Spring 2018 Newsletter
HESI Emerging Systems Toxicology in Risk Assessment
From the Chairs:
After several months of lively discussions, we are thrilled to announce our new committee name:

emerging Systems Toxicology for Assessment of Risk (eSTAR) Committee

We thank all of our members, in particular our steering team, for helping us arrive at this decision. Our new name reflects the evolution of our committee’s focus, with increasing emphasis on quantitative methods that integrate classical toxicology with network-based analysis, the development of mechanistic and biofluid-based biomarkers, and the measurement of functional changes across levels of biological organization as predictive tools in toxicology. The impetus for changing our name came from discussions where we reflected on what we have accomplished, our future goals, and our core expertise and strengths. As we move forward under the eSTAR name, we will continue to be an action-oriented committee that aims to catalyze the adoption of new translational and predictive tools for decision-making. We look forward to continuing to work with eSTAR members to update our mission statement and to develop content for our web page that succinctly describes what we do and why. 

We have also finalized best practices for committee management and for working group engagement. We hope this document will serve as a source of information to new and existing members to define roles and responsibilities, as well as to provide protocols for everything from proposing new project ideas to travel support. You can check out these documents here.

Our eSTAR committee members have been very active over the past several months in carrying out projects and in outreach to the scientific community. In particular, congratulations to all members who chaired workshops, and presented our committee work at the annual Society of Toxicology meeting in San Antonio. 

Alison Harrill & Carole Yauk
Accepting Nominations for Committee Chairs:
It is an election year! After three years of service, Carole Yauk will be relinquishing her co-chair role and we will be seeking to elect an incoming co-chair prior to our Fall face-to-face meeting. In the interest of sector balance, preference will be given to candidates from the private sector (as Alison Harrill will be continuing as a public sector co-chair). Be thinking about who you want to nominate! 
Working Group Updates
Qualification of a Genomic Biomarker Approach to Provide Context to Positive Findings in in vitro Chromosome Damage Assays
Chair: Dr. Jiri Aubrecht, Pfizer
The project team has been busily preparing a Project Status Report for the US Food and Drug Administration to describe recent progress contributing to the qualification of a first-ever transcriptomic biomarker (called TGx-DDI). The work is important to identifying best approaches to qualify such biomarkers (e.g., define what type of validation studies should be undertaken). In addition, it is expected to significantly enhance understanding of the use of signature-based biomarkers for risk assessment. The project team has also launched a case study to demonstrate application of the biomarker as an integrated test with the high-throughput comet assay in drug testing. The group welcomes Dr. Bevin Engelward of the Massachusetts Institute of Technology for this new endeavor. 
Technical Considerations for RNA-Seq of FFPE Tissues
Chair:  Dr. Susan Hester, US EPA
FFPE archival samples are an under-utilized resource because of the damage induced by formalin fixation. Thus, FFPE use for genomic profiling has been limited by technical issues involved in processing. The FFPE workgroup published the results of its research project titled “Demodifying RNA for Transcriptomic Analyses of Archival Formalin-Fixed Paraffin-Embedded Samples” on April 1, 2018. The goal of that research was to characterize FFPE RNA for subsequent RNA sequencing and investigate ways to improve FFPE RNA yield and quality.  A second companion paper focusing on FFPE RNA quality assessments is currently in draft format. This will be distributed for committee review and ready for submission to a journal by summer 2018. Other committee activities included a 2018 SOT Roundtable presentation “Unlocking the ‘Omics Archive: Enabling Toxicogenomic/Proteomic Investigation from Archival Samples (ID 137)”. Future studies will utilize our methods successfully developed for RNA-Seq by extending these methods to DNA-Seq of human tumors. This is a translational step, as we will apply our FFPE methods previously developed for rodent models, by extending those methods to human samples to examine DNA variants.
miRNA Biomarkers
Chairs:  Drs. Brian Chorley, US EPA; Tatiana Sharapova, AbbVie
The group has been focused on efforts to identify specific biomarkers for biliary injury by running in situ hybridization (ISH) studies in normal rat livers. Several ISH optimization steps had been undertaken and discussed among group participants. Using locked nucleic acid (LNA) probes and laser capture microdissection (LCM) were discussed as potential alternatives to the current method. Old serum RNA samples (2011) have been tested for miRNA stability and were shown to have RNA quality acceptable for analysis. The group has also discussed undertaking additional effort to prepare a review article summarizing current challenges in the advancement of miRNA biomarker research. The group agreed on the potential value of the effort. The document outlining the technical and biological issues in developing miRNAs as injury biomarkers has been generated and circulated between the group members.
Genomics in Cancer Risk Assessment Workshop
Workshop Chairs: Drs. Jiri Aubrecht, Pfizer; Heidrun Ellinger-Ziegelbauer, Bayer; Alison Harrill, NIH/NIEHS; Jan Willem van der Laan, Medicines Evaluation Board; Carole Yauk, Health Canada  
It has been one year since we held our highly successful ‘Workshop on Advances and Roadblocks for use of Genomics Data in Cancer Risk Assessment for Drugs and Chemicals’ in Montreal, Quebec. The major outcomes of the workshop have been presented at various meetings. Summary compilations or break-out group discussions have been developed and a manuscript is in preparation to describe the workshop’s outcomes.
Event Updates
Webinar Series
A huge thank you to Dr. Frank Sistare for presenting the highly informative talk titled “Improving the Relevance and Enhancing the Efficiency of Pharmaceutical Carcinogenicity Testing”. Dr. Sistare discussed the work of PhRMA industry members to review the 2-year carcinogenicity study by leveraging decades of experience. Their efforts have defined a revised testing strategy that allows earlier recognition of drug candidates devoid of human carcinogenic risk, proposing adoption of an approach that will eliminate any value of conducting a 2-yr rat study for approximately 40% of new pharmaceuticals. Discussion included utilizing and qualifying genomic biomarkers to be used in regulatory decision making to help eliminate the need for conducting a large fraction of 2-yr rat carcinogenicity studies and enhance the human relevance of these datasets.

The next eSTAR webinar will be held on June 18. Dr. Weida Tong and Dr. Shraddha Thakkar will be present a talk titled “A structured approach to comparing computational, genomic and high content biology screening methods for predicting toxicity."
HESI eSTAR Annual Meeting
Stay tuned for updates regarding the HESI eSTAR Annual Face-to-Face Meeting that will take place this fall.
Recent Committee Publications
Wehmas LC, Wood CE, Gagne R, Williams A, Yauk C, Gosink MM, Dalmas D, Hao R, O’Lone R, Hester S. (2018). “Demodifying RNA for Transcriptomic Analyses of Archival Formalin-Fixed Paraffin-Embedded Samples.” Toxicological Sciences 162:2. Find it here!
HESI Staff
Syril Pettit, MEM
HESI Executive Director

Lauren Peel
Scientific Program Associate