Spherical cancer models in tumor biology.

High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.

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Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer

https://ejmcm.com/article_1037_557a4ffed141d154066ba08c3bc4f683.pdf

Animal models in translational medicine: Validation and prediction

Based on genomic analysis, fifty percent of high grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functionally profiling DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 HGSC patients for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.

/pdf/prediction-of-dna-repair-inhibitor-response-in-short-term-4e6aetgfsz.pdf

Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids

Multicellular cancer spheroids (MCSs) have emerged as a promising in vitro model that replicates many features of solid tumors in vivo. Biomimetic hydrogel scaffolds for MCS growth offer a broad spectrum of biophysical and biochemical cues that help to recapitulate the behavior of natural extracellular matrix, essential for regulating cancer cell behavior. This perspective highlights recent advances in the development of hydrogel environments for MCS growth, release, and drug screening. We review the use of different types of hydrogels for MCS growth, the effect of biophysical and biochemical cues on MCS fate, the isolation of MCSs from hydrogel scaffolds, the utilization of microtechnologies, and the applications of MCSs grown in hydrogels. We conclude with the discussion of new research directions in the development of hydrogels for MCS growth.

Hydrogel microenvironments for cancer spheroid growth and drug screening.

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 is 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. Clin Cancer Res; 20(5); 1288–97. ©2014 AACR .

https://clincancerres.aacrjournals.org/content/clincanres/20/5/1288.full.pdf

Sarah McKinstry

Papers

Tumorgrafts as In Vivo Surrogates for Women with Ovarian Cancer

In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma