Treatment of Ovarian Cancer Beyond PARP Inhibition: Current and Future Options

Abstract

Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) during the last decade have changed the treatment landscape. This has improved outcomes, but unfortunately half the women with ovarian cancer still succumb to the disease within 5 years of diagnosis. Pathways of resistance to PARPi and chemotherapy have been studied extensively, but there is an unmet need to overcome treatment failure and improve outcome. Major mechanisms of PARPi resistance include restoration of homologous recombination repair activity, alteration of PARP function, stabilization of the replication fork, drug efflux, and activation of alternate pathways. These resistant mechanisms can be targeted to sensitize the resistant ovarian cancer cells either by rechallenging with PARPi, overcoming resistance mechanism or bypassing resistance pathways. Augmenting the PARPi activity by combining it with other targets in the DNA damage response pathway, antiangiogenic agents and immune checkpoint inhibitors can potentially overcome the resistance mechanisms. Methods to bypass resistance include targeting non-cross-resistant pathways acting independent of homologous recombination repair (HRR), modulating tumour microenvironment, and enhancing drug delivery systems such as antibody drug conjugates. In this review, we will discuss the first-line management of ovarian cancer, resistance mechanisms and potential strategies to overcome these.

Elucidating the role of liver enzymes as markers and regulators in ovarian cancer: a synergistic approach using Mendelian randomization, single-cell analysis, and clinical evidence

“…Ovarian cancer (OC), a highly lethal malignancy, significantly impacts the female reproductive system and is associated with high mortality rates globally. It is frequently diagnosed in advanced stages due to the general absence of early symptoms and the lack of effective screening strategies [ 3 , 19 ]. Liver enzymes are routine biomarkers in physical examinations and are associated with a variety of diseases.…”

Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options

“…PARP inhibition impairs DNA replication by generating PARP-DNA adducts; however, downregulation of PARP1 or alterations in its DNA-binding domains renders inhibitors of the PARP enzyme ineffective for inducing PARP trapping [296]. Furthermore, PARP1 binds to the damaged DNA through its zinc finger DNA-binding domain that can be modified by the allosteric effects of PARPis joining at the catalytic site [297]. Moreover, mutations or post-translational modifications in PARP1 were linked to a diminished PARP1 trapping activity on DNA and have also been uncovered as a mechanism of resistance [296,297].…”

“…Furthermore, PARP1 binds to the damaged DNA through its zinc finger DNA-binding domain that can be modified by the allosteric effects of PARPis joining at the catalytic site [297]. Moreover, mutations or post-translational modifications in PARP1 were linked to a diminished PARP1 trapping activity on DNA and have also been uncovered as a mechanism of resistance [296,297].…”

Patient-derived functional immuno-oncology platform identifies responders to ATR inhibitor and immunotherapy combinations in ovarian cancer

“…Poly (ADP-ribose) polymerase inhibitors (PARPi) have improved patient's outcome when used as a first-line or maintenance therapy, particularly in patients with homologous recombination deficiency (HRD), and or sensitivity to platinum-based chemotherapy (3). However, 35-45% of the patients discontinue the treatment due to innate or acquired resistance to PARPi (4,5), suggesting that novel combination strategies are required to overcome resistance to PARPi.…”