Abstract 1598: Extensive use of fresh patient-derived tumor samples for drug discovery and drug positioning in oncology

Abstract

Abstract Most preclinical investigations in Oncology research are performed using permanent cancer cell lines that have been kept in continuous in vitro passages since decades. These plastic-cultured cells became very different from their original tumors since accumulated genetic abnormalities and multiple selections of subclones occurred over time. The use of fresh patient-derived tumor samples for ex vivo assays and for establishment of new relevant in vivo tumor models allows investigating the anti-tumor activity of new therapies directly linked with clinical reality. In this respect, Oncodesign has developed a large and international network of clinical centers for the collection of a large number of fresh patient-derived tumor biopsies from all cancer pathologies and from healthy tissues. The collection of these samples is done under ethically approved master agreements and with the signed consent of each patient. The patient's clinical history, the serology results (HIV, HBV and HCV) and tissue banking are centralized in our internal approved biological resource center. Examples of ex vivo assays will be presented based on patient-derived acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia and other hemopathologies using chromium release and Annexin V FACS assays. These studies aimed to demonstrate the CDC, ADCC and apoptosis induction of new therapeutics antibodies whereby approved antibodies such as rituximab and alemtuzumab were used as positive controls. Similarly, these fresh patient-derived models were used to study the direct dose-response effect of new chemotherapeutic agents through apoptosis induction (bortezomib used as positive control). The freshly collected tumors were also used to establish new in vivo tumor models in different strains of mice and rats. The full characterization of the genetic patterns of the xenograft derived tumors was compared with the original collected human tumors and with the clinical data of the patient. A panel of “standard of care” compounds was tested in these new tumor models for pharmacological characterization. The expansion of such tumors at early passages in mice was used to implement a reproducible ex vivo 3D assay. The assay was developed to investigate the potential anti-tumor activity of conventional and targeted therapies, and allows sufficient throughput for use during drug discovery lead optimisation. Ex vivo drug effects were then correlated with in vivo results using the same panel of tumorgrafts. The use of fresh patient-derived tumors in drug discovery and early preclinical development of new therapies aimed at corroborating results with clinical reality. Altogether, these processes from the clinical tumor collection to the in vivo drug efficacy study through ex vivo assays should help the preclinical drug selection, development and clinical positioning as well as companion biomarker identification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1598. doi:10.1158/1538-7445.AM2011-1598