Analysis of Host Obesity and Therapeutic Response in Ovarian Cancer
Abstract
Rationale: The majority of women with epithelial ovarian cancer (OvCa) are diagnosed with metastatic disease, resulting in a poor 5-year survival due to painful complications that result from widely disseminated intra-peritoneal (i.p., abdominal cavity) metastases. Obesity is increasingly widespread in the U.S. and worldwide. A number of studies have shown that there is a link between obesity and incidence of OvCa (serous, endometrioid, and mucinous types). Obesity is also associated with poor survival. A particularly interesting study looking at genes expressed in the tumors of women with high-grade serous OvCa (HGSOC) found that those women whose tumors expressed a large number of obesity- and fat metabolism-related genes had worse survival when compared to women whose tumors did not express these genes. This prompted us to develop experimental models to better understand the relationship between obesity and OvCa. We have used mouse models to explore the link between obesity and OvCa. In these experiments, mice are fed a high fat diet (HFD) and are compared to control mice fed a low-fat diet (LFD). We found that the HFD mice had much larger and more numerous metastatic lesions. These lesions were loaded with fat droplets and expressed a protein called sterol regulatory element binding protein 1 (SREBP1) that is a master regulator in the cell, instructing the tumor to transport fats into the cell and use them for energy and rapid growth. These tumors from HFD mice also contained different types of immune cells, with more tumor-promoting immune cells and fewer tumor-killing immune cells relative to tumors in the LFD mice. We found the same pattern when we analyzed tumors from women with HGSOC who have a high body mass index (BMI>30). These results show that the mouse model faithfully reproduces what is found in women with OvCa. We then treated these groups of mice with standard of care (SOC) chemotherapy (carboplatin and paclitaxel), with the dose adjusted to their weight, and showed that HFD mice respond poorly to treatment, with significantly more residual disease and faster recurrence. Interestingly, if we block SREBP1 together with SOC, we see a much longer time to recurrence, indicating that this novel combination therapy will likely enhance overall survival. Central Problem: We plan to evaluate the effect of several SREBP1-blocking drugs on tumor progression in HFD/LFD mice treated with standard-of-care chemotherapy. We will also evaluate the influence of obesity on immune cells, the cancer stem cell population, and metastatic tumorspheres that participate in recurrence. Area of Emphasis: Proposed studies address two FY22 OCRP areas of interest: (i) understand the basic biology of ovarian cancer progression, metastasis, recurrence, and other critical events and (ii) develop novel therapeutic strategies for treatment. We propose to use our preclinical mouse models of obesity (HFD/LFD) to (i) gain a molecular-level understanding of how and why obesity promotes tumor growth and metastatic spread; (ii) understand why standard-of-care chemotherapy is less effective in the context of obesity; (iii) test drugs that block the activity of molecules we identified as important in HFD models (like SREBP1) to see whether they improve the response to chemotherapy in HFD subjects; and (iv) reverse the immune landscape to more of a tumor-killing scenario. Potential Impact: U.S. active-duty Service Women, women Veterans, and women spouses/partners of Service Members exhibit the same incidence rates of gynecological cancers as the general population; namely a 1 in 78 incidence rate of OvCa and a 1 in 108 lifetime chance of death from OvCa. Obesity has an adverse effect on survival of women with OvCa, implicating a link between host obesity, metastatic success, and response to therapy. Our preliminary data support the hypothesis that therapeutic targeting of SREBP1 in combination with SOC del
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310781
Entities
People
- Mary Stack
Organizations
- United States Army
- University of Notre Dame