Funding opportunities

EXECUTIVE SUMMARY Project Synopsis The applicant proposes to develop a new treatment for brain metastases in breast cancer patients. The therapeutic approach uses neural stem cells engineered to produce a protein that converts a prodrug into a toxic one that kills cells. The engineered neural stem cells will be injected into the brain and will home to the metastases where the expressed protein then coverts systemically administered prodrug into the active chemotherapy drug, killing tumor cells. This award will support planning for the completion of IND-enabling studies, IND filing and completion of Phase I/II clinical trials as well as planning of the Phase III trial within the four year funded timeframe. Significance and Impact -The proposed indication is a significant unmet medical need, since the target patient population is those failing standard treatments. -A positive result in these studies could potentially lead to a more generalized approach to treat other cancers. - One reviewer questioned the competitiveness of this more complex therapeutic approach against current standard of care for CNS metastatic disease including surgical intervention and/or radiation therapy and other newer non-invasive approaches such as gamma knife and proton beam therapy. -The approach was not viewed as novel. . -A question was raised about the potential impact, since the treatment targets metastases without addressing the primary breast cancer. Project Rationale and Feasibility -There was desire among reviewers to see results from a similar ongoing Phase 1 trial before pursuing this program, in case any key issues with the overall approach are identified. -Performing anything more than a Phase I trial by the end of four years may be unrealistic. -Many of the tumors will likely be resistant to the cytotoxic drug used in this project and it is unclear if targeting pro-drug conversion to metastases would result in concentrations of active drug sufficient to overcome tumor drug resistance. -Unclear how long the allogeneic cells would persist at the delivery site. -Investigators proposed to conduct genomic profiling for which the rationale was not clear. - Strong preclinical data supporting the proof of concept. -The same cell line proposed here is being used in a clinical trial for another indication and has thus already been made under GMP conditions, so the approach is feasible in the proposed timeframe assuming access to the GMP cell bank and ability to cross reference relevant regulatory filings. They also have a backup manufacturing plan. Principal Investigator (PI) and Planning Leader -PI has excellent training as a physician scientist and a strong publication record. S/he has participated in a number of clinical trials so is well qualified. Reviewers were mixed, however, in their views of whether the PI has appropriate experience to lead a clinical program. -Planning Leader has expertise in breast cancer and is experienced both with clinical trial execution and with the regulatory process.