Grant: Operating Grant

Chemotherapy is still the treatment of choice in breast cancer, but it is not curative. Intolerable toxicities emerge after intensive chemotherapy because of their non-specific distribution/action in normal tissues. The side effects of chemotherapy can also force clinicians to use sub-optimal doses of the drug. Insufficient chemotherapy may lead to the selection of drug-resistant cells and/or transformation of sensitive cells to resistant ones. The resistant tumor cells that have survived the first line of therapy can regrow and progress to fatal metastasis. Development of resistance in breast cancer is associated with abnormal expression of several oncogenes. Silencing of oncogenes has been successfully tried to unravel molecular mechanisms behind drug resistance, but the therapeutic application of oncogene silencers has achieved limited success. This is mostly due to the biological instability of oncogene silencers and/or their inadequate access to their cellular targets. Our objective is to develop new therapeutic strategies to overcome drug resistance in breast cancer. We propose silencing of oncogenes responsible for breast cancer survival followed by delivery of "a high payload" of chemotherapy to breast tumor cells. We have developed nano-carriers that can specifically interact with breast tumor cells; successfully deliver silencers of oncogenes responsible for drug resistant to these cells; and, as a result, make resistant breast cancer cells chemo-sensitive. In this proposal, these nano-carriers will be optimized to correct the abnormal expression of key oncogenes orchestrating several mechanisms of breast cancer survival and invasiveness. This approach is expected to prevent the transformation of sensitive tumors to resistant ones and be particularly powerful in the treatment of breast tumors, when combined with FDA approved nano- chemo-therapeutics that deliver "a high payload" of anti-cancer drugs to breast tumor cells.