Tumorgrafts as In Vivo Surrogates for Women with Ovarian Cancer

Abstract

Purpose Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design Clinically-relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models are annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment.

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

“…In these experimental conditions, we obtained 25% xenografts, regardless of the transplantation route, a tumor take in line with earlier studies establishing patient-derived EOC xenografts in athymic nude mice (11,39,40). A better take could probably be obtained by transplanting ovarian tumors in more immunodeficient mice (SCID and NOD-SCID-IL2gR,) as recently reported (13,14). Interestingly, we found the engraftment being correlated with residual tumor in high-serous ovarian carcinomas, further supporting residual tumor as a poor prognostic factor in this disease.…”

“…19), including breast (30,31), colorectal (32,33), lung (34), pancreatic cancers (35,36), and glioblastoma (37,38). While we were preparing this manuscript, two papers were published on tumor grafts obtained from ovarian tumors, one focusing on a small series of high-grade serous type (13), whereas the other presenting a large tumor bank of ovarian cancer of different histotype (14).…”

“…Cancer cell lines are reproducible, easy to use, and useful for studying specific mechanisms, but their resemblance to the original tumor and thus their therapeutic predictive value is very limited (12). Two studies describing ovarian cancer patientderived xenografts have been recently published (13,14). However, in those studies little characterization was carried out in relation to the recently proposed origin and pathogenesis of ovarian cancer (i.e., type I or type II), that is now basis for novel target therapy.…”

AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer

“…The recent development of PDXs, in which small pieces of undigested primary tumors are serially passaged in immunocompromised mice, has ushered in a new era of precision medicine, where mice function as avatars to evaluate patient-specific therapies (22)(23)(24)(25)(26). Some of the limitations of PDXas are the serial passaging of the tumors, which can be lengthy and cause loss of clonal diversity, and replacement of human stroma and human vasculature (27,28).…”

New Strategies in Ovarian Cancer: Translating the Molecular Complexity of Ovarian Cancer into Treatment Advances

“…Combination strategies are also being applied to other histologic subtypes of ovarian cancer; in LGSC, MEK inhibitors have demonstrated activity, and a combination of MEK inhibitors and PI3K inhibitors is currently being tested and has preclinical rationale (62). Ideally, because of the multiple permutations of combination biologic agents, these combinations should be tested preclinically before human phase I studies through use of ovarian cancer patient-derived xenografts or appropriate genetically engineered model systems (63,64).…”