Sapacitabine, a novel, orally available, pro-drug of CNDAC (2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine), is currently being evaluated in SEAMLESS, a pivotal Phase 3 trial in elderly patients with AML, and Phase 2 trials in AML, MDS, NSCLC, and CLL/SLL. CNDAC acts by a unique DNA-damaging mechanism. After CNDAC is incorporated into DNA, single-strand DNA breaks are generated via a β-elimination reaction. If unrepaired, these are subsequently converted to double-strand breaks during further replication. These DNA breaks can also activate the G2 checkpoint, leading to cell cycle arrest in G2. Parallel approaches have been utilized to identify further rational therapeutic development strategies for sapacitabine, particularly focusing on solid tumors. These approaches include synthetic lethality screening using focused siRNA libraries in CNDAC-treated cells, and screening for agents that could synergistically induce cell death when administered in combination with CNDAC. These have demonstrated that depletion or inhibition of components of the homologous recombination DNA repair (HRR) pathway (including ATM, BRCA1/2, Rad 51 and XRCC3) or disruption of the G2 checkpoint greatly sensitizes tumor cell lines to CNDAC-induced cell death. For example, cell lines in which BRCA1 or BRCA2 has been depleted through siRNA are significantly more sensitive to the compound than control cells. Moreover, inhibitors of the ATM or Chk1 kinases also sensitize cells to CNDAC, the latter through abrogation of the G2 checkpoint. These complementary approaches have underscored the potential clinical utility of sapacitabine in patients carrying homologous recombination DNA repair deficient (HRD) tumors, and have also highlighted promising combination strategies. Drug combination screening has also assessed the potential for combining sapacitabine with other agents active in HRD tumors, including platins and PARP inhibitors. Ongoing work is extending these findings to several solid tumor indications, including breast, ovarian and non-small cell lung cancers. Correlation of HRR status and CNDAC sensitivity will be reported for a panel encompassing cell lines derived from each of these target indications, in order to guide future clinical development of sapacitabine in solid tumors, and to aid development of biomarkers to identify suitable patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5666. doi:1538-7445.AM2012-5666