Development of targeted radiosensitizers for human cancers

DESCRIPTION (provided by applicant): Radiotherapy is broadly used in modern cancer treatment regimes. However, many cancers are incurable by radiotherapy because of non-specific cytotoxic effects and inherent or acquired resistance of cancer cells. Cancer therapies that specifically target molecular pathways of tumor cell growth are ideal approach to cancer treatment. Bcl-2, a pro-oncogenic product of the bcl-2 gene, is frequently overexpressed in human cancers and the Bcl-2 mediated signaling pathway has b een recognized as a potential target for therapeutic intervention. The design of small molecule inhibitors that target the active part of a globular protein has been considered a great challenge in the field of drug discovery. Our approach to developing a new target-selective anticancer treatment strategy is strongly influenced by our recent discovery that a small molecule inhibitor of Bcl-2, HA14-1, is a potent apoptosis inducer and radiosensitizer. Reversal of radiation resistance in Bcl-2 overexpressed c ancer cells has been achieved by sequential exposure to a non-cytotoxic concentration of HA14-1 followed by a low dose of gamma radiation. We have already demonstrated the validity and feasibility of inhibiting Bcl-2 functioning by targeting its surface re gions that bind pro-apoptotic proteins. Our hypothesis is that agents that specifically target Bcl-2 are able to sensitize tumor cells selectively to radiation therapies, thus providing a great advantage in eradicating cancer cells. In this proposal, we pl an to develop new radiosensitizers based on the modification of drug lead HA14-1. The proposed work will be essential for advancing promising lead compounds to clinical trials in humans. Project Narrative: Radiotherapy is broadly used in modern cancer trea tment regimes. However, many cancers are incurable by radiotherapy because of non-specific cytotoxic effects and inherent or acquired resistance of cancer cells. Cancer therapies that specifically target molecular pathways of tumor cell growth are ideal ap proach to cancer treatment. Bcl-2, a pro-oncogenic product of the bcl-2 gene, is frequently overexpressed in human cancers and the Bcl-2 mediated signaling pathway has been recognized as a potential target for therapeutic intervention. The design of small molecule inhibitors that target the active part of a globular protein has been considered a great challenge in the field of drug discovery. Our approach to developing a new target-selective anticancer treatment strategy is strongly influenced by our recent discovery that a small molecule inhibitor of Bcl-2, HA14-1, is a potent apoptosis inducer and radiosensitizer. Reversal of radiation resistance in Bcl-2 overexpressed cancer cells has been achieved by sequential exposure to a non-cytotoxic concentration o f HA14-1 followed by a low dose of gamma radiation. We have already demonstrated the validity and feasibility of inhibiting Bcl-2 functioning by targeting its surface regions that bind pro-apoptotic proteins. Our hypothesis is that agents that specifically target Bcl-2 are able to sensitize tumor cells selectively to radiation therapies, thus providing a great advantage in eradicating cancer cells. In this proposal, we plan to develop new radiosensitizers based on the modification of drug lead HA14-1. The p roposed work will be essential for advancing promising lead compounds to clinical trials in humans.