhibition across cancer types. Combinations with other targeted agents and immunotherapy also show promise to expand the utility of these drugs.

Safety and Tolerability

In general, Polymerase inhibitors have been well-tolerated in clinical trials. The most common side effects reported have included low blood counts, nausea, vomiting, fatigue and muscle/joint pain. Grade 3 or higher adverse events occurred in less than 10% of patients typically. However, long-term effects beyond 2 years of therapy are still unknown. Some risk of increased rates of certain cancers with Polymerase inhibitor use over many years has also been hypothesized based on preclinical data, though no human evidence has emerged so far. Overall, Polymerase inhibitors appear to have a safety profile suitable for chronic administration as maintenance therapy when the benefits outweigh risks.

Polymerase inhibitors have become a mainstay of treatment for BRCA-mutated ovarian and breast cancers in just a few short years. Continued research aims to further improve and expand their clinical applications. Identification of new biomarkers is ongoing to predict sensitivity beyond BRCA status. Novel combinations with other targeted agents, immunotherapy and even radiation therapy hold promise to achieve synergistic anti-tumor effects. Longer follow-up of existing studies will provide more insight into optimal sequencing, duration and long-term outcomes. Overall, PARP inhibition has opened up a new therapeutic paradigm and remains an area of intense focus for precision cancer medicine.

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Ravina Pandya, Content Writer, has a strong foothold in the market research industry. She specializes in writing well-researched articles from different industries, including food and beverages, information and technology, healthcare, chemical and materials, etc. (https://www.linkedin.com/in/ravina-pandya-1a3984191)