Dimitrios H Roukos

Spatiotemporal diversification of intrapatient genomic clones and early drug development concepts realize the roadmap of precision cancer medicine

The unmet clinical needs of high relapse and cancer-related death rates are reflected by the poor understanding of the genome-wide mutational landscape and molecular mechanisms orchestrating therapeutic resistance. Emerging potential solutions to this challenge include the exploration of cancer genome dynamic evolution in time and space. Breakthrough next-generation sequencing (NGS) applications including multiregional NGS for intratumor heterogeneity identification, repeated cell-free DNA/circulating tumor DNA-NGS for detecting circulating genomic subclones and their comparison to reveal intrapatient heterogeneity (IPH) could identify the dynamic emergence of resistant subclones in the neoadjuvant, adjuvant and metastatic setting. Based on genome-phenotype map, and potential promising findings, rigorous evaluation of IPH spatiotemporal evolution and early drug development concepts in innovative clinical trials could dramatically speed up the translational process to achieve clinical precision oncology.

Crossroad between linear and nonlinear transcription concepts in the discovery of next-generation sequencing systems-based anticancer therapies.

The unprecedented potential of standard and new next-generation sequencing applications and methods to explore cancer genome evolution and tumor heterogeneity as well as transcription networks in time and space shapes the development of next-generation therapeutics. However, biomedical and pharmaceutical research for overcoming heterogeneity-based therapeutic resistance is at an important crossroads. Focus on linear transcription-based drug development targeting dynamics of simple intrapatient structured genome diversity represents a realistic medium-term goal. By contrast, the discovery of nonlinear transcription drugs for targeting structural and functional genome and transcriptome heterogeneity represents a long-term rational strategy. This review compares effectiveness, challenges and expectations between linear and nonlinear drugs targeting simple intrapatient variation and aberrant transcriptional biocircuits, respectively.

Discovering novel valid biomarkers and drugs in patient-centric genomic trials: the new epoch of precision surgical oncology

Despite standardization of multimodal treatment and approval of several targeted drugs for resectable, non-metastatic cancer (M0 patients), intrinsic and acquired resistance and relapse rates remain high, even in early-stage aggressive tumors. Genome analysis could overcome these unmet needs. Our comprehensive review underlines the controversy on stable or spatiotemporally evolving clones as well as promising yet inconclusive data on genome-based biomarkers and drug development. We propose clinicogenomic trials in M0 patients for the validation of intratumor heterogeneity (ITH), circulating genomic subclones (cGSs) and intra-patient genomic heterogeneity (IPGH) as biomarkers and simultaneous discovery of novel oncotargets. This evidence-based strategy highlights the coming of precision surgical oncology with a future perspective of understanding and disrupting deregulated transcriptional networks.

Novel translational therapeutic strategy by sequencing primary liver cancer genomes

Department of Surgery, Ioannina University Hospital, Ioannina, Greece Centre for Biosystems & Genome Network Medicine, Ioannina University, Ioannina, Greece Department of Surgery, ‘G. Hatzikosta’ General Hospital, Ioannina, Greece Department of Plastic Surgery, Ioannina University Hospital, Ioannina, Greece Unit of Systems Biology, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece *Author for correspondence: Tel.: +302651005572; droukos@uoi.gr

Primary liver cancer genome sequencing: translational implications and challenges

ABSTRACT Introduction: The prognosis of primary liver cancer (PLC) remains poor and is explained by the slow progress in understanding the molecular pathways driving tumorigenesis, therapeutic resistance and relapse. For early PLCs, complete surgical resection is the only effective treatment, with sorafenib and, more recently, regorafenib prolonging overall survival by a few months. Areas covered: Application of next-generation sequencing (NGS), including targeted NGS (tNGS), whole-exome sequencing (WES), whole-genome sequencing (WGS) and RNA sequencing (RNAseq), on clinical samples from patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) could aid in comprehending tumorigenesis, genetic and genomic heterogeneity, as well as developing molecular classifications for specialized targeted therapy. Expert commentary: Despite the many overenthusiastic original and opinion reports, we have critically reviewed available NGS studies, with focus on the challenges to achieve clinical implications. Based on the recommendations for valid identification of clinically crucial genomic alterations (GAs) by NGS, we propose NGS integration into appropriately designed clinical trials. Furthermore, valid detection of genomic heterogeneity enables the conduction of clinical trials investigating the efficacy both of GAs as prognostic and predictive tools, as well as the discovery of novel oncotargets, on the basis of an early drug development strategy.