P1, N=155, Active, not recruiting, Debiopharm International SA | Trial primary completion date: Jan 2026 --> Apr 2026

P1, N=48, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest activity, which was validated in TP53mut SHH-MB patient-derived organoids. Despite the drugs' limited efficacy in the in vivo PDX model, WEE1 knockdown led to significant growth reduction in in vitro and in vivo TP53mut SHH-MB models. Our findings identify WEE1 as a promising target in LFS SHH-MB, suggesting its inhibition combined with vincristine treatment as a potential chemotherapeutic strategy.

P1, N=464, Recruiting, Debiopharm International SA | Trial completion date: Dec 2026 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Dec 2027

Elevated expression of CPSF73 is associated with aggressive disease in prostate cancer patients, and combining JTE-607 with adavosertib synergistically reduced prostate cancer cell survival. Our findings suggest that transcription termination helps prevent toxic conflicts between transcription and replication following increased replication initiation caused by WEE1 inhibition.

P2, N=96, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

P1/2, N=78, Active, not recruiting, Filipa Lynce, MD | Recruiting --> Active, not recruiting

P2, N=49, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2026 --> Jul 2027 | Trial primary completion date: Dec 2025 --> Jul 2026

The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53% and 33% respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives.

We evaluated cell cycle-targeted strategies to overcome HR-proficient chemoresistance using either volasertib (a selective PLK1 inhibitor) or adavosertib (a potent WEE1 inhibitor) in BRCA-WT/HR-proficient and BRCA-mutant/HR-deficient HGSOC models. Functional and xenograft models confirmed selective vulnerability of BRCA-WT tumors to either PLK1 or WEE1 inhibition. Our work highlights a mechanistic framework linking cell cycle checkpoint inhibition to DNA repair pathway selectivity, providing a rationale for targeting mitotic regulators in HR-proficient ovarian cancer-a subgroup with high clinical unmet need.

P1/2, N=76, Active, not recruiting, MedSIR | Recruiting --> Active, not recruiting

P1, N=76, Terminated, Debiopharm International SA | Trial completion date: Nov 2027 --> Oct 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Nov 2027 --> Oct 2025; This trial was concluded for strategic reasons.