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 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 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 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 proposed work will be essential for advancing promising lead compounds to clinical trials in humans.
Project narrative: 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 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 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 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 proposed work will be essential for advancing promising lead compounds to clinical trials in humans.
Thesaurus Terms: Apoptosis Promoter; Assay; B-Cell Cll/Lymphoma 2 Gene; Bcl2; Bcl2 Gene; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Cancer Radiotherapy; Cancer Treatment; Cancers; Cells; Cellular Expansion; Cellular Growth; Clinical Trials; Clinical Trials, Unspecified; Development; Dose; Exposure To; Gamma Rays; Genes, Bcl-2; Human; Human, General; Inducer Of Apoptosis; Lead; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Mediating; Molecular Interaction; Molecular Target; Oncogenic; Pathway Interactions; Pb Element; Radiation Sensitizers; Radiation Therapy; Radiation, Gamma; Radiation-Sensitizing Agents; Radiation-Sensitizing Drugs; Radiosensitizing Agents; Radiosensitizing Drugs; Radiotherapeutics; Radiotherapy; Resistance; Signal Pathway; Surface; Therapeutic Intervention; Tumor Cell; Work; Xenograft Model; Anticancer Therapy; Anticancer Treatment; Base; Cancer Cell; Cancer Therapy; Ced9 Homolog; Cell Growth; Clinical Investigation; Combinatorial Chemistry; Cytotoxic; Design; Designing; Drug Discovery; Drug Modification; Globular Protein; Heavy Metal Pb; Heavy Metal Lead; Improved; Inhibitor; Inhibitor/Antagonist; Intervention Therapy; Irradiation; Malignancy; Neoplasm/Cancer; Neoplastic Cell; Novel; Overexpression; Pathway; Pro-Apoptotic Protein; Radiation Resistance; Radiosensitizer; Resistant; Small Molecule; Treatment Strategy; Tumor; Tumor Xenograft
