P10.15.B Next generation drug screening platform: generation of patient-derived cells forex vivo drug response studies of gliomas
Authors: El-Heliebi A , Prietl B , Mahdy-Ali K , Urbanic Purkart T , Gerlitz L , Skofler C , Stanzer S , Franz J , Harbusch N , Madl T , Widhalm G , Rössler K , Tomberger M , Mattersdorfer K , Kroneis T , Oberhuber M , Pieber T R 
Published: September 2022

Abstract

Background
Precision oncology aims to provide individual treatment options for each patient. In this regard, ex vivo drug screening systems have the potential to improve clinical outcomes. Traditionally, cancer drugs are tested on long-term cultured cancer cell line models, but cell lines cannot represent an individual patient from a clinic and are biologically too distinct to be informative for drug screening purposes. Drug screening systems of tumor cells usually rely on viability assays and correlations to genomic alterations. Beside genomic alterations, the cellular metabolism is significantly altered during tumor growth, tumor cell proliferation and tumor cell resistance development. Here we aim to establish a drug screening platform using tumor cells derived directly from the individual patient glial tumor, create patient derived tumor cells (PDCs) and combine the outcomes from standardized viability- and genetic-assays with a new developed metabolomics platform.

Material and Methods
Fresh native tissue from both low- and high-grade glioma are collected. Tumor tissue is used for NMR-based metabolomic analyses and targeted sequencing based genomic analyses as well as PDC isolation using mechanical and enzymatic tissue dissociation. To preserve the original tumor similarity, tissue is short term cultured for two weeks, and PDCs are seeded and treated with a panel of clinical- and preclinical drugs followed by viability assessment, sequencing and metabolomic profiling.

Results
Culturing of PDCs is successful in ≥85% of patient cases, provided that at least 2 g of tumor are available. The automatized high throughput ex vivo drug response helps to identify potential drug candidates which might become relevant for therapeutic approaches in future. Further, it is possible to distinguish between IDH1-wild type and IDH1-mutant glial tumors based on the metabolomic profile, which is confirmed by immunohistochemical staining and molecular analysis of IDH1 R132H-mutation. Strong metabolomic variations have been identified, including GABA, lactate, and myo-inositol levels between tumor and healthy tissue. Data retrieved by the systematic evaluation is retrospectively associated with the clinical course of the patients.

Conclusion
Entangling drug screening and genetic assays with metabolomic profiling of glial tumors enriches the information about cellular drug response and paves the way for future clinical studies and better understanding of underlying drug resistance mechanisms in gliomas.

Disclosure
Funding: K1 COMET Competence Centre CBmed, funded by the Federal Ministry of Transport, Innovation and Technology; the Federal Ministry of Science, Research and Economy, Land Steiermark (Dep. 12, Business and Innovation), the Styrian Business Promotion Agency (SFG), and the Vienna Business Agency. COMET is executed by the Austrian Research Promotion Agency (FFG).