A multi-site feasibility study for personalized medicine in canines with Osteosarcoma

Abstract

BackgroundA successful therapeutic strategy, specifically tailored to the molecular constitution of an individual and their disease, is an ambitious objective of modern medicine. In this report, we highlight a feasibility study in canine osteosarcoma focused on refining the infrastructure and processes required for prospective clinical trials using a series of gene expression-based Personalized Medicine (PMed) algorithms to predict suitable therapies within 5 days of sample receipt.MethodsTumor tissue samples were collected immediately following limb amputation and shipped overnight from veterinary practices. Upon receipt (day 1), RNA was extracted from snap-frozen tissue, with an adjacent H&E section for pathological diagnosis. Samples passing RNA and pathology QC were shipped to a CLIA-certified laboratory for genomic profiling. After mapping of canine probe sets to human genes and normalization against a (normal) reference set, gene level Z-scores were submitted to the PMed algorithms. The resulting PMed report was immediately forwarded to the veterinarians. Upon receipt and review of the PMed report, feedback from the practicing veterinarians was captured.Results20 subjects were enrolled over a 5 month period. Tissue from 13 subjects passed both histological and RNA QC and were submitted for genomic analysis and subsequent PMed analysis and report generation. 11 of the 13 samples for which PMed reports were produced were communicated to the veterinarian within the target 5 business days. Of the 7 samples that failed QC, 4 were due to poor RNA quality, whereas 2 were failed following pathological review. Comments from the practicing veterinarians were generally positive and constructive, highlighting a number of areas for improvement, including enhanced education regarding PMed report interpretation, drug availability, affordable pricing and suitable canine dosing.ConclusionsThis feasibility trial demonstrated that with the appropriate infrastructure and processes it is possible to perform an in-depth molecular analysis of a patient’s tumor in support of real time therapeutic decision making within 5 days of sample receipt. A number of areas for improvement have been identified that should reduce the level of sample attrition and support clinical decision making.

Using a rhabdomyosarcoma patient-derived xenograft to examine precision medicine approaches and model acquired resistance

“…The first PMed system (used for the Study 1 drug predictions) was developed internally at VARI and include a list of 188 compounds both developmental and FDA approved. The later PMed system (Intervention Insights—used in Study 2), is a system that evolved from the original software to be used for human patients and therefore included only 183 FDA approved drugs along with the addition of the Biomarker Rules . The five methods utilized in this report include expression based methods, drug target expression (raw score) and drug sensitive/resistant biomarker rules .…”

“…The methods for predicting suitable therapies based on the RNA analyte have been described in detail previously and are currently being used in both human (FDA approved) and canine clinical trials. As a brief overview, the PMed system utilized in this study is a conglomeration of five predictive methodologies which predict suitable drugs based on the RNA expression data, subsequently ranking these based on the strength of prediction (target expression) combined with the number of targets and number of methods that predict a given drug.…”

“…In an attempt to support the therapeutic decisions of the oncologist beyond the SOC protocols, we have established an approach to personalizing cancer treatment using rational drug selection based on tumor transcriptome analysis using a panel of drug prediction methods combined with validation of the predictions in patient‐derived xenografts (PDX—also known as tumorgrafts or patient Avatars). This molecular‐guided approach was recently highlighted in a pilot clinical trial in patients with recurrent neuroblastoma and is being translated into other species such as canines .…”

Osteosarcoma in Dogs: Diagnosis and Treatment - A Literature Review

“…In other words, different responses can be considered to be differentially affect the phenotype of these cells. Therefore, the tumors gene expression analysis could elucidate new therapeutic targets leading to personalized treatments, as presented by the study of Monks et al [16] which showed that it is possible to provide a report to the veterinarian from a single biopsy from amputation of the affected limb within 5 days. In relation to the study by O'Donoghue et al [6], we explored differences in gene expression between primary tumors of OSA of dogs with disease-free interval (DFI) less than 100 days and greater than 300 days after chemotherapy.…”

Genomic and proteomic profiling for cancer diagnosis in dogs

“…Ultimately, gene expression patterns from individual tumours may direct personal patient treatment plans, using therapy targeted to specific pathways of gene expression (Chantrill et al, 2015). The feasibility of prospective molecular profiling of canine cancers for personalised medicine (PMed) has already been investigated successfully, making it a practical option for clinical use (Monks et al, 2013;Paoloni et al, 2014). In the shorter term, genomic profiling can usefully identify a few key genes for which IHC or RT-PCR assays can be developed for clinical diagnostic use.…”