1.Clinical Trials of Poly(ADP-Ribose) Polymerase Inhibitors for Cancer Therapy: A Review.
Buege M, Mahajan PB1. Rev Recent Clin Trials. 2015;10(4):326-39.
Poly(ADP-Ribose) Polymerase (PARP) is a family of enzymes involved in DNA repair, genome stability, cellular energy metabolism and cell division. Inhibition of PARP-1, the well characterized member of this family, has been explored as a strategy for enhancing anti-cancer activity of existing drugs and for developing new drugs. Recently unique enzymatic properties and biological functions of PARP-2 and PARP-3 have been discovered, further expanding the utility of PARP as a target for cancer pharmacotherapy. We compare and contrast the structural and enzymatic properties of these three members of the PARP family. Interactions of these enzymes with proteins specific to different DNA repair pathways are summarized. Further, we evaluate progress on development of PARP inhibitors as anticancer agents. Results of Phase I and Phase II clinical trials of seven PARP inhibitors, used alone or in combination with known anticancer agents are reviewed highlighting common observations regarding the maximum tolerable dose, adverse reactions profile, PARP inhibition and anticancer effects.
2.Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer.
Zhang M1, Liu G2, Xue F2, Edwards R3, Sood AK4, Zhang W5, Yang D6. Gynecol Oncol. 2016 Apr;141(1):57-64. doi: 10.1016/j.ygyno.2016.01.004.
OBJECTIVE: To identify novel prognostic and therapeutic markers for PARP inhibitors in BRCA wild type ovarian cancer (OvCa).
3.What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?
Liu JF1, Matulonis UA2. Curr Oncol Rep. 2016 May;18(5):29. doi: 10.1007/s11912-016-0515-z.
Poly-ADP-ribose polymerase (PARP) inhibitors have been one of the most exciting developments in the treatment of ovarian cancer in recent years. Demonstration of anti-cancer activity has led to the European Medicines Agency (EMA) approval of the PARP inhibitor (PARPi) olaparib as maintenance therapy in women with BRCA-mutated (BRCAm) ovarian cancer with platinum-sensitive recurrence following response to platinum therapy and the US Food and Drug Administration (US FDA) approval of olaparib in relapsed germline BRCA-mutated (gBRCAm) ovarian cancer in women who have received at least three prior chemotherapy treatments, both occurring in 2014. Additional trials are underway or awaiting final analysis with olaparib, other PARPis, and PARPi combinations to further elucidate the activity of these drugs in various clinical settings. This review will focus on the current clinical experience and ongoing trials with PARPis in ovarian cancer.
4.Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer.
Parkes EE1, Kennedy RD2. Oncologist. 2016 Mar 28. pii: theoncologist.2015-0438. [Epub ahead of print]
: High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required.
