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"Data presented today provide important new insights into SNS-595'smechanism as a site-selective DNA intercalator and topoisomerase poison withselectivity for proliferating cells. Through its unique chemical structureand molecular mechanism, SNS-595 avoids common drug resistance pathways andmay have advantages over other topoisomerase poisons," said Daniel C. Adelman,M.D., Senior Vice President, Development and Chief Medical Officer. "Takentogether, these data support our ongoing clinical trials of SNS-595 inplatinum-resistant ovarian cancer and acute myeloid leukemia, and providecompelling evidence for future studies of SNS-595 in indications such asbreast cancer where topoisomerase II poisons are active."
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Sunesis researchers conducted in vitro and cell-based studies elucidatingSNS-595's mechanism of action. SNS-595 selectively intercalates DNA andpoisons topoisomerase II, resulting in replication-dependent DNA damage,irreversible G2 arrest and rapid apoptosis. SNS-595's targetedDNA-topoisomerase II interactions may contribute to the broad therapeuticwindow observed in patients treated with SNS-595.
In a translational research study designed to evaluate SNS-595's activityin primary patient samples of breast and ovarian cancers and acute myeloidleukemia against other agents, SNS-595 demonstrated potent activity andcompared favorably with doxorubicin, etoposide and platinum therapy atclinically relevant concentrations. SNS-595 is not a P-glycoprotein substrateand its activity is independent of the p53 family. This finding isnoteworthy, as high or increased expression of P-glycoprotein is a common formof drug resistance. In addition, the activity of many cancer agents requiresfunctional p53 family members, and p53 mutations or deletions are also afrequent cause of drug resistance. Based on these findings, evidence fromprior nonclinical studies in drug-resistant tumor models and the objectiveclinical responses observed to date among patients who have failed prioranthracycline-based therapies, SNS-595 may be active in settings where othertopoisomerase poisons are no longer effective. These findings support theongoing clinical trials in AML and ovarian cancer, and indicate that SNS-595may also be well-suited to the treatment of breast cancer.
In a third set of studies reported today, Sunesis researchers profiled thepotential relationship between SNS-595 activity and DNA repair pathways.Since SNS-595 causes double-strand breaks, the integrity of DNA repairpathways could impact cell sensitivity to SNS-595. Identification of the roleof various DNA repair pathways may contribute to the identification ofbiomarkers for patient stratification. Researchers found that the DNA damageinduced by SNS-595 is repaired by homologous recombination repair (HRR), andthat cells deficient in HRR have greater sensitivity to SNS-595. Breast andovarian cancers with BRCA mutations have compromised HRR and may beparticularly sensitive to SNS-595.
Data from these nonclinical studies of SNS-595 were presented today at theAACR Annual Meeting in three posters:
SNS-595 is a novel naphthyridine analog, structurally related toquinolones, a class of compounds which has not been used previously in thetreatment of cancer.
About Sunesis Pharmaceuticals
Sunesis is a clinical-stage biopharmaceutical company focused on thediscovery, development and commercial
