Most patients with common epithelial malignancies (i.e., prostate, breast, colon, and lung cancers) are likely to receive radiation as either their sole or primary treatment in combination with other modalities. For all tumors, there is a dose-response curve that indicates better control with higher doses of radiation. Since an increase in radiation dosage is limited by the tolerance level of the healthy organs, sensitizing the malignant cells by specific radiosensitizers has long been a goal of cancer researcher.
In studying mechanisms of epithelial cancer cell death following irradiation, scientists at Memorial Sloan Kettering Cancer Center showed that type II programmed cell death (autophagy) is a dominant mechanism of cell death in breast, prostate, and colon cancer cell lines. Components of this pathway may constitute new targets for radiosensitization. Our researchers have observed that radiation induces accumulation of acidic organelles in cancer cells. Morphologically, these organelles resemble autophagic bodies and secondary lysosomes. Acidification of these organelles is mediated by V-ATPase. The accumulation of acidic organelles in surviving colonies following irradiation suggests that these organelles modulate cellular response to radiation damage.
Further experiments proved that low concentrations of V-ATPase inhibitors increased the clonogenic death of cancer cells following radiation and exposure to chemotherapy agents. These results showed that V-ATPase plays a major role in protecting the cells against radiation and chemotherapy agents, demonstrating its value as a target for development of drugs for radiosensitization and chemosensitization.
The present invention relates to methods and compositions for inhibiting cell survival and/or promoting cell death following exposure to toxic agents and stress, such as radiation or chemotherapy applied in cancer treatment. This invention also provides a method to screen such compositions.
Memorial Sloan Kettering Cancer Center is interested in finding a licensee or partner to develop and/or screen lead compounds for radiosensitization and/or chemosensitization. Memorial Sloan Kettering researchers would be ready to help in developing and characterizing such specific inhibitors.
Research tool, drug target, therapeutic
Proof of principle obtained in mice
Joachim Yahalom, MD, FACR, Vice Chair for Academic Programs, Department of Radiation Oncology
U.S. patent issued: 6, 982, 252