Untapped Therapeutic Targets in the Tumor Microenvironment
Abstract
High-grade serous ovarian carcinoma is among the most lethal cancers affecting women in the United States. While most therapeutic approaches have focused on malignant epithelial tumor cells and their genetic alterations, it is becoming increasingly clear that the tumor microenvironment plays an equally important role in tumor evolution. We now recognize that the microenvironment serves not only as a scaffold for tissue organization and integrity but also provides key biomechanical and molecular signals that can affect every aspect of tumor growth and biology, including proliferation, survival, metabolism, stem cell fate, and response to chemotherapy. The presence of cancer cells induces a reaction in the surrounding stromal cells similar to fibrosis after an injury. These reactions can also reduce therapeutic efficacy of chemotherapy by creating a physical barrier for drug transport while providing a protective environment for cancer cells to repopulate after completion of treatment. Thus, it is thought that anti-cancer therapies should target not only malignant cancer cells but also the microenvironment that fosters tumor growth and survival. Our goal is to demonstrate that targeting processes responsible for the formation of carcinoma associated fibroblasts (also known as CAFs) in the tumor microenvironment will effectively attenuate tumor growth, improve intratumoral drug delivery, and restore antitumor immune responses. We will use three different approaches to targeting CAFs. Approach 1: Repurposing existing therapy. CAFs are thought to be the key players in orchestrating the tumor environment. However, not all CAFs are tumor-promoting. CAFs are actually thought to prevent tumor progression until they receive activating signals from cancer cells and convert into "activated CAFs," which in turn confer invasive and metastatic abilities upon cancer cells and provide a "safe haven" from chemotherapy. Preferential targeting of activated CAFs has been challenging because of poor understanding of the signaling pathways involved in CAF activation. Recent studies have revealed that CAF activation in tumors shares many signaling pathways with the conversion of fibroblasts into myofibroblasts in organ fibrosis, a process that has been extensively studied for targeted therapy and for which several therapies are currently being tested in clinical trials. We have selected key signaling pathways that are shared between myofibroblast activation in fibrosis and CAF activation in cancer. Early clinical trials with agents targeting different aspects of these pathways have shown promising results in reducing lung and renal fibrosis. We will test these agents for their efficacy in preventing CAF activation and increasing sensitivity to chemotherapy in a mouse model of ovarian cancer that was developed in our laboratory. Demonstrating therapeutic efficacy of these anti-fibrotic agents in the mouse model will provide preclinical data for the use of such agents in ovarian cancer patients. Since a large number of systemic anti-fibrotic agents are currently in clinical trials, we envision that repurposing these agents for cancer treatment could have an immediate impact on therapeutic strategies in ovarian cancer. Approach 2: Improving treatment precision. Although the use of anti-fibrotic agents has the advantage of repurposing approved agents to treat ovarian cancer, we anticipate that any agents targeting processes in noncancerous tissues may be associated with toxicity. For example, most current chemotherapies indiscriminately destroy any fast-growing cells, including cells in the bone marrow, heart, kidney, bladder, lung and nervous system, leading to significant side effects and limiting the dose of chemotherapy. To increase the precision of targeting activated CAFs, our laboratory has identified a protein present in activated CAFs but absent from fibroblasts associated with non-cancerous conditions such as fibrosi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610190
Entities
People
- Sandra Orsulic
Organizations
- Cedars-Sinai Medical Center
- United States Army