The application of tumoroids for therapy response prediction in functional precision oncology

Abstract

Cancer treatment is a global challenge, and the incidence rates in Brazil are expected to increase by 68% by 2040. The best estimate of cancer treatment costs in Brazil (SUS and supplementary health) published in 2018 showed that systemic treatment (chemotherapy) was around R$8 billion. The high resistance rate to standard-of-care medications is a significant limitation in treating advanced or metastatic cancer. About 70% of patients with progressive disease are candidates for chemotherapy, and 50-60% have little or no response to treatment. As there are no predictive markers of response to chemotherapy, there is a high risk of the treatment being ineffective. On the other hand, drugs developed for specific genomic alterations (targeted therapy) benefit a relatively small number of patients, even those who present specific markers for the drug. That indicates that the complexity of molecular and morphological changes in tumor cells is beyond genomic testing and needs to be addressed functionally. In this context, precision functional oncology emerges, where the vulnerability of tumor cells to antitumor agents is tested ex vivo to predict the most effective therapy in a precise and personalized way. The technology that uses patient-derived tumoroids is the one that best represents the molecular complexities of tumors, with predictive power of response to chemotherapies and targeted therapies. However, the technology still requires standardization at an analytical and clinical level in prospective studies. Intending to make a platform for functional tests that predict therapeutic responses in cancer patients available on the market, we developed a PIPE-1 proposal. In this first phase, we standardize the acquisition of gastrointestinal tumoroids, and their histological validation and establish ex-vivo treatments with standard-of-care chemotherapy agents. In this PIPE-2 proposal, we intend to finalize personalized treatment protocols with the combination of therapies, automate all stages of the functional platform, generate a data analysis algorithm, and scale the number of patients to reach a sample size that allows validating the correlation between the response of tumoroids and the patient's response to chemotherapy treatment. At the end of this phase 2, we intend to place functional tests on the market for at least two tumor types, the first to be validated in Brazilian patients, which will allow their integration into therapeutic decisions, impacting better treatment and lower toxicity for the patient and lower costs for the system of health. (AU)