Abstract 203: A characterization of drug sensitivity and resistance in sarcoma
Authors: Shihabi Ahmad Al , Tebon Peyton J. , Nguyen Huyen T. , Chantharasamee Jomjit , Sartini Sara , Davarifar Ardalan , Jensen Alexandra , Diaz-Infante Miranda , Cox Hannah , Gonzalez Alfredo , Tavanaie Nasrin , Dry Sarah , Singh Arun , Chmielowski Bartosz , Crompton Joseph G. , Kalbasi Anusha , Eilber Fritz C. , Hornicek Francis J. , Bernthal Nicholas , Nelson Scott D. , Boutros Paul C. , Federman Noah , Yanagawa Jane , Soragni Alice 
Published: June 2023

Abstract
Bone and soft tissue sarcomas are a rare and diverse family of malignancies. Sarcomas disproportionally impact young patients, and most subtypes have limited therapeutic options. Given the rarity of these tumors and their heterogenous nature, there is a need for developing clinically relevant models to broadly characterize the landscape of drug resistance and sensitivity in sarcoma in order to identify effective therapies. We leverage patient-derived tumor organoids (PDTOs) to create models across an array of bone and soft tissue sarcomas. We have procured n=193 specimens from n=127 patients undergoing biopsies or surgical resections at UCLA Health hospitals and successfully generated PDTOs from over 100 samples so far originating from primary, recurrent, or metastatic bone and soft tissue sarcomas. We performed molecular and histologic characterization to compare the PDTOs with the parent tumor and monitored PDTOs growth using a machine learning-based imaging pipeline (Al Shihabi et al, 2022). Our results show that sarcoma PDTOs closely resemble the tumor of origin in their molecular features and exhibit diverse growth patterns across subtypes. We leveraged our existing organoid high-throughput drug screening pipeline (Phan et al, 2019) to perform functional screenings of chemotherapies, targeted agents, and combination therapies, with results within one week from surgery. By screening a large number of samples, we could identify patterns of response with respect to diagnosis, prior treatment, patient age, lesion type, and disease trajectory. We observe tumor-specific susceptibilities with high heterogeneity both across and within sarcoma subtypes. As an example, we will focus on osteosarcoma, a bone tumor common in the pediatric and AYA population. We characterized PDTOs from n=33 osteosarcoma specimens and observed significant heterogeneity in response to NCCN-recommended therapies, suggesting that some patients may benefit from a personalized selection of approved therapeutic regimens. Finally, we compare functional and genomic screening to show how drug sensitivity and resistance characterization can facilitate optimal drug selection, avoid ineffective therapies, and mirror patient outcomes.
Citation Format: Ahmad Al Shihabi, Peyton J. Tebon, Huyen T. Nguyen, Jomjit Chantharasamee, Sara Sartini, Ardalan Davarifar, Alexandra Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Gonzalez, Nasrin Tavanaie, Sarah Dry, Arun Singh, Bartosz Chmielowski, Joseph G. Crompton, Anusha Kalbasi, Fritz C. Eilber, Francis J. Hornicek, Nicholas Bernthal, Scott D. Nelson, Paul C. Boutros, Noah Federman, Jane Yanagawa, Alice Soragni. A characterization of drug sensitivity and resistance in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 203.