Mouse Models of Ovarian Cancer
The study of ovarian carcinogenesis has been limited by the lack of appropriate immuno-competent syngeneic mouse models that recapitulate genetic changes in human ovarian carcinoma. The Orsulic Laboratory engineered the mouse ovarian cancer cell line BR5-Luc with combinations of genetic alterations (p53-/-, Brca1-/-, myc, and Akt) that are frequently present in human high-grade serous ovarian cancer. The tumors in this model are infiltrated with the host stromal cells while the luciferase and HA tags allow for convenient visualization and quantification of cancer cells by whole animal imaging and immunohistochemistry. There are several characteristics of this model that make it suitable for studying cancer-stromal dynamics during ovarian cancer progression:
- Intact immune system
- Tumors form with 100 percent penetrance and predictable latency
- The main genetic and pathologic aspects of human ovarian cancer are represented
- Visualization, separation and quantification of cancer and stromal cell subsets is possible
The Orsulic Lab has shown that this ovarian cancer model recapitulates the human serous histology, pattern of metastatic spread and response to standard and targeted therapies. In collaboration with other laboratories, the Orsulic Lab has analyzed tumor and ascites immune cell infiltrates, including CD4+ and CD8+ T cells, B cells, natural killer (NK) cells, CD4+ Tregs, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs).
Ovarian Cancer Biomarkers
Survival rates for advanced stage ovarian cancer have not changed significantly in the past 40 years, and ovarian cancer remains the most lethal gynecologic cancer in women. Our goal is to change the status quo by developing new paradigms in the laboratory and efficiently translating them into the clinic. The most common type of ovarian cancer, and the one that accounts for the majority of deaths from ovarian cancer, is serous papillary carcinoma. Approximately 20 percent of patients with this ovarian cancer subtype are intrinsically resistant to chemotherapy or develop chemoresistant disease within one year from initial treatment. A reliable method to identify these poor prognosis patients would facilitate their inclusion into clinical trials or personalized treatment strategies at an earlier point. The lack of reliable biomarkers and curative treatment strategies for ovarian cancer inspired work in the Orsulic Lab aimed at identifying biomarkers for early detection, prognostication and personalization of therapy. The Orsulic Laboratory identified a gene signature that is strongly correlated with poor prognosis in ovarian cancer patients. Orsulic lab members are currently optimizing the gene signature and developing a quantitative assay for use in the clinical setting.
Immune Infiltrate Dynamics in Cancer Progression
Immunotherapies have demonstrated remarkable efficacy as anti-tumor agents in some patients; however, it is unclear why the majority of patients are unresponsive to immune activation. Recent evidence suggests that immune cells can both promote and inhibit tumor progression depending on the signals received from the tumor microenvironment. The two prevalent cell types in the tumor stroma are immune cells and cancer-associated fibroblasts (CAFs). The percentage of CAFs increases during tumor progression and correlates with poor survival. There is compelling evidence that CAFs may interfere with the anti-tumor immune response by changing the landscape of immune cell infiltrates in tumors. CAFs secrete a dense extracellular matrix that traps immune cells, thus physically restricting their access to tumor islets. CAFs are also a rich source of biologically active molecules that attract or repel certain immune cell types. The Orsulic Laboratory is testing the hypotheses that the accumulation of CAFs during tumor progression skews the immune infiltrate toward the immunosuppressive profile and that this state can be reversed with CAF-targeted therapies. A systematic characterization of specific immune cell types that are affected by targeting CAFs may provide new approaches to enhancing immunotherapeutic efficacy and improving response rates in ovarian cancer patients.
Therapeutic Targets in the Tumor Microenvironment
Current chemotherapeutic agents are largely selected for their ability to destroy rapidly dividing cancer cells rather than the less mitotically active tumor infrastructure that indirectly protects the rare specialized cells that drive tumor recurrence and chemoresistance. Recognizing the crucial role of stroma in most aspects of tumor progression, it has been proposed that rational anticancer therapy design should not only target the cancer cells but also the stroma. Cancer-associated fibroblasts (CAFs) are the most prominent component of the tumor stroma. It is becoming increasingly apparent that a subset of CAFs can be activated by cancer cells to generate a more nurturing microenvironment that is vital for cancer survival, progression, invasion and metastasis. These "activated CAFs" are characterized by increased contractility, linearization of collagen fibers and stiffening of the extracellular matrix. Activated CAFs can also directly compromise the efficacy of therapeutic delivery by increasing interstitial pressure, impeding the diffusion of large molecular weight drugs or sequestering drugs. The Orsulic Laboratory postulates that agents effective in preventing myofibroblast formation in organ fibrosis may also be effective in preventing CAF activation in cancer. Orsulic lab members are testing several anti-fibrotic agents with different mechanisms of action for their efficacy in preventing CAF activation in an immunocompetent mouse ovarian cancer model. The desired outcome is increased chemotherapeutic efficacy of platinum agents in combination with anti-fibrotic agents.