A Collaborative Initiative to Establish Genomic Biomarkers for Assessing Tumorigenic Potential to Reduce Reliance on Conventional Rodent Carcinogenicity Studies

Abstract

There is growing recognition across broad sectors of the scientific community that use of genomic biomarkers has the potential to reduce the need for conventional rodent carcinogenicity studies of industrial chemicals, agrochemicals, and pharmaceuticals through a weight-of-evidence approach. These biomarkers fall into 2 major categories: (1) sets of gene transcripts that can identify distinct tumorigenic mechanisms of action; and (2) cancer driver gene mutations indicative of rapidly expanding growth-advantaged clonal cell populations. This call-to-action article describes a collaborative approach launched to develop and qualify biomarker gene expression panels that measure widely accepted molecular pathways linked to tumorigenesis and their activation levels to predict tumorigenic doses of chemicals from short-term exposures. Growing evidence suggests that application of such biomarker panels in short-term exposure rodent studies can identify both tumorigenic hazard and tumorigenic activation levels for chemical-induced carcinogenicity. In the future, this approach will be expanded to include methodologies examining mutations in key cancer driver gene mutation hotspots as biomarkers of both genotoxic and nongenotoxic chemical tumor risk. Analytical, technical, and biological validation studies of these complementary genomic tools are being undertaken by multisector and multidisciplinary collaborative teams within the Health and Environmental Sciences Institute. Success from these efforts will facilitate the transition from current heavy reliance on conventional 2-year rodent carcinogenicity studies to more rapid animal- and resource-sparing approaches for mechanism-based carcinogenicity evaluation supporting internal and regulatory decision-making.

EMA commentary on the ICH guideline for testing for carcinogenicity of pharmaceuticals

“…Unfortunately, the number of genomics‐based evidence that was submitted was very limited, which is seen as a missed opportunity. However, further initiatives are being taken to move the field forward 40 . EMA experts welcome evidence provided from new emerging tools (e.g.…”

“…However, further initiatives are being taken to move the field forward. 40 EMA experts welcome evidence provided from new emerging tools (e.g. in vitro, in silico, etc.…”

Increased Cell Proliferation as a Key Event in Chemical Carcinogenesis: Application in an Integrated Approach for the Testing and Assessment of Non-Genotoxic Carcinogenesis

“…These biomarkers are being increasingly recognized by broad sectors of the scientific community to make accurate predictions of key events in adverse outcome pathways underlying chemical carcinogenesis. NAMs applied in in vivo and in vitro contexts that use batteries of biomarkers could be used in IATA strategies, such as those proposed by Oku and colleagues [99], or could have utility in the context of a longer-term outlook [106].…”

Toxicogenomics Approaches to Address Toxicity and Carcinogenicity in the Liver

“…Currently, there is project support through Health and Environmental Sciences Institute (HESI) that is attempting to formalize the models to facilitate acceptance for regulatory decision-making. 14 At the outset of building and applying a model, it is critical to consider its applicability. The first question the modeler should address is, "Will this test article exhibit substantial elevations in liver cancer at any administered dose level in a cancer bioassay?"…”