Breaking Resistance, Shaping the Future | Research Voices (Episode 7) - Prof. Mary V. Relling, St. Jude Children's Research Hospital

Prof. Mary V. Relling Reflects on the Host Genome, Germline Pharmacogenomics, and Clinical Implementation Barriers in Pediatric Oncology

As part of Breaking Resistance, Shaping the Future, a scientific series celebrating the eighth anniversary of Cancer Drug Resistance (CDR), the journal is pleased to present the latest episode of Research Voices, an interview series spotlighting leading scientific experts and clinical pioneers from around the world.

This episode features Professor Mary V. Relling, a globally recognized authority in pharmacogenomics and pediatric oncology, Member of the Clinical Pharmacogenomics Implementation Consortium (CPIC), and Faculty Member in the Department of Pharmacy and Pharmaceutical Sciences at St. Jude Children's Research Hospital.

In this engaging conversation, Prof. Relling discusses the critical concept of "two genomes" in cancer therapy - the host germline genome and the somatically acquired tumor genome. She explores how germline genetic variation dictates both host toxicity and systemic drug exposure, using thiopurine methyltransferase (TPMT) as a landmark example. Furthermore, Prof. Relling provides deep insights into the clinical barriers hindering the routine integration of germline pharmacogenomics into precision oncology. She addresses healthcare system fragmentation, the necessity of discrete computational data storage over narrative PDF reports, and the gap between available evidence-based research and real-world clinical implementation.

Watch the Full Interview

Interview Highlights

• The concept of "two genomes" in cancer therapy: host germline vs. somatically acquired tumor genetics
• How germline variation influences drug exposure, host toxicity, and treatment tolerance (e.g., TPMT in thiopurine therapy)
• The role of pharmacokinetics (PK) and pharmacodynamics (PD) in actionable CPIC guidelines
• Expanding precision oncology beyond tumor profiling to include germline pharmacogenomics and supportive care drugs
• Addressing major barriers to clinical implementation: system fragmentation, lifetime data tracking, and high costs
• Moving from unstructured text and PDF reports to discretized data to enable future clinical decision support and AI application

Key Takeaways

Balancing the "Two Genomes" to Optimize Therapy

Prof. Relling highlights that cancer therapy must account for both the host germline genome and the somatically acquired tumor genome. While tumor mutations dictate targeted therapies, germline variations heavily influence drug disposition, systemic exposure, and host toxicity. If a patient experiences severe host toxicity that prevents them from receiving the prescribed regimen, the tumor cannot be effectively treated. Germline testing, such as for TPMT, allows clinicians to adjust dosages to maintain anti-leukemic efficacy while avoiding unacceptable myelosuppression, achieving a crucial balance between tolerability and efficacy.

Integrating Germline Pharmacogenomics into Precision Oncology

Addressing current clinical trends, Prof. Relling emphasizes that modern precision oncology relies too heavily on tumor profiling alone. Comprehensive care requires evaluating germline actionable pharmacogenes—not only for anti-cancer agents but also for supportive care medications like analgesics, antiemetics, and proton pump inhibitors (e.g., CYP2D6 and CYP2C19). Incorporating germline profiles alongside age, organ function, and drug interactions is essential for holistic treatment decisions.

Bridging the Research-to-Implementation Gap

Prof. Relling reflects on the future of the field, stressing that generating data is only the first step. A primary barrier to implementation is the fragmentation of healthcare systems and the lack of integrated clinical decision support (CDS) to link lab results directly to prescribers. Furthermore, much of current genetic data remains stored in non-computational PDF reports rather than discrete data fields, hindering automated alerts and AI utilization. Prof. Relling notes that while sufficient research knowledge exists, the true challenge lies in securing the infrastructure, resources, and standardized systems required to implement actionable genomic knowledge into everyday practice.

This interview marks a key installment of the Research Voices series. Stay tuned for upcoming conversations with leading experts as we continue to explore the theme Breaking Resistance, Shaping the Future.

Editor: Stella Jin
Language Editor: Amir Khan
Production Editor: Xingyue Luo
Respectfully Submitted by the Editorial Office of Cancer Drug Resistance