Advances in precision oncology research with personalized drug testing: zPDo-X platform to target resistance in advanced Breast Tumors

Abstract

Breast cancers (BC) currently have a cure rate of more than 80%, but remain the most frequent and deadly neoplasm in the female population, with more than 2 million cases and 685,000 deaths occurring globally each year. Its treatment includes both locoregional and systemic therapy approaches. With classification refinement, systemic strategies differ according to molecular subtype, including endocrine therapy for hormone receptor-positive disease and anti-HER2 therapy for HER2-positive disease. Multigene panels have guided the choice of additional therapies based on individual genetics, predicting clinical outcome and treatment responses. Despite stratification, less than half of patients are eligible for treatments guided by genetic information, for most antitumor agents there are no predictive markers of response, and few treatment options are available in the metastatic setting. The consequence of this is seen in the rapid progression of advanced cases. Thus, additional predictive models are critical for the advancement of personalized medicine and the improvement of patient survival. In this sense, organoid and xenotransplantation technologies are complementary to molecular and genetic testing, presenting themselves as potential biomarkers of response and of relatively low cost. To explore this hypothesis we have designed an integrated preclinical research platform, named zPDo-x, based on the sequential use of patient-derived organoids (PDO) and xenotransplants in zebrafish embryos (zPDX). The basic experimental setup proposed consists of obtaining the BC sample directly from biopsy, followed by cultivation and expansion of this material as PDOs, then undergoing two sequential, customized screenings of resistance/sensitivity tests to various antitumor compounds under special in vitro conditions, including the clinician's choice chemotherapy. Only at a later stage will the clinical potential of zPDo-x be assessed: resistant PDOs will be dissociated and inoculated into zPDXs, promoting a more complex model for analyzing invasive and metastatic behavior and assessing the degree of toxicity in vivo. These animals will be treated with the clinician's therapy of choice and compared to the best therapeutic alternative(s) identified in screenings. The complete experimental design of the zPDo-X platform is shown in Figure above. We believe that the zPDo-x platform will provide preclinical information about the susceptibility of each biopsy to different therapies and guide the choice of personalized treatments for each patient. (AU)