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Role of Biomarkers in the Development of PARP Inhibitors
Bratati Ganguly1, Sonia C Dolfi1, Lorna Rodriguez-Rodriguez2
1Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Abstract:
Defects in DNA repair lead to genomic instability and play a critical role in cancer development. Understanding the process by which DNA damage repair is altered or bypassed in cancer may identify novel therapeutic targets and lead to improved patient outcomes. Poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) has an important role in DNA repair, and novel therapeutics targeting PARP1 have been developed to treat cancers with defective DNA repair pathways. Despite treatment successes with PARP inhibitors (PARPi), intrinsic and acquired resistances have been observed. Preclinical studies and clinical trials in cancer suggest that combination therapy using PARPi and platinating agents is more effective than monotherapy in circumventing drug resistance mechanisms. Additionally, identification of biomarkers in response to PARPi will lead to improved patient selection for targeted cancer treatment. Recent technological advances have provided the necessary tools to examine many potential avenues to develop such biomarkers. This review examines the mechanistic rationale of PARP inhibition and potential biomarkers in their development for personalized therapy.
Insights
DNA repair defects drive cancer. Poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) inhibitors show promise, but resistance necessitates combination therapies and biomarkers for personalized cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genomic instability from DNA repair defects is a hallmark of cancer.
- Poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) is crucial for DNA repair, making it a therapeutic target.
- PARP inhibitors (PARPi) are effective but face intrinsic and acquired resistance.
Purpose of the Study:
- To review the mechanistic rationale behind PARP inhibition in cancer therapy.
- To explore potential biomarkers for predicting response to PARP inhibitors.
- To discuss combination therapies for overcoming PARPi resistance.
Main Methods:
- Literature review of preclinical studies and clinical trials.
- Analysis of molecular mechanisms of PARP1 function and inhibition.
- Examination of emerging biomarker strategies for PARPi therapy.
Main Results:
- Combination therapy with PARPi and platinating agents can overcome resistance mechanisms.
- Biomarker identification is crucial for patient selection and personalized treatment.
- Technological advancements facilitate the development of novel biomarkers.
Conclusions:
- Understanding PARP1 inhibition mechanisms is key to developing effective cancer treatments.
- Combination therapies and personalized biomarker approaches are essential for improving patient outcomes.
- Targeting DNA repair pathways offers a promising strategy for precision oncology.
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