Grant: Project Grant

In order for cancer to evolve, grow and spread, normal cells must first undergo oncogenic transformation, evade safeguards that suppress unregulated proliferation and cause programmed cell death of transformed cells, evade the immune system, invade the vascular system, travel to distant tissues and escape blood vessels to establish new metastatic sites of cancer growth. We previously determined that the enzyme calpain is involved in several of these processes and may therefore represent a potential novel therapeutic target in cancer. Calpain is an enzyme that cleaves other proteins, thereby modifying their functions. In this way, calpain can regulate cell functions including proliferation, survival, migration and invasion. Paradoxically, calpain can either promote or inhibit cell death in response to different toxic challenges, including many therapeutic drugs currently used to treat cancers. The reasons for this relate to the many different roles of calpain, and the context in which it becomes engaged. We have developed genetic models to explore calpain functions, and we are using them to identify specific therapeutic challenges where calpain inhibition will enhance their ability to kill cancer cells. We found that blocking calpain reduces the ability of breast cancer cells to grow into tumors and to spread to other sites. We also learned that blocking calpain makes breast cancer cells more susceptible to some cancer drugs. This leads to our hypothesis that calpain inhibition will make some cancer drugs more effective when used in combination. We propose to develop biosensors to add in the identification of calpain inhibitors suitable for clinical use, and to identify specific cancer therapeutics that can be made more effective by combining them with calpain inhibitors.