Background

CD Laboratories are established at universities and non-university research institutions. The CD model enables cooperations between science and business that are meaningful, useful and productive both for the participating partners and for society. The CDL Liquid Biopsies for early Detection of Cancer” was established in October 2017 and will run until 2024 with an overall budget of more than 2 Mio EUR. The lab is organized into two Modules with two industry partners Freenome and PreAnalytiX.

Scope

The utility of cell-free circulating tumor DNA (ctDNA) as a reliable biomarker for the early detection of cancer recurrence, for predicting tumor burden and treatment response, as well as for identifying resistance mechanisms and the emergence of novel actionable targets has been proven in numerous studies.

Moreover, the assessment of ctDNA levels can be used as a prognostic marker and it has been shown that patients having higher ctDNA levels at certain time points had significantly shorter progression-free survival (PFS) and/or overall survival (OS).

In contrast to applications with bearing on established and late stage disease, there is a paucity of valid studies published that prove the applicability of ctDNA as a diagnostic biomarker enabling early detection of cancer. Nevertheless, the early detection of cancer is a desirable objective as it greatly increases the chances for successful treatment.

The biotech company Freenome aims to develop a multivalent diagnostic test based on ctDNA for the early detection of cancer. However, lack of knowledge about the nature and biology of ctDNA prevents a swift application of the intended test. And this is where the CD laboratory comes into play as the main objective of the existing CD laboratory “Liquid Biopsies for early Detection of Cancer” is to further elucidate ctDNA biology, to improve existing analysis methods and to develop advanced bioinformatics tools that enable detection of cancer at its earliest stage. The pairing of clinical and genomic data by the use of sophisticated bioinformatics approaches and databases, will eventually improve the rate of early diagnosis for cancer patients.

In general, each liquid biopsy specimen is a challenging analyte and distinct and complementary types of information can be retrieved from the various types of constituents. Pre-analytical recommendations for blood processing for ctDNA analysis have already been generally accepted; however, there are currently no systematic data and guidelines either for the analysis of other circulating components from blood or for the analysis of cfDNA from other body fluids.

To address this important issue, we teamed up with the Institute of Pathology at the Medical University of Graz (MUG) and the company PreAnalytiX, in order to develop sample stabilization solutions for biospecimen from minimally-invasive accessible tissues and body fluids.

Organisation

Module 1 focuses on the data analytics of cfDNA in blood in order to elucidate the biology and identify potential further relevant parameters beyond mutation and copy number alterations, while Module 2 takes a step towards reliable data generation and assesses pre-analytical requirements for the analysis of liquid biopsy constituents.

In particular parameters such as fragment sizes, methylation pattern, nucleosome occupancy and expression profiles - which are central subjects of investigation in Module 1 - are prone to changes by pre-analytical factors such as time and temperature of sample processing, sample stabilization, etc. However, to establish clinically relevant biomarkers from liquid biopsies it is of utmost importance to assess the true biological status rather than performing research on artefacts introduced by sample treatment outside of the body.

Therefore, as soon as robust and reproducible pre-analytical workflows are established, tasks from Module 1 will be expanded to cfDNA from other body fluids. Moreover, we will investigate whether combination strategies (i.e. combined analyses cfDNA and exosome-derived nucleic acids or combined analysis of cfDNA from multiple body fluids) might enhance the power of liquid biopsy analyses.

References

• Smith, CG; Moser, T; Mouliere, F; Field-Rayner, J; Eldridge, M; Riediger, AL; Chandrananda, D; Heider, K; Wan, JCM; Warren, AY; Morris, J; Hudecova, I; Cooper, WN; Mitchell, TJ; Gale, D; Ruiz-Valdepenas, A; Klatte, T; Ursprung, S; Sala, E; Riddick, ACP; Aho, TF; Armitage, JN; Perakis, S; Pichler, M; Seles, M; Wcislo, G; Welsh, SJ; Matakidou, A; Eisen, T; Massie, CE; Rosenfeld, N; Heitzer, E; Stewart, GD. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors. Genome Med. 2020; 12(1): 23-23
• Heitzer, E; Haque, IS; Roberts, CES; Speicher, MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. NAT REV GENET. 2019; 20(2): 71-88.
• Heitzer, E; Speicher, MR. One size does not fit all: Size-based plasma DNA diagnostics. SCI TRANSL MED. 2018; 10(466): eaav3873
• Moser; T; Ulz; P; Zhou; Q; Perakis; S; Geigl; JB; Speicher; MR; Heitzer; E. Single-Stranded DNA Library Preparation Does Not Preferentially Enrich Circulating Tumor DNA. Clin Chem. 2017; 63(10):1656-1659
• Ulz, P; Perakis, S; Zhou, Q; Moser, T; Belic, J; Lazzeri, I; Wölfler, A; Zebisch, A; Gerger, A; Pristauz, G; Petru, E; White, B; Roberts, CES; John, JS; Schimek, MG; Geigl, JB; Bauernhofer, T; Sill, H; Bock, C; Heitzer, E; Speicher, MR. Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection. Nat Commun. 2019; 10(1): 4666-4666
• Lampignano, R; Neumann, MHD; Weber, S; Kloten, V; Herdean, A; Voss, T; Groelz, D; Babayan, A; Tibbesma, M; Schlumpberger, M; Chemi, F; Rothwell, DG; Wikman, H; Galizzi, J-P; Bergheim, IR; Russnes, H; Mussolin, B; Bonin, S; Voight, C; Musa, H; Pinzani, P; Lianidou, E; Brady, G; Speicher, MR; Pantel, K; Betsou, F, Schuuring, E; Kubista, M; Ammerlaan, W; Sprenger-Haussels, M; Schlange, T; Heitzer, E. Multicenter Evaluation of Circulating Cell-Free DNA Extraction and Downstream Analyses for the Development of Standardized (Pre)analytical Work Flows The Open Clinical Chemistry Journal. 2020; 66(1): 149-160.
• Weber, S; Spiegl, B; Perakis, SO; Ulz, CM; Abuja, PM; Kashofer, K; Leest, PV; Azpurua, MA; Tamminga, M; Brudzewsky, D; Rothwell, DG; Mohan, S; Sartori, A; Lampignano, R; Konigshofer, Y; Sprenger-Haussels, M; Wikman, H; Bergheim, IR; Kloten, V; Schuuring, E; Speicher, MR; Heitzer E. Technical Evaluation of Commercial Mutation Analysis Platforms and Reference Materials for Liquid Biopsy Profiling. Cancers (Basel). 2020 Jun 16;12(6):E1588.

Funding

• Austrian Science Fund (FWF) (grants P20338; P23284; and W 1226-B18)
• DKplus Metabolic and Cardiovascular Disease)
• Oesterreichische Nationalbank (project 15093)

Status

Completed