Background: While we often think of ovarian cancer as an aggregate of cancer cells, in reality cancer cells are embedded in dense stroma which provides both structural scaffolding and gelatinous matrix that serves as a foundation of growth factors and nutrients necessary for cancer growth. At the same time, stroma shields cancer cells from normal immune recognition and physically limits the access of chemotherapies, anti-angiogenic therapies, and immunotherapies. Whereas in the past most therapeutic approaches have focused on the cancer cell, it is becoming apparent that the effects of anti¬cancer therapies could be significantly improved by simultaneously targeting of the cancer-protective stroma.
Problem: The main challenge in targeting cancer stroma is its similarity to normal stroma, which serves as a barrier to cancer metastasis and is necessary for the integrity of most human organs. To date there have been no effective methods to separate cancer-activated stroma from normal stroma. Experiments in animal models have shown that indiscriminate targeting of both types of stroma can actually promote cancer metastasis and cause serious damage to normal organs.
Proposed solution: Our laboratory has identified a protein called COL11A1 that is specifically expressed in cancer-activated stroma but not in normal stroma. We have also shown that high levels of COL11A1 are associated with ovarian cancer metastasis, recurrence, and poor patient survival. Our goals are to understand the roles of COL11A1 in stromal activation and cancer growth, and show the usefulness of COL11A1 as an anti-cancer target.
Research plan: We will study COL11A1 in ovarian cancer using a mouse model that was developed in our laboratory, and test whether targeting COL11A1 will greatly improve the effectiveness of anti-cancer therapy and prevent cancer growth. We will use genetic and immunology-based approaches to eliminate COL11A1 expression in cancer stroma in order to enhance chemotherapeutic accessibility to cancer cells and stop ovarian cancer growth.
Impact: Cancer-activated stroma promotes cancer progression and shields cancer cells from chemotherapy. Thus, simultaneous targeting of cancer stroma and cancer cells is necessary to achieve chemotherapeutic efficacy. COL11A1 is a particularly attractive therapeutic target because it is expressed in cancer-activated stroma but not in normal stroma. Testing COL11A1 as a precise target will be important for future anti-cancer drug development, to accurately and safely deliver drugs directly to cancer cells without damaging the normal stroma. In the clinical setting, this approach should lead to more effective and less toxic anti-cancer therapies.