Breast Cancer Therapeutic Agents Based on Telomerase Misfunction

Project 4:
Breast Cancer Therapeutic Agents Based on Telomerase Misfunction

Principal Investigator - Elizabeth H Blackburn, PhD Clinical Co-Principal Investigator - John W. Park, MD

Advocates: Louise Heyneman, Carolene Marks and Bambi Schwartz

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:

1. Further test and characterize the previously developed immunoliposome (“ILS”) constituted with Her2-targeting antibody-developed in SPORE Project 3-containing the MT-hTer/anti-hTER siRNA construct (“MT-Rx” agent). In order to monitor MT-Rx efficacy we will use relevant biomarkers of response to the agent, suitable for early stage clinical trials.
2. Identify telomere/telomerase-based biomarker patterns predictive of apoptotic response to anticancer treatments and to specific MT-Rx therapy. We will identify the subset(s) of breast cancers that will be most responsive to existing therapies and to “MT-Rx” using (i) a panel of 60 breast cancer cell lines grouped by genomic and expression profiling, telomere maintenance status and other clinically relevant characteristics and (ii) patient-derived primary breast cancer cells, including stem/progenitor cell lines; that targets the most sensitive patient subpopulation, as identified.
3. Develop the validated and optimized assays of telomerase and telomere status on tumor and biopsy specimens as biomarkers, with the specific goal of adapting these assays per CLIA regulations to become biomarkers usable in CLIA certified laboratories in the clinic. Toward translation of MT-Rx, we will finalize the product configuration, perform initial manufacturing scale up, and evaluate initial toxicology targeted systemic delivery of MT-Rx agent in rodent models.