Tumor organoids for precision functional medicine: the best therapeutic decision

Abstract

Cancer treatment is a major challenge in the world and, in Brazil, as in other middle-income countries (according to the World Bank), incidence rates are expected to increase by 68% by 2040. The estimate of direct costs for the treatment of cancer in Brazil (Supplementary Health and SUS) in 2020 was R$19 billion, of which R$7.8 billion were related to chemotherapy treatments. About 70% of patients with advanced tumors are candidates for chemotherapy, and about 60% of these patients do not respond to the initial treatment, which represents the loss of lifetime, low quality of life, and a significant waste of resources. Despite expectations regarding genetic testing, only 8.3% of patients with metastatic disease are candidates for targeted therapies, considering all tumors combined, and only 4.3% of them benefit from treatment. Thus, the isolated search for genetic markers does not allow for predicting the tumor response to different drugs. Therefore, functional approaches are needed to evaluate live tumor cells for their response to therapy. In this condition, tumor vulnerabilities can be tested considering the complexity of each tumor individually as a genuinely functional precision medicine for cancer. Patient-derived organoids (PDO) are among the models developed for this approach. PDOs are self-renewing sources of morphological and molecular complexities similar to the original tumor tissue, where individualized treatments can be tested to predict sensitivity or resistance to antitumor agents. This proposal aims to standardize the protocol for producing PDOs from gastrointestinal tumors and assess, in an observational study, its predictive ability to identify patients who respond or not to protocol treatments according to established guidelines. These organoids will be produced and cultured ex-vivo from patient biopsies and treated with chemotherapeutic or target drugs approved for treating each type of tumor. The response to ex-vivo treatment will be compared to the patient's response to the treatment chosen by the oncologist. It is expected to find 80% sensitivity and specificity in the methodology. The technology described in scientific articles will be improved, validated, and scaled at the Startup to be offered on the market. The validation of this approach has a great appeal in the oncology area. It will allow the Startup to establish its presence in the market, scale its products and develop strategies for other tumors. It is expected that these tests will aid the oncologists in therapeutic decisions, impacting the choice of the best treatment with less toxicity for the patient, besides the economy of resources in the health services. (AU)