The NCT Personalized Oncology Program (NCT POP) seeks to achieve rapid clinical implementation of in-depth molecular analysis for all patients at NCT, ideally by 2015. The program organizes the workflow of data acquisition and interpretation to capture large-scale molecular information on individual cancers for mechanism-based treatment development.
By funding hypothesis-driven, high-throughput clinical studies, DKFZ-HIPO and NCT POP enable clinical investigators to rapidly implement novel molecular analyses in the patient context. Consequently, patient stratification seeks to match patients’ molecular profiles with available treatments.
The clinical implementation of molecular diagnostics at NCT is organized in the center-wide umbrella protocol NCT MASTER, which provides the complete workflow (managed by the DKH-funded NCT POP coordinator) for high-throughput diagnostics and comprises all steps from bedside to bench and back. Steps include: quality-assured sample acquisition by surgery or biopsy; histopathological evaluation; quality-managed analyte extraction; NGS and other “omics” technologies; bioinformatic processing according to standardized pipelines; GLP-certified validation of variants; and and clinical evaluation by a molecular tumor board of translational oncologists, bioinformaticians, molecular biologists, and pathologists. DKFZ-HIPO, the DKFZ Sequencing Core Facility, and bioinformatics groups on campus streamline data acquisition and analysis in close collaboration with NCT POP. Currently, more than 48 projects focusing on gastrointestinal tumors, brain tumors, hematologic malignancies, lung cancer, soft-tissue sarcoma, and other entities, provide high-resolution genetic information on more than 800 cases.
The genomics infrastructure of DKFZ/NCT has contributed 250 prostate and 600 childhood brain tumor whole genomes to the International Genome Sequencing Consortium (ICGC). The groups of P. Lichter, S. Pfister and R. Eils have discovered important characteristics of chromothripsis (Rausch Cell 2012), characterized the genomic landscapes of medulloblastoma (Jones Nature 2012) and pilocytic astrocytoma (Jones Nat Genet 2013).
Prostate cancer studies demonstrated that early-onset disease is driven by androgen-dependent fusion genes (Weischenfeldt Cancer Cell 2013) and novel driver genes in Burkitt lymphoma were characterized (Richter Nat Genet 2012). The von Kalle and Schmidt group has used mutational analysis to study the genetic effects of gene therapy (Stein Nat Med 2010; Botzug N Engl J Med 2012; Kaeppel Nat Med 2013).
As part of the rapid clinical implementation process through NCT MASTER, the NCT POP “Individual Patient” program (S. Fröhling, H. Glimm) enrolls patients with particularly challenging advanced cancers and surprise responders to undergo cancer genome sequencing. The current workflow leverages the expertise of multiple NCT/HUMS departments to identify rational treatment options, achieving a 6-8 week turnaround time from sample acquisition to clinical evaluation. Cases are discussed in a dedicated molecular tumor board led by a DKH-funded physician-scientist. Approximately 30 percent of patients analyzed showed alterations amenable to targeted therapies (Dietrich N Engl J Med 2012).
Strategic developments within NCT POP include a Professorship for Applied Functional Genomics and a Professorship for Applied Bioinformatics, translating high-throughput molecular data into innovative, individualized therapies. The NCT medical ethicist (E. Winkler, partially DKH-funded) leads the EURAT Working Group (Ethical and Legal Aspects of Whole-Genome Sequencing), which analyzes and advises on the ethical, legal, and economic dimensions of genome sequencing in clinical applications. The NCT DataThereHouse will aggregate data from multiple research projects and clinical sources into a central database for clinical decision making and research use.
- Provide optimal molecular diagnostics for all NCT patients, performing exome and transcriptome sequencing in all children with relapsed malignancies (INFORM; Fig. 3) and all adult patients under 50 with advanced-stage cancers in 2014 (NCT MASTER 2014).
- By 2015, provide all relevant information on the molecular status of every tumor as a stratification tool for each individual NCT patient at major treatment decision milestones.
- Develop NCT GUIDE, a bioinformatics and systems medicine extension of the NCT POP workflow that incorporates bioinformatic modeling and experimental validation and supports clinical decision making through a physician interface for interpretation of molecular data.
- Development of a Program for Anti-Cancer Targets (PACT) to fund, support, and coordinate access to novel anti-cancer agents for their implementation in IITs.