Grant: Operating Grant

In order for cancer to evolve, grow and spread, the transformed cancer cells must evade the normal safeguards that usually cause programmed cell death of transformed cells. Then they must acquire the ability to enter the vascular system, travel to distant tissues and escape the blood vessel to establish metastatic tumors. Calpain is an enzyme that cleaves other proteins, thereby modifying their functions. In this way, calpain is involved in the regulation of a number of important cell functions including proliferation, survival, programmed cell death and migration. Paradoxically, calpain can either promote or inhibit cell death in response to different toxic challenges, including many therapeutic approaches currently used to treat cancers. The reasons for this are complex, but appear to relate to the many different roles of calpain in the cell. Thus, calpain inhibition is predicted to have cumulatively different effects depending on the cellular context in which it occurs. In our previous work, we have explored these apparently opposing roles for calpain in an attempt to identify specific therapeutic challenges where calpain inhibition enhances the death of tumor cells, but either protects normal cells or at least does not further sensitize them to the toxic effects of the therapy. We have found that blocking calpain reduces the ability of human breast cancer cells to grow into tumors when transplanted into mice. This appears to involve a requirement of tumor cells to engage a specific survival mechanism that requires calpain. Interestingly, breast tumor cells that become resistant to a drug called trastuzumab can be made sensitive to this drug again when calpain is inhibited. This supports our hypothesis that calpain inhibition will promote tumor cell death in response to specific therapeutic challenges. We will pursue this observation and identify other cancer treatments that can be made more effective by combining them with calpain inhibition.