Development of Novel Small-Molecule Rb Protein Modulator for Ovarian Cancer Immunotherapy
Abstract
Rationale: Previous studies have demonstrated that, in ovarian cancer, having more of a cell called a T lymphocyte detected inside tumors is associated with better survival outcomes. Thus, it is believed that these T lymphocyte cells exert a potent antitumor effect if they can reach the tumor cells. However, in most cases, the T lymphocyte cells are antagonized by other types of cells, called tumor associated macrophages (TAM), regulatory dendritic cells (rDCs), and myeloid-derived suppressor cells (MDSCs), which also reside within the tumor and inhibit incoming T lymphocyte cells from killing tumor cells. It has been shown that, if one can remove these inhibitory cells, more T lymphocytes can come in, kill, and shrink the tumor. Problem: According to National Cancer Institute statistics, ovarian cancer represents 1.3% of all cancers, and more than 21,000 women are diagnosed every year in the United States. An estimated one woman in 75 will develop ovarian cancer during her lifetime. With an estimated 14,240 deaths due to ovarian cancer in 2015, ovarian cancer is the fifth most common cause of cancer-related death in women. Although many therapeutic approaches have been tested, including surgery, radiation, chemotherapy, and immunotherapy, ovarian cancer remains extremely difficult to treat, and novel therapeutic approaches are needed. How Proposed Research is New: This proposal is based on our discovery of a novel small molecule, AP-3-84, that can target TAMs, rDCs and MDSCs. The molecule reacts with a protein called retinoblastoma (Rb), which is associated with cell proliferation and other cellular functions, including triggers for cell death. Importantly, we have found that in laboratory conditions, AP-3-84 has the ability to preferentially make the inhibitory cells die without significantly affecting the T lymphocyte cells that can subsequently react against the tumor. We have shown that this activity can happen in TAMs, rDCs, and MDSCs from human ovarian tumors when ?treated? in the laboratory. Moreover, in pilot experiments, a small number of mice bearing an established ovarian cancer were treated with AP-3-84; in all mice the tumor shrank and stopped growing in alignment with the depletion of TAMs. Our data suggest that these molecules may have an antitumor effect by decreasing those inhibitory cells and increasing T lymphocyte cell access to kill tumor cells. Though a drug called palbociclib (IBRANCE?) targeting CDK4/CDK6 (an inhibitory binding protein of Rb) is in clinical trial for certain ovarian cancer, our data to date show that AP-3-84 is acting differently from palbociclib. Thus, the proposed research is completely new, especially because of its focus on a molecular target that has not yet been investigated as an immunotherapy target. Why the Proposed Research is Relevant: Here, we propose to study the mechanisms by which AP-3-84 blocks tumor growth, both in the laboratory using fresh human ovarian cancer tissue (to study how TAMs, rDCs, and MDSC cells respond to therapy) and in mouse-based ovarian cancer models. Several strategies on the concept of empowering a T cell to kill tumor cells are under active investigation, including newly ?armed? T cell responses by inhibiting molecules that could restrain T cells from killing (anti-PD-L1) by (1) giving vaccines to instruct new T cells against cancer cells or (2) gene therapy, giving T cells a better strategy to kill CAR T cells. The limitation to all of these strategies is that their anti-tumor activity in vivo may be limited by resident TAMs, rDCs, and/or MDSCs. Therefore, our approach is relevant because it may have the potential to be used alone or in combination with other strategies to help T-cell responses against the tumor that are already present in cancer patients (as studied here) or because it may help make other T cell empowering strategies work better (to be studied in the future). Who will benefit: Developing new ther
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910092XX0
Entities
People
- Luis Montaner
Organizations
- United States Army
- Wistar Institute