Abstract Precision oncology has transformed cancer treatment by using genomic and molecular profiling to identify actionable changes that inform targeted therapy. However, despite these advances, genomic information alone often cannot predict how individual patients will respond to treatment. Tumors with similar mutational profiles can have very different responses because of epigenetic regulation, tumor heterogeneity, metabolic changes, and therapy-resistant cell subpopulations. These challenges emphasize the need for complementary methods that can directly assess drug sensitivity in patient-derived tumor cells. This presentation will outline the development and translational application of a live tumor-based functional precision oncology platform designed to predict therapeutic response using viable patient tumor cells. The approach evaluates drug sensitivity in both bulk tumor cells and cancer stem cell (CSC) -enriched populations, which are increasingly recognized as key drivers of therapeutic resistance, tumor persistence, and disease recurrence. Fresh tumor specimens obtained from surgical resections, biopsies, or malignant effusions are processed to isolate viable tumor cells while maintaining the biological heterogeneity of the original tumor. Cells are cultured under defined conditions that promote enrichment of CSC populations based on functional properties such as sphere-forming ability and selective growth environments. Both CSC-enriched and bulk tumor cell populations are then exposed ex vivo to panels of clinically relevant chemotherapeutic agents and targeted therapies. Drug-induced cytotoxicity is measured using viability assays that determine the relative susceptibility of different tumor cell compartments to each therapeutic agent. This strategy forms the basis of the ChemoID functional precision oncology assay, which evaluates differential drug sensitivity in proliferating tumor cells and CSC populations. In 2025, ChemoID received Breakthrough Device Designation from the U. S. Food and Drug Administration, acknowledging its potential to enhance clinical decision-making for patients with life-threatening cancers. Since CSCs display increased resistance to conventional therapies through improved DNA repair capacity, drug efflux mechanisms, and metabolic plasticity, assessing drug activity in this compartment provides clinically relevant information that genomic profiling alone cannot capture. The assay produces a patient-specific drug response profile that ranks candidate therapies based on their cytotoxic effects against both CSC and bulk tumor populations, thereby helping identify treatment strategies capable of targeting resistant tumor compartments. Preclinical validation studies demonstrated that CSC populations isolated from patient tumors have significantly greater resistance to multiple chemotherapeutic agents compared to bulk tumor cells. Importantly, these resistant populations also exhibit different sensitivities to specific therapeutic agents, suggesting that personalized drug-response testing can identify treatment options capable of overcoming inherent resistance mechanisms. The clinical utility of this functional testing platform has been evaluated in multiple malignancies characterized by high therapeutic resistance. We will present findings from a prospective randomized clinical trial in recurrent glioblastoma, one of the most aggressive primary brain tumors. Despite multimodal therapy, glioblastoma remains associated with poor outcomes and limited therapeutic options. In this study, treatment plans chosen using ChemoID functional testing were linked to better clinical results compared to empiric therapy choices. Patients treated with assay-guided therapies showed significant improvements in progression-free and overall survival compared to those receiving treatments selected by physicians without functional testing. A second prospective randomized clinical trial in recurrent platinum-resistant ovarian cancer further evaluated the clinical value of functional drug-response profiling in a patient population with limited treatment options and historically low response rates to subsequent chemotherapy. Functional testing identified patient-specific drug sensitivities that were not predicted by previous treatment exposure or clinical parameters. Patients treated with therapies predicted to be effective by the assay demonstrated improved response rates and longer progression-free survival compared to those receiving empiric, physician-selected regimens. These studies demonstrate how functional tumor testing can uncover clinically actionable therapeutic vulnerabilities that are not apparent from genomic analysis alone. In several cases, drugs predicted to be ineffective based on previous treatment history showed significant cytotoxic activity in CSC populations when tested directly in patient-derived tumor cells. Conversely, some therapies commonly used in standard treatment regimens exhibited limited activity against CSC populations, offering a possible mechanistic explanation for treatment failure and tumor recurrence. Beyond guiding treatment selection, live tumor functional assays also offer a powerful platform for investigating mechanisms of therapeutic resistance. Comparative analysis of drug sensitivity profiles between CSC and bulk tumor compartments can reveal patterns of intrinsic resistance that may inform rational combination therapies designed to eliminate resistant tumor populations. Integration of functional drug-response testing with genomic and transcriptomic profiling can further improve precision oncology by creating detailed predictive models of therapeutic response. In summary, live patient tumor-based functional testing offers a clinically actionable approach for predicting therapeutic response and customizing treatment plans. By directly assessing drug activity in both bulk tumor cells and therapy-resistant CSC populations, functional precision oncology can reveal therapeutic vulnerabilities that are not captured by genomic profiling alone. Randomized clinical trials in glioblastoma and platinum-resistant ovarian cancer demonstrate that treatment strategies guided by functional tumor testing can improve patient stratification and outcomes. These results support integrating live tumor functional assays into precision oncology workflows and underscore their potential to connect molecular tumor characterization with effective clinical decision-making. Citation Format: Pier Paolo Claudio, Jagan Valluri. Functional precision oncology: Predicting therapeutic response using live patient tumor models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr SY36-03.
Claudio et al. (Fri,) studied this question.