Despite the progress in molecular therapy and immunotherapy, multiple underlying cellular mechanisms cause resistance to cancer therapy. There are urgent needs to develop innovative approaches to meet these challenges. The proposed study is to develop subcellular enzyme-instructed self-assembly (sEISA), which includes mitochondrial EISA (mitoEISA) and cytoplasmic EISA (cytoEISA), for generating molecular nanofibers to overcome drug resistance and immunosuppression in cancer therapy. Our preliminary studies have shown that sEISA selectively targets the mitochondria of cancer cells and minimizes drug resistance. Most importantly, our preliminary study shows that sEISA inhibits the growth of immunosuppressive tumors in vivo. Thus, we propose to further develop sEISA against drug resistant cancer cells and tumors. The proposed research has three specific aims:
Aim 1, developing mitoEISA for selectively targeting cancer cells;
Aim 2, developing cytoEISA for minimizing drug resistance and immunosuppression;
and Aim 3, evaluating sEISA in ovarian cancer xenograft murine models. The central hypothesis is that sEISA spatiotemporally generates molecular nanofibers, which interact with multiple cellular proteins and interrupt multiple cellular processes inside cancer cells to minimize drug resistance. Our preliminary results support the central hypothesis. The innovation is that the mechanisms of the action of the molecular nanofibers significantly depart from the ligand-receptor dogma of the current anticancer drugs. The long-term goal of the proposed work is to develop sEISA to generate molecular nanofibers for overcoming resistance in cancer therapy. We anticipate that this research will provide innovative anticancer approaches to address the problems of drug resistance and immunosuppression in cancer therapy, thus ultimately will improve the survivorship of cancer patients.

Public Health Relevance

The overall goal of this research is to develop innovative approaches for overcoming drug resistance in cancer therapy. Developing nanomedicines by subcellular enzyme-instructed self-assembly (sEISA) to selectively kill cancer cells and to overcome the drug resistance, this approach will ultimately lead to a new cancer therapy for millions of people who will need anticancer treatment in the future, and thus improving health of the Nation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA142746-11A1
Application #
10120154
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
2010-02-08
Project End
2026-02-28
Budget Start
2021-03-09
Budget End
2022-02-28
Support Year
11
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Brandeis University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02453
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