Prioritizing targeted therapies in an evidence-based manner, integrating biological context and functional precision medicine.

Abstract

e14065 Background: It is becoming increasingly common for cancer patients to undergo molecular profiling of their tumors in order to see whether there are any actionable DNA, gene expression, or protein expression signatures. For example, individuals with ER+ or HER2+ breast cancer or KRAS wild type (non-mutated) colorectal cancer are prescribed specific targeted therapies. When an individual’s molecular alterations do not match any currently-approved recommendations for their tumor type, their clinician may consider prescribing a therapy approved in a different tumor type. Unfortunately, tumors often eventually become resistant to the therapies they are exposed to, leading to a narrowing of options after each therapy line. Methods: We previously developed CDGnet, an evidence-based approach and web-based tool for prioritizing targeted therapies based on tumor molecular profiles based on known pathways which provide biological context. CDGnet considers approved therapies with biomarkers among the alterations for the individual’s tumor type and other tumor types as the first and second evidence level categories respectively. These are followed by therapies that target or have as biomarkers genes or proteins downstream of altered oncogenes, considering curated pathways for the individual’s tumor type and other tumor types as the third and fourth evidence level categories respectively. We are currently expanding CDGnet in order to include data from high-throughput screening (HTS) experiments of NCI oncologic drugs performed on patient-derived organoids. The concept of “functional precision medicine” consists of using functional drug efficacy determination directly on individual patients, in this case by considering drugs with low half maximal effective concentrations (EC50) which are tested on tissues derived from the actual patients. Results: We will present extensions to CDGnet that allow users to upload both the molecular profiles and the HTS data to see whether any drugs are predicted by both approaches or whether specific combinations appear promising for further testing. Preliminary results on a set of glioblastoma samples will be presented. Conclusions: We hope that extending CDGnet to also include HTS data will eventually allow a truly multi-factorial personalized oncology approach, whereby both molecular alterations at the DNA, RNA, and protein levels and patient-derived organoids will be considered in deciding on treatment plans for individuals.