Enhancement of Breast Tumor Cell Immunogenicity as a Strategy for Chemosensitization
Abstract
Cytotoxic drugs are the predominant type(s) of therapies used to treat advanced stage metastatic breast cancer. While these therapies can be effective initially, recurrence of therapy-resistant disease is unfortunately not a rare outcome. Immunotherapies have emerged as a novel means to treat human cancer. In this approach, therapeutics enhance the antitumor immune response, which can dramatically reduce tumor growth resulting in durable remission; however, immunotherapies are successful in only a small fraction of patients and have not generally demonstrated effectiveness in breast cancer. Our proposed strategy is to combine these two therapeutic approaches (immunotherapy and cancer drugs) to achieve consistent and robust antitumor responses. In our preclinical studies, we combined the standard of care breast cancer chemotherapies doxorubicin and paclitaxel with a novel immunotherapy achieved by depleting the nucleosome remodeling factor (NURF) complex, which is described below. Further investigating the effectiveness of this combination could provide a novel therapeutic strategy for suppressing breast tumor growth and metastasis. The NURF complex is a multi-subunit enzyme that regulates gene expression. It is highly conserved from fruit flies to humans, having similar composition and molecular functions. It is not essential for adult mammals and is not required for normal cells to live and therefore could be targeted by drugs without toxicity. As such, several new drugs specific to NURF have been developed that are used in this proposal. From our previous publications, we have shown that inhibiting NURF enhances the immune response to breast tumors using preclinical mouse models. We extended these results with preliminary data presented in this proposal showing that NURF-depleted breast cancer cells are more sensitive to the commonly used breast cancer chemotherapies doxorubicin and paclitaxel. The enhanced sensitivity to doxorubicin (paclitaxel studies are still ongoing) occurs in addition to an enhanced ability of the immune system to destroy NURF-depleted cancer cells. These two effects could combine to dramatically enhance the therapeutic benefits of doxorubicin and NURF depletion. In this proposal we will: (1) further characterize how the combination of doxorubicin (and paclitaxel) and pharmacologic NURF inhibition can suppress tumor growth and metastasis using mouse models of advanced stage breast cancer and (2) develop an understanding, at the molecular level, how NURF regulates tumor cell sensitivity to doxorubicin and paclitaxel. Inhibition of NURF activity in breast cancer combined with doxorubicin treatment should result in enhanced antitumor immune activity to breast cancers, thereby promoting their elimination by the patient’s own immune system. Use of several new NURF small molecule inhibitors have recapitulated these findings, providing a novel drug that can be translated into the clinic in a few short years. By using a screening approach, our studies will also determine whether the pharmacologic inhibition of NURF can sensitize triple-negative breast cancers to other standard-of-care chemotherapies used for this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910490
Entities
People
- David A. Gewirtz
Organizations
- United States Army
- Virginia Commonwealth University