Elsevier

Drug Discovery Today

Volume 23, Issue 11, November 2018, Pages 1848-1872
Drug Discovery Today

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

https://doi.org/10.1016/j.drudis.2018.07.008Get rights and content

Highlights

  • Genomic characterization is crucial to assess the static vs dynamic nature of clones.

  • The minor pre-existent stable resistant clones require aggressive primary therapy.

  • Dynamic clonal evolution, ITH and cGSs can be identified with NGS systems.

  • Trials on dynamic ITH, cGSs and IPGH could discover new biomarkers and oncotargets.

  • These trials enable individualized precise prediction and optimized drug combinations.

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.

Introduction

Innovation in next-generation sequencing (NGS) technologies and methods exploring regulatory networks has revolutionized genome and life sciences 1, 2, 3, 4. Particularly impressive progress has been accomplished in cancer research, with the implementation of NGS, in conjunction with multiregional sampling (MR-NGS) [5], circulating cell-free DNA (cfDNA-NGS) 6, 7 and single-cell genome sequencing [8], shaping the basis to shift from traditional medicine as an inexact science [9] to precision cancer medicine 10, 11. Translating major basic research discoveries on inter- and intra-patient comprehensive structural and functional heterogeneity holds rational promises to discover robust predictive biomarkers and highly effective novel drugs 11, 12, 13, 14, 15, 16.

The establishment of complete tumor resection (R0) as the cornerstone of therapeutic modalities in the multidisciplinary treatment of patients with solid tumors, including chemotherapy and radiotherapy, has improved survival rates over the past decades [17]. Nevertheless, progress in the improvement of recurrence-free survival and overall survival (OS) rates has recently been slow 17, 18, 19, whereas great expectations in the development of novel biomarkers and targeted drugs are limited by the temporary efficacy and scarce approval of targeted agents in the adjuvant and neoadjuvant settings [20]. Moreover, multiple Phase III randomized controlled trials (RCTs) in the fields of robust biomarkers and targeted drugs have failed to provide high-quality evidence of improved patient survival 21, 22.

The validity, advances and continuously lowering costs of NGS, coupled with appropriate methodology and recommendations 23, 24, 25, have led to an explosion of NGS studies, including targeted NGS (tNGS), whole-exome sequencing (WES) and whole-genome sequencing (WGS), in three directions. First, static, single-biopsy genome analyses have led to the valid identification of novel cancer driver genes, molecular classifications and druggable mutations 12, 26, 27. Moreover, static cfDNA-NGS paves new paths to noninvasive diagnosis and early detection [6]. Second, small but highly promising breakthrough studies have provided exciting new data on spatiotemporal intratumor heterogeneity (ITH), either with MR-NGS [5] or single-cell NGS analysis [28], and dynamic emergence of circulating genomic subclones (cGSs), detected by serial cfDNA-NGS [7], raising rational expectations to overcome the fatal hallmarks of cancer including progression, heterogeneity, therapeutic resistance, metastasis and relapse 11, 29, 30. These advances enable a shift from established inter-patient heterogeneity [24] to comprehensive, dynamic intra-patient genetic/genomic heterogeneity (IPGH) [11]. Third, beyond intra-individual structural mutational landscapes, identification of functional, noncoding, regulatory alterations enhances our understanding of nonlinear transcriptional network controllability 4, 31, representing the basis for next-generation drugs disrupting deregulated transcriptional biocircuits [14].

This review discusses the potential and challenges of static and dynamic genome analysis with NGS systems (MR-NGS, cfDNA-NGS, single-cell genome NGS) to overcome the aforementioned clinical unmet needs (see Fig. S1 in supplementary material online). Exploiting valid published data, we describe two strategic targets. With a realistic medium-term perspective, we propose a novel design of patient-centric genome trials evaluating the potential to translate personalized structural tumoral and circulating mutational landscapes into clinical precision surgical oncology. In the longer-term, we highlight the fundamental advantages of intraindividual comprehensive structural and functional heterogeneity, essential for the future pharmaceutical controllability of deregulated transcriptional networks.

Section snippets

Modern surgical oncology

Pre-treatment diagnosis and tumor TNM staging in current surgical oncology, including histological confirmation of malignancy and imaging approaches (EUS, CT, MRI), is essential for distinguishing patients without (M0) from those with distant (M1) metastasis 32, 33. Further distinction of M0 patients to those with potentially feasible complete tumor resection (R0), either with or without neoadjuvant therapy (NAT), and those with either nonresectable or residual locoregional disease bares

Cancer genome analysis: novel translational discoveries

The successful integration of NGS for the first time, coupled with computational systems-biology methods, into the modENCODE [53] and ENCODE [2] projects exploring genome functionality has revolutionized biomedical research. Particularly in cancer, two large-scale international programs: The Cancer Genome Atlas [54] and the International Cancer Genome Consortium [55], aim toward understanding cancer genome heterogeneity and developing biomarkers, druggable mutations and targeted drugs, with the

Future perspectives

The long-term vision of personalized precision in early diagnosis, prognosis, prediction of therapeutic response, comprehensive dynamic therapeutic targeting of key mutations and patient monitoring is becoming a realistic perspective. Translational genome research concentrates on how to overcome these unmet needs in M0 patients, toward five strategic goals. First, to increase rates of early-stage diagnosis, including early pathologic and genomic diagnosis, and R0 resection through novel

Concluding remarks

Cancer-genome-based translational implications on the development of diagnostic, prognostic and predictive tools, as well as a personalized early drug development strategy, could revolutionize surgical oncology in several ways. First, increasing R0 resection rates through early diagnosis with blood tests implementing promising gene panels and protein biomarkers. Second, developing individualized decision making on AT, NAT or POT by applying dynamic ITH and cGS detection as predictive

Conflicts of interest

The authors report no conflicts of interest.

Dimitrios H. Roukos Dimitrios H. Roukos, MD, PhD, is Professor of Surgery – Precision Cancer Medicine and Founding Director of the Centre for Biosystems and Genome Network Medicine at Ioannina University, School of Medicine. Assessing the unmet needs of traditional linear single-gene research, he has shifted to intrapatient comprehensive coding and noncoding genomic and regulatory network heterogeneity in time and space toward the achievement of precision cancer medicine. He has published >240

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    Dimitrios H. Roukos Dimitrios H. Roukos, MD, PhD, is Professor of Surgery – Precision Cancer Medicine and Founding Director of the Centre for Biosystems and Genome Network Medicine at Ioannina University, School of Medicine. Assessing the unmet needs of traditional linear single-gene research, he has shifted to intrapatient comprehensive coding and noncoding genomic and regulatory network heterogeneity in time and space toward the achievement of precision cancer medicine. He has published >240 PubMed papers, 32 on precision medicine and oncology with >8800 citations (h-index: 73, Scopus). He acts as a reviewer for many high impact journals and in innovative research projects (EU 2011, 2012, 2018). He is a member of the editorial board for 25 international journals and the organizing committees for >20 international conferences.

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