P11. Cyclacel Limited, Dundee, United Kingdom
Principal Investigator: David Blake

OCTIPS personnel:               
David Blake PhD
Sheelagh Frame PhD
Daniella Zheleva PhD
Morag Hogben

Cyclacel Ltd
Cyclacel is a biopharmaceutical company dedicated to the discovery and development of novel, mechanism-targeted drugs to treat cancer and other diseases involving abnormal cell proliferation. Cyclacel was founded in 1996 by Professor Sir David Lane, a recognized leader in the field of tumour suppressor biology, who discovered the p53 protein. Based on the company’s core expertise in cell cycle biology, Cyclacel has built a deep pipeline of small molecule drug candidates, including three clinical-stage compounds, a large portfolio of development candidates and a productive drug discovery engine. Cyclacel has significant experience in the preclinical assessment of oncology drug combinations[1],[2] and has developed a fully-automated screening platform to facilitate identification of synergistic drug combinations.

Cyclacel’s sapacitabine (CYC682), an orally available, cell cycle modulating nucleoside analogue, is in the SEAMLESS Phase 3 trial being conducted under a Special Protocol Assessment agreement with the US Food and Drug Administration for the front-line treatment of acute myeloid leukemia in the elderly, and in Phase 2 studies for myelodysplastic syndromes, lung cancer and chronic lymphocytic leukaemia.  Additionally, sapacitabine has been shown to have increased activity in cancers with BRCA- or HR repair-deficient backgrounds,[3],[4]  including ovarian cancer cell lines.  Seliciclib (CYC202 or R-roscovitine), a CDK inhibitor, is in Phase 2 studies for the treatment of lung cancer and nasopharyngeal cancer and in a Phase 1 trial in combination with sapacitabine. A lead CDK inhibitor back-up compound has been selected for IND-directed development in oncology. CYC116, an Aurora kinase and VEGFR2 inhibitor, is in a Phase 1 trial in patients with solid tumours.

Cyclacel will examine the activity of a panel of anti-cancer agents to identify those agents that may be effective in relapsed ovarian tumours, making use of the paired ovarian cancer cell lines generated by other partners in OCTIPS. In addition, Cyclacel will conduct a high throughput combination screen within the same cellular systems, to identify agents that could be combined with cisplatin in front-line treatment of ovarian cancer, as a strategy to prevent relapse. This work will also provide pathway analysis data to inform synthetic lethality modelling by the consortium. http://www.cyclacel.com

Contact person: David Blake

[1] Frame S, MacKay RH, Hogben M, Connolly C, Anderson S, Fleming IN, Davis S, Blake D, Green S. Exploiting the unique mechanism of action of sapacitabine (CYC682) to obtain synergy with other therapeutic agents for clinical use in Acute Myeloid Leukemia, 14th Congress of the EHA, Poster 0761, 2009. 

[2] Green SR, Choudhary AK, Fleming IN. Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. Br. J. Cancer. 103: 1391-9, 2010.

[3] Frame S, Armour S, Munro C, Hogben M, Jones R, Blake DG, MacCallum DE, Green SR. Understanding the pathways involved in the repair of CNDAC induced DNA damage. 101st Ann Meeting of the AACR, Poster 3502, 2010. 

[4] Liu X, Wang Y, Benaissa S, Matsuda A, Kantarjian H, Estrov Z, Plunkett W. Homologous recombination as a resistance mechanism to replication-induced double-strand breaks caused by the antileukemia agent CNDAC. Blood. 116:1737-46, 2010.