The patient-derived xenograft as a platform to identify cancer biomarkers in circulating exosomes in renal cell carcinoma

Abstract

Among the new approaches that have been established for precision cancer therapy and drug development, Patient-Clerked Xenografis (PDX) have emerged as one of the most promising. PDXs are preclinical models that faithfully represent the individuality of human cancer, by grafting fresh human tumor is severely immunodeficient mice, which allows for higher tumor implantation rates and growth. PDXs can be interrogated for different treatment strategies based on the individualized gene signature of the human tumor, and the results can inform clinically relevant treatment strategies for the patient. It is hypothesized that PDX models can he used to detect circulating biomarkers in exosomes, cell-derived structures that represent a watershed for cancer biology understanding and for tumor burden monitoring. It is anticipated that the results of PDX-EV studies will be directly translatable into human applications for biomarker and drug development. This proposal seeks to establish a collaborative research project between the UC Davis Comprehensive Cancer Center (UCDCCC) in Sacramento. California and the AC Camargo Cancer Center, in Sao Paulo, Brazil In which a Renal Cell Carcinoma (RCC) PDX resource will be jointly developed. The techniques on stablishing PDX models will be introduced to the AC Camargo Cancer Center and expertise on exome, research will be introduced to the UC Davis Comprehensive Cancer Center. RCC was mimed for this initiative since: 1) biomarkers for prognosis, disease recurrence and response to treatment for RCC is presently unknown; 2) this tumor type is of major interest for both institutions, with a suitable patent base and availability of tumor specimens for molecular studies; 3) AC Camargo a leading The Latin America Renal Cancer Group (LARCG) which currently has 6.000 annotated cases of RCC, including clinical date archival formalin-fixed paraffin embedded tumor tissue samples, and tissue microarrays and 4) UCDCCC has an established clinical and scientific program in Genitourinary Cancer, with a developing focus on RCC preclinical models and drug development, and world-class faculty devoted to RCC research. Already, UCDCCC and AC Camargo investigators have initiated working relationships that will ensure the success of this effort. RCC has been estimated to account for more than 140,000 deaths per year worldwide. Despite the increasing availability of radiographic testing, 25% of patients are diagnosed with advanced disease (local invasion and/or metastasis). Patients with metastatic disease are essentially incurable. Furthermore, up to 30% of patents with localized disease who underwent complete kidney resection will relapse. Patients with metastatic disease receive chemotherapy or immunomodulatory drugs, but present poor outcome. Thus, this proposal aims to stablish and promote an international scientific exchange between UCDCCC and AC Camargo centered on the development of a RCC PDX resource and with the characterization of EVs from PDX mice in order to identify novel biomarkers for RCC monitoring and therapeutic targeting. (AU)