Co-targeting hallmarks of cancer for therapeutic benefit in ovarian cancer: a scoping review

The conceptualization of cancer characteristics into 14 hallmarks is now widely adopted. Simultaneous targeting of multiple cancer hallmarks represents a promising strategy to overcome therapeutic resistance and improve clinical outcomes. This approach is particularly relevant in epithelial ovarian cancer, which remains highly lethal despite significant advances in first-line treatment. This scoping review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines and included searches of Medline, Scopus, the Cochrane Library, and ClinicalTrials.gov for studies published up to September 30, 2024. To be eligible, trials were required to be phase I to III clinical trials (both completed and ongoing) enrolling patients with any histotype of epithelial ovarian cancer and to target ≥2 of the 14 cancer hallmarks. Studies were screened and data extracted independently by 3 reviewers. Out of 1461 records screened at the title and abstract level (data cutoff: September 30, 2024), 225 studies were identified, comprising 111 completed and 114 ongoing trials. The adoption of co-targeting strategies has notably increased, with a 3-fold increase in trials between 2007-2013 and 2021-2024. Among 94 trials reporting clinically meaningful benefits, the most frequent combination involved targeting "sustaining proliferative signaling" and "genome instability and mutations." In ongoing trials, 40 are focused on modulating "avoiding immune destruction." However, no clinical trials were identified for 4 of the 14 hallmarks: "unlocking phenotypic plasticity," "senescent cells," "non-mutational epigenetic re-programming," and "polymorphic microbiomes." These hallmarks remain underexplored, highlighting critical gaps and potential areas for future research. In conclusion, co-targeting approaches in epithelial ovarian cancer rely on combining genomic instability and angiogenesis inhibition with chemotherapy. Current research trends are shifting toward chemotherapy-free regimens and novel therapeutic targets, aiming to address resistance mechanisms and improve long-term outcomes.