Abstract
The high mortality rate from ovarian cancers can be attributed to late-stage diagnosis and lack of effective treatment. Despite enormous effort to develop better targeted therapies, platinum-based chemotherapy still remains the standard of care for ovarian cancer patients, and resistance occurs at a high rate. One of the rate limiting factors for translation of new drug discoveries into clinical treatments has been the lack of suitable preclinical cancer models with high predictive value. We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53 and Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. Here, we describe an adaptation of these GEM models to orthotopic allografts that uniformly develop tumors with short latency and are ideally suited for routine preclinical studies. Ovarian tumors deficient in Brca1 respond to treatment with cisplatin and olaparib, a PARP inhibitor, whereas Brca1-wild type tumors are non-responsive to treatment, recapitulating the relative sensitivities observed in patients. These mouse models provide the opportunity for evaluation of effective therapeutics, including prediction of differential responses in Brca1-wild type and Brca1–deficient tumors and development of relevant biomarkers.
Highlights
Ovarian cancer is the second most common gynecologic cancer and the most frequent cause of gynecologic cancer-related deaths in the USA [1], with over 50% presenting as serous epithelial ovarian cancer (SEOC)
Loss of Brca1 or 2 combined with RB-tumor suppression (TS) inactivation did not result in disease progression beyond stage I without concurrent Tp53 aberration, and did not noticeably influence the biology of disease progression when combined with perturbation of Rb and Tp53
The de novo SEOC models are excellent for understanding disease etiology and for biomarker discovery, they exhibit a long latency to advanced disease, making the timing of cohort production for preclinical studies challenging
Summary
Ovarian cancer is the second most common gynecologic cancer and the most frequent cause of gynecologic cancer-related deaths in the USA [1], with over 50% presenting as serous epithelial ovarian cancer (SEOC). Despite initially high response rates, most patients relapse with a median progression-free survival of 18 months [4], making the search for new therapeutics imperative. Over the last several years much progress has been made in identifying hallmark genetic lesions associated with SEOC. The Cancer Genome Atlas (TCGA) study of a large high grade SEOC cohort revealed that mutations in TP53 predominated, occurring in at least 96% of tumors [5]. Alterations in the RB network were observed in 67% of cases, and about 20% of tumors had germ line or somatic mutations in BRCA1/2 with an additional 11% having lost BRCA1 expression through epigenetic silencing [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
