Abstract B032: Use of patient-derived organoids to model tumor evolution in response to chemotherapy

Abstract

Abstract Serous endometrial and ovarian cancers represent significant morbidity and mortality for gynecologic cancers due to the high rate of resistance to chemotherapy and recurrence after treatment. Among the many reasons for poor outcomes is a lack of preclinical models that reflect the complex heterogeneity across patients. Our objective was to create patient-derived organoid (PDO) models of serous endometrial and ovarian cancer and examine how genomic profiles evolve in response to standard therapy. This study was performed in four PDO models of serous gynecologic cancer, including serous endometrial, high grade and low grade serous ovarian, and high grade serous fallopian tube. We first compared genomic alterations in the primary tumors and PDOs using a 484-gene NGS panel (NovoPM 2.0, Novogene). A large overlap in single nucleotide variants (SNVs), copy number variations (CNVs) and indels was observed between primary tumor tissue and the corresponding PDO model. For example, there was an average of 175 shared SNVs between each primary tumor and PDO model and <20 unique variants in the PDO that were not present in primary tumor specimen. For the patient with serous fallopian tube cancer, we were further able to generate PDO models from tumor tissue acquired from three different sites: ovary, omentum, and ascites fluid. We found that 217 SNVs were shared among the PDOs from the three sites, with only 2-11 variants unique to each location. Interestingly, eight unique CNVs were detected in the ovary and ascites PDOs but not in the metastatic (omentum) PDO. We next exposed each PDO to a short 3-day pulse of carboplatin+paclitaxel to create chemoexposed models. The rationale for this duration of exposure is that clinical response in patients has been shown to correlate with drug response at 72 hrs in PDO models of ovarian cancer. As expected, all chemoexposed PDOs were more resistant to chemotherapy as compared to treatment-naïve counterparts. Genomic analysis of the treatment-naïve vs. chemoexposed PDOs revealed acquisition of new variants, such as a p53 mutation in the serous endometrial model after the pulse of chemotherapy. Finally, we compared drug sensitivity of the treatment-naïve vs. chemoexposed PDOs to agents used in the adjuvant and recurrent settings. The chemoexposed models yielded different drug profiles, with some showing increased sensitivity and others increased resistance. Taken together, these data substantiate that PDO models retain tumor heterogeneity, exhibited by the different genomic profiles and varying chemosensitivity. In addition, PDO models can be used to model the genomic and drug response profiles that arise in response to chemotherapy. Citation Format: Andreea Newtson, Emily Symons, Paige Malmrose, Eric Devor, Samantha Parks, Craig Rush, Jessica Andrew-Udoh, Haley Losh, Jay Gertz, Kristina Thiel, Kimberly Leslie. Use of patient-derived organoids to model tumor evolution in response to chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B032.