Precision Oncology Beyond Genomics: The Future Is Here-It Is Just Not Evenly Distributed

Abstract

Cancer is a multifactorial disease with increasing incidence. There are more than 100 different cancer types, defined by location, cell of origin, and genomic alterations that influence oncogenesis and therapeutic response. This heterogeneity between tumors of different patients and also the heterogeneity within the same patient's tumor pose an enormous challenge to cancer treatment. In this review, we explore tumor heterogeneity on the longitudinal and the latitudinal axis, reviewing current and future approaches to study this heterogeneity and their potential to support oncologists in tailoring a patient's treatment regimen. We highlight how the ideal of precision oncology is reaching far beyond the knowledge of genetic variants to inform clinical practice and discuss the technologies and strategies already available to improve our understanding and management of heterogeneity in cancer treatment. We will focus on integrating multi-omics technologies with suitable in vitro models and their proficiency in mimicking endogenous tumor heterogeneity.

Keywords: cancer models; intra-tumor heterogeneity; multi-omics technology; patient-derived organoids; personalized oncology.

Figure 1

PDO vs. PDX cancer models to study a tumor’s drug response incorporating intra-tumor heterogeneity. Multi-regional sampling of a tumor is required to take ITH into account when assessing the tumor’s drug response. Compared to multi-regional PDX models, multi-regional PDO-based pre-therapeutic drug screenings are significantly more time- and cost-effective. These PDO-based screens, in addition to amplicon sequencing of multiple areas of tumor tissue and derived cell culture models, combined with targeted proteomic approaches, are both feasible and available within a timeframe that allows discussing guided treatment options.

Figure 2

Cancer models and omics technologies to obtain a comprehensive picture of biological processes within a patient’s tumor. An appropriate combination of different omics technologies and relevant tumor models allows a more comprehensive analysis of intra-tumor heterogeneity, relevant to improve patient treatment. (PDX—patient-derived xenograft; GEMM—genetically engineered mouse models; 2D—two-dimensional cell culture; 3D—three-dimensional cell culture).