Untapped Therapeutic Targets in the Tumor Microenvironment
Technical Report,01 Aug 2016,31 Jul 2019
Cedars-Sinai Medical Center Los Angeles United States
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Most therapeutic approaches have focused on the tumor cell and its genetic alterations. However, it is becoming clear that the microenvironment plays an important role in tumor evolution. We hypothesized that conventional chemotherapy for ovarian cancer will be more effective if the microenvironment that harbors the resistant cancer cells is simultaneously targeted. Since activated cancer-associated fibroblasts CAFs have a prominent role in most aspects of tumor progression, including responses to anticancer agents by forming a physical barrier that prevents chemotherapy access and promotes resistance, we predicted that targeting CAFs would inhibit tumor progression andor increase chemotherapeutic efficacy. 1. Our attempts to test anti-fibrotic agents showed largely negative results. One confounding factor in these pre-clinical tests was the modest presence of fibrosis in the existing ovarian cancer models. Therefore, we generated two new mouse models that exhibit extensive fibrosis and rapid onset of ovarian carcinomatosis. These models will be a valuable resource for studying the role of fibroblasts in ovarian cancer initiation and progression. 2. We made advances in targeting and characterizing the functional properties of COL11A1, which we previously identified as a molecular target that distinguishes CAFs from other fibroblasts. 3. We largely disproved our hypothesis that induction of terminal differentiation in CAFs may minimize cancer growth.
- Medicine and Medical Research
- Anatomy and Physiology