The goal of UCSF Breast Cancer SPORE Project 4 is to develop and assess the translational potential of agents we have developed that force telomerase interference in breast cancer. This project focuses on exploitation for clinical use of a new strategy: to turn the action of active telomerase against the breast cancer cells. In this current funding cycle, we have successfully demonstrated that a low threshold of expression of mutant-template telomerase RNA (MT-hTer) genes in human breast cancer cells is sufficient for a potent killing and growth inhibitory effect on these cells. The telomeres that result from MT-hTer action are “toxic” to cells, inducing a robust apoptotic response.
Additionally, during the previous SPORE funding period, new science arising from the Blackburn laboratory’s research on telomerase also led to two unanticipated discoveries: first, that simply decreasing the endogenous telomerase level by ribozyme or RNA targeting methods rapidly decreased cancer potential. Specifically, we found that lowering overall telomerase diminishes the metastatic potential of cancer cells in vivo, and rapidly inhibited the growth of breast and other cancer cells in vitro. Second, cell death induced by MT-hTer expression is dominant and does not require the p53 or pRb checkpoint pathways. Based on these findings, we then showed that combining the expression of MT-hTer with small interfering RNA directed against the endogenous WT-hTER of cancer cells synergistically increases the potency of the MT-hTer effects in killing cancer cells.
We have the following specific aims, which have the goal of bringing this work to the clinic: