Although the emphasis in the field of anticancer drug discovery has been on the development of targeted therapies, cytotoxic agents continue to be the standard of care for many tumor types. Among these, therapeutic molecules which cause DNA damage, including the antitumor antibiotics and platinum agents, are commonly used. However, resistance to these agents is also commonplace, as cells upregulate the factors involved in DNA damage repair and avoid cytotoxicity. In order to combat this development of resistance and increase the potency of DNA damaging agents, compounds are needed that will abrogate the DNA repair pathway.

The Rad51 protein is an important part of the cellular response to DNA damage and subsequent repair of DNA double strand breaks, which are commonly induced by the platinum compounds and by radiation. SuperGen has developed a novel compound, MP470, which blocks the induction of Rad51 by anticancer platinums. This activity reduces the ability of tumor cells to withstand platinum treatment, thereby decreasing the required dose and widening the therapeutic window. These effects are seen in representative small cell and non-small cell lung cancer lines, including those which exhibit resistance to DNA damage-inducing agents through upregulated Rad51. MP470 does not, however, induce DNA damage when administered as a single agent. In xenograft models of non-small cell lung cancer, oral administration of MP470 in combination with carboplatin and paclitaxel significantly improved the tumor response over carboplatin/paclitaxel alone. Treatment with MP470 alone or in combination does not appear to cause toxicity, as no deaths occurred throughout the study, and no weight loss was observed.

Previous studies have shown that the DNA damage-enhancing effects of MP470 are not limited to the platinum-based cytotoxic agents; radiation-induced DNA damage and tumor cell death is also perpetuated by MP470 in the context of melanoma skin cancer and glioblastoma, two tumor types which are commonly treated with radiation therapy. It is expected that the addition of MP470 to DNA-damaging cytotoxic therapeutic regimens will reduce the dose (and therefore the toxicity) of the cytotoxic agent required to show a therapeutic response.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA