PARP inhibitors are a category of targeted therapies used in cancer treatment. These medications specifically block the function of PARP, an enzyme that cells use to repair damaged DNA. By interfering with this repair process, PARP inhibitors aim to selectively harm cancer cells while sparing healthy ones. They represent an advancement in oncology, offering a more precise approach compared to traditional chemotherapy.
Understanding DNA Repair and PARP
Cells continuously encounter damage to their DNA, the molecule containing genetic instructions for all cellular functions. To maintain genomic stability and proper cellular operation, cells possess intricate DNA repair mechanisms. These systems are constantly at work, identifying and correcting errors or breaks in the DNA structure, which can arise from normal metabolic processes or external factors like radiation. The ability to efficiently repair DNA is fundamental for cell survival and proliferation.
Among DNA repair pathways, the Poly ADP-ribose polymerase (PARP) family of enzymes, particularly PARP-1, plays an important role. PARP-1 is a protein that detects and binds to single-strand breaks in DNA. Once bound, it initiates a cascade of events that recruit other repair proteins to the site of damage. This mends single-strand breaks, preventing them from becoming more severe double-strand breaks.
Without proper PARP-1 function, cells would struggle to repair these common DNA lesions. This accumulation of unrepaired single-strand breaks could lead to genomic instability, potentially causing cell dysfunction or death. PARP enzymes, especially PARP-1, act as first responders to certain types of DNA damage, ensuring the integrity of the cell’s genetic blueprint. This foundational repair capacity is present in both healthy and cancerous cells, setting the stage for how PARP inhibitors can selectively target cancer.
How PARP Inhibitors Target Cancer
PARP inhibitors work by disrupting the DNA repair machinery within cancer cells. These drugs prevent PARP enzymes from repairing single-strand breaks in DNA. When PARP is inhibited, these single-strand breaks are not mended and can accumulate, eventually leading to more severe double-strand breaks during DNA replication.
The effectiveness of PARP inhibitors is amplified in cancer cells that already have defects in other major DNA repair pathways, such as homologous recombination repair (HRR). This pathway is responsible for repairing double-strand breaks, and its impairment is often seen in cancers with mutations in genes like BRCA1 or BRCA2. When PARP is inhibited in these HRR-deficient cancer cells, they lose their primary mechanism for repairing single-strand breaks and their backup system for double-strand breaks, leading to an overwhelming amount of DNA damage.
This concept is known as “synthetic lethality,” where the inhibition of PARP is not lethal on its own but becomes lethal when combined with an existing defect in another DNA repair pathway within the cancer cell. Some PARP inhibitors can also “trap” the PARP enzyme on the DNA, preventing it from detaching and further obstructing DNA repair. This trapping mechanism contributes to the accumulation of DNA damage, ultimately leading to the death of the vulnerable cancer cells.
Cancers Treated with PARP Inhibitors
PARP inhibitors are used in the treatment of several cancer types, particularly those linked to specific genetic mutations that impair DNA repair. Ovarian cancer is a key indication, especially for patients with BRCA1 or BRCA2 gene mutations. These drugs are often used as maintenance therapy after initial chemotherapy to prevent recurrence or for recurrent disease, extending the time before cancer progression.
Breast cancer patients, particularly those with inherited BRCA1 or BRCA2 mutations, also benefit from PARP inhibitors. These medications are used in certain advanced or metastatic breast cancer cases. Similarly, PARP inhibitors have found application in prostate cancer, specifically for metastatic castration-resistant prostate cancer with BRCA or other homologous recombination repair gene alterations.
Pancreatic cancer, although less frequently associated with BRCA mutations compared to ovarian or breast cancer, can also be treated with PARP inhibitors in specific contexts. For patients with metastatic pancreatic adenocarcinoma who harbor germline BRCA mutations and have responded to platinum-based chemotherapy, PARP inhibitors can be used as maintenance therapy.
Considerations and Side Effects of PARP Inhibitors
PARP inhibitors are typically taken orally, as pills or capsules, making administration relatively convenient. However, like most cancer treatments, these medications can cause a range of side effects. Common side effects include nausea, fatigue, and anemia (a reduction in red blood cells).
Other potential side effects involve low blood cell counts, such as neutropenia (low white blood cells) and thrombocytopenia (low platelets). These conditions can increase the risk of infection or bleeding. Healthcare providers closely monitor blood counts throughout treatment to manage these issues. Side effects are generally managed through supportive care, including anti-nausea medications, transfusions for anemia, or dose adjustments if necessary.