Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP), a biopharmaceutical company developing oral therapies that target the various phases of cell cycle control for the treatment of cancer and other serious diseases, announced today publication of data demonstrating that its sapacitabine oral nucleoside analog works synergistically with histone deacetylase (HDAC) inhibitors to induce significant reductions in tumor cell growth in both in vitro and in vivo preclinical models. Further evidence of promising combinations of sapacitabine with targeted agents was recently published by independent investigators demonstrating synergy of sapacitabine with agents interfering with DNA repair, such as inhibitors of the function of ATM, BRCA1/2 and PARP. Taken together the publications suggest promising combination treatment strategies for future clinical evaluation in a rational and targeted manner, in addition to clinical trials currently evaluating sapacitabine and the planned SEAMLESS Phase 3 pivotal trial in acute myeloid leukemia (AML).
The data in the publication in the British Journal of Cancer suggest that sapacitabine given in combination with HDAC inhibitors, such as vorinostat or sodium valproate, results in significantly enhanced cell death in AML cells and cell lines derived from other tumor tissues, including cutaneous T-cell lymphoma (CTCL), non-Hodgkins lymphoma (NHL) and non-small cell lung cancer (NSCLC). In an AML xenograft model combined treatment with low doses of sapacitabine and the HDAC inhibitor vorinostat resulted in tumor regression with no apparent toxicity associated with the treatment regimen.
A second publication recently published in the journal Blood demonstrated that CNDAC, the major metabolite of sapacitabine, induces DNA damage that is repaired by the homologous recombination pathway. The publication describes how defects in proteins involved in the homologous recombination DNA damage pathway, such as ATM, BRCA2 and XRCC3, result in significantly increased sensitivity to CNDAC as a consequence of the cells reduced capacity to repair DNA. Patients with cancers known to have defects in the homologous recombination pathway may benefit by treatment with sapacitabine as a single agent or in combination with targeted agents interfering with DNA repair or targeting components of the homologous recombination pathway, such as PARP inhibitors or ATM inhibitors. Examples of such cancers include triple negative breast cancer and ovarian cancer, both of which have a high incidence of defects in BRCA 1/2 genes, and B-cell chronic lymphocytic leukemia (CLL), a leukemia frequently associated with a high level of ATM chromosomal deletions.
The publications support and extend data previously published by Cyclacel scientists evaluating combinations of sapacitabine with agents involved in the DNA damage pathway at the 2009 Congress of the European Hematology Association and assessing determinants of sapacitabine sensitivity at the 2010 Annual Meeting of the American Association for Cancer Research.
Green, S, et al, British Journal of Cancer, 26 October 2010, Vol. 103, No. 9, 1391-9.
Liu, X, et al, Blood, 9 September 2010, Vol. 116, No. 10, 1737-46.
Source: Cyclacel Pharmaceuticals, Inc.