1. Academic Validation
  2. A first-in-class CDK4 inhibitor demonstrates in vitro, ex-vivo and in vivo efficacy against ovarian cancer

A first-in-class CDK4 inhibitor demonstrates in vitro, ex-vivo and in vivo efficacy against ovarian cancer

  • Gynecol Oncol. 2020 Dec;159(3):827-838. doi: 10.1016/j.ygyno.2020.09.012.
Laychiluh Bantie 1 Solomon Tadesse 1 Jimma Likisa 1 Mingfeng Yu 1 Benjamin Noll 1 Gary Heinemann 1 Noor A Lokman 2 Carmela Ricciardelli 2 Martin K Oehler 3 Andrew Beck 4 Rupal Pradhan 4 Robert Milne 1 Hugo Albrecht 1 Shudong Wang 5
Affiliations

Affiliations

  • 1 Drug Discovery and Development, Cancer Research Institute and Clinical and Health Sciences, University of South Australia, Australia.
  • 2 Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Australia.
  • 3 Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Australia; Department of Gynaecologic Oncology, Royal Adelaide Hospital, Adelaide, Australia.
  • 4 Clinical and Health Sciences, University of South Australia, Australia.
  • 5 Drug Discovery and Development, Cancer Research Institute and Clinical and Health Sciences, University of South Australia, Australia. Electronic address: shudong.wang@unisa.edu.au.
Abstract

Introduction: Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are involved in the initiation and progression of various cancers. Deregulation of the CDK4/6-cyclin D-retinoblastoma (Rb) pathway is common in ovarian Cancer and is associated with an aggressive phenotype and poor prognosis. Patients with advanced ovarian Cancer whose tumor demonstrates Rb-positivity, a low expression of p16 and overexpression of cyclin D1 are most likely to benefit from CDK4/6 inhibition.

Materials and method: Anti-proliferative activity and mechanistic investigations for CDDD2-94, employing palbociclib as comparator, were evaluated by MTT assay, cell cycle and Apoptosis analysis, western blotting as well as senescence and colony formation assay. In vivo safety and efficacy studies were done in A2780 tumor-bearing nude mice. Combinations of CDDD2-94 with mTOR, MEK, PI3K or PARP inhibitors were evaluated in A2780 and OVCAR5 ovarian Cancer cells.

Results: Consistent with a CDK4-targeted mechanism, CDDD2-94 arrested the G1/G0 cell cycle, induced senescence and inhibited the proliferation of Rb-proficient ovarian Cancer cells. CDDD2-94 exhibited synergistic anti-proliferative activities with mTOR, MEK, PI3K or PARP inhibitors. Importantly, unlike palbociclib which caused significant reductions in the number of lymphocytes and neutrophils, CDDD2-94 had little effect. CDDD2-94, as single agent and in combination with everolimus, delayed tumor growth and significantly increased survival of mice.

Conclusion: Given its high specificity in targeting CDK4 and excellent anti-tumor efficacy with low toxicity, CDDD2-94 has potential to be developed as a standalone agent or in combination with targeted therapeutics for the treatment of ovarian Cancer.

Keywords

CDK4 inhibitor; Cyclin-dependent kinases; Drug discovery and development; Ovarian cancer; Palbociclib.

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