Ovarian cancer recurrence:is the definition of platinum resistance modified by PARPi and other intervening treatments?The evolving landscape in the management of platinum-resistant ovarian cancer

Definitions of platinum resistance have been questioned and changed over the last five years,even though no predictive biomarker of resistance exists.These have sculpted how we approach platinum retreatment and,consequently,how we devise new treatment strategies for those patients with tumour progression on platinum therapy.Platinum-non-eligible ovarian cancer is treated with single-agent non-platinum drugs.When bevacizumab can be added to chemotherapy,progression-free survival improves significantly.For patients with a BRCA mutation,PARP inhibitor monotherapy is an option compared to chemotherapy.There is currently no clearly identified role for immune-checkpoint inhibition in this patient population.This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response,angiogenesis or immune modulation.It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.

Ovarian cancer resistance to PARPi and platinumcontaining chemotherapy

Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies.Although initial response to therapy is observed,recurrence and ultimately chemoresistance result in overall therapeutic failure.This pattern has been evident with platinum therapy since the 1980s.Significant excitement surrounded the approval of poly(ADP-ribose)polymerase inhibition(PARPi)as a novel therapeutic option,especially with the advent of personalized medicine,but resistance has similarly developed to these treatments.Novel agents are constantly being sought,but if the obstacle of chemoresistance remains,the durability of responses will remain tenuous.Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured.Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.

The evolving role of DNA damage response in overcoming therapeutic resistance in ovarian cancer

Epithelial ovarian cancer(EOC)is treated in the first-line setting with combined platinum and taxane chemotherapy,often followed by a maintenance poly(ADP-ribose)polymerase inhibitor(PARPi).Responses to first-line treatment are frequent.For many patients,however,responses are suboptimal or short-lived.Over the last several years,multiple new classes of agents targeting DNA damage response(DDR)mechanisms have advanced through clinical development.In this review,we explore the preclinical rationale for the use of ATR inhibitors,CHK1 inhibitors,and WEE1 inhibitors,emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer.We also present an overview of the clinical development of the leading drugs in each of these classes,emphasizing the rationale for monotherapy and combination therapy approaches.

La_2Zr_2O_7 TBCs toughened by Pt particles prepared by cathode plasma electrolytic deposition

La2Zr2O7 thermal barrier coatings（TBCs） with dispersed Pt particles were prepared by cathode plasma electrolytic deposition（CPED） with ceramic balls added to the cathode region. Compared with the conventional CPED, when ceramic balls are used in the cathode region, the plasma discharge ignition current density decreases approximately 62-fold and the stable plasma discharges occur at the whole cathode surface. Such TBCs with a thickness of 100 μm exhibit a crack-free surface and are composed of pyrochlore-structured La2Zr2O7. Cyclic oxidation, scratching, and thermal insulation capability tests show that such TBCs not only exhibit high resistance to oxidation and spallation but also provide good thermal insulation. These beneficial effects are attributed to the excellent properties of TBCs, such as good thermal insulation because of low thermal conductivity, high-temperature oxidation resistance because of low-oxygen diffusion rate, and good mechanical properties because of the toughening effect of Pt particles.

Revisiting chemoresistance in ovarian cancer:Mechanism,biomarkers,and precision medicine

Among the gynecological cancers,ovarian cancer is the most lethal.Its therapeutic options include a combination of chemotherapy with platinum-based compounds and cytoreductive surgery.Most ovarian cancer patients exhibit an initial response to platinum-based therapy,however,platinum resistance has led to up to 80%of this responsive cohort becoming refractory.Ovarian cancer recurrence and drug resistance to current chemotherapeutic options is a global challenge.Chemo-resistance is a complex phenomenon that involves multiple genes and signal transduction pathways.Therefore,it is important to elucidate on the underlying molecular mechanisms involved in chemo-resistance.This inform decisions regarding therapeutic management and help in the identification of novel and effective drug targets.Studies have documented the individual bidmarkers of platinum-resistance in ovarian cancer that are potential therapeutic targets.This review summarizes the molecular mechanisms of platinum resistance in ovarian cancer,novel drug targets,and clinical outcomes.

How to win the ovarian cancer stem cell battle: destroying the roots

Ovarian cancer has the highest mortality rate among gynecologic malignancies.The combination of cytoreductive surgery and chemotherapy is the standard regimen for the treatment of ovarian cancer.The initial treatment is usually effective,but many patients with ovarian cancer experience recurrence,and treatment options for recurrent disease remain challenging.Cancer stem cells(CSCs)are suggested to play an essential role in cancer recurrence after initial chemotherapy.Furthermore,they are of great interest as CSCs may also be involved in chemotherapy susceptibility.Thus,understanding the characteristics and mechanisms by which CSCs display resistance to therapeutic agents is important to design effective cancer treatments.In this review,we describe and discuss current therapeutic regimens for ovarian cancer,as well as the various CSC markers,association between CSCs and disease progression,correlation of CSCs with poor prognosis,enrichment of CSCs in tumor tissues following repeated chemotherapy cycles,activation of major signaling pathways following chemotherapy,and potential inhibitors that suppress these signaling cascades.In addition,clinical trials evaluating novel targeted therapies to overcome chemotherapy resistance will be reviewed.The combination of traditional chemotherapy and CSC-targeted therapy could be an effective and promising anticancer treatment for ovarian cancer.Understanding the biological properties of CSCs and the mechanism of chemotherapy resistance are critical to design and develop new therapeutic strategies to overcome CSC-associated chemotherapy resistance.

Relationship between ovarian cancer stem cells,epithelial mesenchymal transition and tumour recurrence

Investigating the biological processes that occur to enable recurrence and the development of chemoresistance in ovarian cancer is critical to the research and development of improved treatment options for patients.The lethality of ovarian cancer is largely attributed to the recurrence of disease with acquired chemoresistance.Cancer stem cells are likely to be critical in ovarian cancer progression,contributing to tumour malignancy,metastasis and recurrence by persisting in the body despite treatment with anti-cancer drugs.Moreover,cancer stem cells are capable of mediating epithelial-to-mesenchymal transition traits and secrete extracellular vesicles to acquire therapy resistance and disease dissemination.These attributes merit in depth research to provide insight into the biological role of ovarian cancer stem cells in disease progression and chemotherapy response,leading to the development of improved biomarkers and innovative therapeutic approaches.