Dados do Resumo

Título

Functional Precision Oncology using patient-derived tumoroids to predict therapy response in gastrointestinal tumors

Introdução

Cytotoxic chemotherapy offers variable tumor objective responses in patients with metastatic tumors, ranging from 5 to 40% in most cases. The lack of accurate predictive factors in this setting limits treatment effectiveness, contributing to shorter patient survival, unwanted toxicity, and waste of resources. Thus, more precise approaches are necessary to identify effective treatments for cancer patients.

Objetivo

To establish a functional testing platform based on gastrointestinal (GI) patient-derived tumoroids (PDT) to assess their vulnerability to stand-of-care antineoplastic drugs (5-FU, oxaliplatin, irinotecan, temozolomide, docetaxel and cisplatin). We investigated correlations between PDT responses and patients' tumor responses.

Métodos

A prospective and observational clinical study (approved by the A.C. Camargo Cancer Center Ethics Committee CAAE 61026022.2.0000.5432) involved collecting fresh biopsies from metastatic lesions of patients with adenocarcinomas of the colon, rectum, pancreas, stomach and neuroendocrine pancreatic tumors. The tissue was disaggregated, and isolated cells were resuspended in Matrigel®/Geltrex® and plated in culture. The formed PDTs were dissociated and treated with increasing concentrations of antineoplastic drugs protocolized for GI tumor treatments. Cell viability was assessed with CellTiter -Glo 3D kit. The response of tumoroids to treatment was measured by the inhibition of growth rate, and a response score was defined for each PDT. The correlation between PDT treatment responses and patients' tumor responses to therapy was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), categorizing outcomes as a partial response, stable disease or disease progression.

Resultados

We established PDTs from metastatic lesions from all the tumor types. Immunohistochemistry and immunofluorescence assays demonstrated that tumoroids expressed the same biomarkers and showed a cell morphology similar to that of the original tumor. Treatment with six antineoplastic agents was standardized and dose response curves showed differences across PDTs indicating their heterogeneity in therapy responses. The biological replicates were highly reproducible (Spearman correlation 0.87 to 0.95, p< 10-6). We compared the tumoroid treatment response scores of six PDTs (three colorectal, one pancreatic, one gastric adenocarcinoma, and one neuroendocrine pancreatic tumor) to the patient's objective response to treatment (partial response and disease progression). Our data showed that PDTs presented a sensitivity of 83% to predict therapy response in patients’ tumors.

Conclusões

We have established the methodology for tumoroids production from GI tumors with a sensitivity of 83% to predict tumor response to standard-of-care cancer-directed therapies. Our findings need validation in a larger cohort, which is underway at our center.

Financiador do resumo

Supported by FAPESP-PIPE 1 and 2 (2022/10646-4, 2023/1285-3), MKM Venture Biotech and INCT Model3D (CNPq/CAPES).

Palavras Chave

Patient-derived-tumoroids - PDT; prediction of treatment response; chemotherapy