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A 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...
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... the time of the surgery, immediately post amputation of the limb, up to 5 tumor specimens (measuring approxi- mately 4 mm 3 each) were obtained per patient. Sample requirements and prioritizations are described in Table 2. Samples numbered 1-3 were mandatory collections, whereas samples numbered 4-5 were optional and only collected if excess representative tumor tissue was avail- able. ...
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The practice of evidence-based veterinary medicine involves the utilisation of scientific evidence for clinical decision making. To enable this, research topics pertinent to clinical practice need to be identified, and veterinary clinicians are best placed to do this. The main aim of this study was to describe the veterinary population, the common...
Citations
... A multisite feasibility study evaluated the turn-around time for the molecular analysis of 20 dogs with OSA. 76 The team established a processing pipeline that generated a report of tumor expression within 5 days of sample receipt, demonstrating that the practical application of precision medicine in the clinical setting is reasonable. 76 Another canine case study was used to show the efficacy of personalized therapy for OSA. ...
... 76 The team established a processing pipeline that generated a report of tumor expression within 5 days of sample receipt, demonstrating that the practical application of precision medicine in the clinical setting is reasonable. 76 Another canine case study was used to show the efficacy of personalized therapy for OSA. Davis et al. used a primary OSA tumor sample from a 7 year old Golden Retriever to establish a cell line, which was then screened for sensitivity to a panel of kinase inhibitors. ...
Dogs are remarkable, adaptable, and dependable creatures that have evolved alongside humans while contributing tremendously to our survival. Our canine companions share many similarities to human disease, particularly cancer. With the advancement of next-generation sequencing technology, we are beginning to unravel the complexity of cancer and the vast intra- and intertumoral heterogeneity that makes treatment difficult. Consequently, precision medicine has emerged as a therapeutic approach to improve patient survival by evaluating and classifying an individual tumor's molecular profile. Many canine and human cancers share striking similarities in terms of genotypic, phenotypic, clinical, and histological presentations. Dogs are superior to rodent models of cancer because they are a naturally heterogeneous population in which tumors occur spontaneously, are exposed to similar environmental conditions, and show more similarities in key modulators of tumorigenesis and clinical response, including the immune system, drug metabolism, and gut microbiome. In this chapter, we will explore various canine models of human cancers and emphasize the dog's critical role in advancing precision medicine and improving the survival of both man and man's best friend.
... A precision medicine approach leveraging data in the quantities produced by NGS requires specialist informatics skills and significant computer processing power to produce results in a form usable by clinicians. Two studies have evaluated such approaches in the veterinary context and found that results could be provided in 5 to 10 days, if appropriate infrastructure is available (Monks et al. 2013, Paoloni et al. 2014. It is feasible that this time frame could be reduced further by using the new generation of miniaturised sequencers (such as MinION, Oxford Nanopore, UK) to produce data in the clinical setting before transferring the data for analysis at a centralised external facility. ...
... Genomic techniques use minute amounts of material (milligrams or less) and this small sample size leads to an increase risk of assay failure due to inadequate numbers of tumour cells and excessive necrosis. In two of the aforementioned studies, these problems were associated with a sample quality failure rate of around 25% (Monks et al. 2013, Paoloni et al. 2014. A further biological issue alluded to above is that due to heterogeneity, the chances of a single sample being unrepresentative of the genetic diversity of the cancer as a whole (and the lethal clones specifically) is high (Cyll et al. 2017). ...
Molecular pathology is a developing sub‐microscopic discipline of pathology that studies the effects of molecular variations and mutations on disease processes. The ultimate goal of molecular pathology in cancer is to predict risk, facilitate diagnosis and improve prognostication based on a complete understanding of the biological impact of specific molecular variations, mutations and dysregulations. This knowledge will provide the basis for customised cancer treatment, so‐called precision medicine. Rapid developments in genomics have placed this field at the forefront of clinical molecular pathology and there are already a number of well‐established genetic tests available for clinical use including PCR of antigen receptor rearrangement and KIT mutational analysis. Moving beyond tests assessing a single gene, there are significant research efforts utilising genomics to predict cancer risk, forecast aggressive behaviour and identify druggable mutations and therapeutic biomarkers. Researchers are also investigating the use of circulating cells and nucleic acid for clinically useful low morbidity genomic assessments. If we are to realise the full potential of molecular pathology and precision medicine there are a number of challenges to overcome. These include developing our understanding of the underlying biology (in particular intra‐tumoural heterogeneity), methodological standardisation of assays, provision of adequate infrastructure and production of novel therapeutics backed by high‐quality clinical data supporting the precision medicine approach. The era of molecular pathology holds the potential to revolutionise veterinary cancer care, but its impact on clinical practice will depend upon the extent to which the inherent challenges can be overcome.
... Other veterinary research projects have characterized the genotypes of several canine cancers including hemangiosarcoma (143), melanoma (144), and osteosarcoma (145), with the aim of identifying potential "actionable" targets. Although somatic mutations in these cancer types (in genes including TP53, PIK3CA, NRAS, PTEN, and BRAF) have similarities to those oncogenic mutations found in human cancers, veterinary clinical trials still need to be performed to confirm if they respond to targeted inhibition. ...
Treating individual patients on the basis of specific factors, such as biomarkers, molecular signatures, phenotypes, environment, and lifestyle is what differentiates the precision medicine initiative from standard treatment regimens. Although precision medicine can be applied to almost any branch of medicine, it is perhaps most easily applied to the field of oncology. Cancer is a heterogeneous disease, meaning that even though patients may be histologically diagnosed with the same cancer type, their tumors may have different molecular characteristics, genetic mutations or tumor microenvironments that can influence prognosis or treatment response. In this review, we describe what methods are currently available to clinicians that allow them to monitor key tumor microenvironmental parameters in a way that could be used to achieve precision medicine for cancer patients. We further describe exciting novel research involving the use of implantable medical devices for precision medicine, including those developed for mapping tumor microenvironment parameters (e.g., O2, pH, and cancer biomarkers), delivering local drug treatments, assessing treatment responses, and monitoring for recurrence and metastasis. Although these research studies have predominantly focused on and were tailored to humans, the results and concepts are equally applicable to veterinary patients. While veterinary clinical studies that have adopted a precision medicine approach are still in their infancy, there have been some exciting success stories. These have included the development of a receptor tyrosine kinase inhibitor for canine mast cell tumors and the production of a PCR assay to monitor the chemotherapeutic response of canine high-grade B-cell lymphomas. Although precision medicine is an exciting area of research, it currently has failed to gain significant translation into human and veterinary healthcare practices. In order to begin to address this issue, there is increasing awareness that cross-disciplinary approaches involving human and veterinary clinicians, engineers and chemists may be needed to help advance precision medicine toward its full integration into human and veterinary clinical practices.
... A recent pioneering effort among US veterinary hospitals also supports that personalized medicine is feasible as an approach for OSA treatment. This multi-site study adopted personalized medicine algorithms involving genomic profiling and bioinformatics to look at the feasibility of determining suitable therapies for an individual dog with an average turnaround time of 5 business days (50). After submission, the samples were verified by quality control for RNA quality prior to processing, after which the personalized medicine algorithms report was relayed to the attending veterinarian. ...
... After submission, the samples were verified by quality control for RNA quality prior to processing, after which the personalized medicine algorithms report was relayed to the attending veterinarian. Of the 20 patient samples submitted, 13 were successfully profiled, while others were hindered by either pathology or RNA quality control failure (50). Based on the report, opinions that were communicated from attending veterinarians about feasibility of the process were overall positive, with constructive information provided that could potentially guide further clinical trials. ...
Osteosarcoma (OSA) is an aggressive primary bone tumor in the domestic dog that most often occurs within the appendicular skeleton. Despite the use of adjuvant chemotherapy, most dogs succumb to metastatic disease within 1 year of diagnosis. To improve this outcome, substantial research is currently focused on investigating novel therapies. Herein, we review emerging treatments and clinical trials that, if proven efficacious, could revolutionize the standard of care for canine appendicular OSA. This article includes a critical perspective on the safety, efficacy, and limitations of select immunotherapy, virotherapy, radiotherapy, targeted therapy, and personalized medicine trials, all of which reflect similar investigations taking place in human oncology. These clinical trials represent a major evolution in the overall approach to therapy for dogs with appendicular OSA that could have significant implications for improving survival.
Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.
... The potential for personalized medicine has been a goal of the genomic area, and such approach has begun to be implemented in the management of canine OS. In a multi-institutional effort, genomic profiling of individual dog OS cases and development of a personalized medicine algorithm (termed Pmed) concluded that such an approach is feasible, with good quality data obtained in an average turnaround time of 5 business days [75]. Another recent study employed a gene expression model to predict sensitivity to doxorubicin and platinum chemotherapy using a retrospective comparison of clinical outcome in canine OS cases. ...
Purpose of Review
Osteosarcoma (OS) is the most common cancer of bone, yet is classified as a rare cancer. Treatment and outcomes for OS have not substantively changed in several decades. While the decoding of the OS genome greatly advanced the understanding of the mutational landscape of OS, immediately actionable therapeutic targets were not apparent. Here we describe recent preclinical models that can be leveraged to identify, test, and prioritize therapeutic candidates.
Recent Findings
The generation of multiple high fidelity murine models of OS, the spontaneous disease that arises in pet dogs, and the establishment of a diverse collection of patient-derived OS xenografts provide a robust preclinical platform for OS. These models enable evidence to be accumulated across multiple stages of preclinical evaluation. Chemical and genetic screening has identified therapeutic targets, often demonstrating cross species activity. Clinical trials in both PDX models and in canine OS have effectively tested new therapies for prioritization.
Summary
Improving clinical outcomes in OS has proven elusive. The integrated target discovery and testing possible through a cross species platform provides validation of a putative target and may enable the rigorous evaluation of new therapies in models where endpoints can be rapidly assessed.
... Ongoing research has identified potential "actionable" genotypes in several canine neoplasms including hemangiosarcoma (Wang et al. 2017), melanoma (Hernandez et al. 2018), osteosarcoma (Monks et al. 2013), and others. Several somatic mutations in these canine tumors are thought to correspond to well-characterized oncogenic mutations in human cancers, including PIK3CA, TP53, PTEN, PLCG1, NRAS, BRAF, and others. ...
Interindividual variation in drug response occurs in canine patients just as it does in human patients. Although canine pharmacogenetics still lags behind human pharmacogenetics, significant life-saving discoveries in the field have been made over the last 20 years, but much remains to be done. This article summarizes the available published data about the presence and impact of genetic polymorphisms on canine drug transporters, drug-metabolizing enzymes, drug receptors/targets, and plasma protein binding while comparing them to their human counterparts when applicable. In addition, precision medicine in cancer treatment as an application of canine pharmacogenetics and pertinent considerations for canine pharmacogenetics testing is reviewed. The field is poised to transition from single pharmacogene-based studies, pharmacogenetics, to pharmacogenomic-based studies to enhance our understanding of interindividual variation of drug response in dogs. Advances made in the field of canine pharmacogenetics will not only improve the health and well-being of dogs and dog breeds, but may provide insight into individual drug efficacy and toxicity in human patients as well.
... 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. ...
... 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 [12] and is being translated into other species such as canines [13]. ...
... The methods for predicting suitable therapies based on the RNA analyte have been described in detail previously [12,13] 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. ...
... 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 Insightsused 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 [13]. The five methods utilized in this report include expression based methods, drug target expression (raw score) [25] and drug sensitive/resistant biomarker rules [26]. ...
Background
Precision (Personalized) medicine has the potential to revolutionize patient health care especially for many cancers where the fundamental disease etiology remains either elusive or has no available therapy. Here we outline a study in alveolar rhabdomyosarcoma, in which we use gene expression profiling and a series of drug prediction algorithms combined with a matched patient-derived xenograft (PDX) model to test bioinformatically predicted therapies.ProcedureA PDX model was developed from a patient biopsy and a number of drugs identified using gene expression analysis in combination with drug prediction algorithms. Drugs chosen from each of the predictive methodologies, along with the patient's standard-of-care therapy (ICE-T), were tested in vivo in the PDX tumor. A second study was initiated using the tumors that re-grew following the ICE-T treatment. Further expression analysis identified additional therapies with potential anti-tumor efficacy.ResultsA number of the predicted therapies were found to be active against the tumors in particular BGJ398 (FGFR2) and ICE-T. Re-transplanted ICE-T treated tumorgrafts demonstrated a decreased response to ICE-T recapitulating the patient's refractory disease. Gene expression profiling of the ICE-T treated tumorgrafts identified cytarabine (SLC29A1) as a potential therapy, which was shown, along with BGJ398, to be highly active in vivo.Conclusions
This study illustrates that PDX models are suitable surrogates for testing potential therapeutic strategies based on gene expression analysis, modeling clinical drug resistance and hold the potential to assist in guiding prospective patient care. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
... Companion animals with cancer have been increasingly used to provide insight into tumor biology and in clinical studies of drug development [15,21,22]. As noted above, this is particularly germane to PMed where traditional rodent xenograft models do not collectively represent the heterogeneity known to exist in a population of human patients with a given histological diagnosis of cancer [14,23]. ...
Background
Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting.MethodologyA proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type.Conclusions
Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (
... Genetic analysis of these samples confirmed that the gene expression signatures of canine and human OS are highly similar, and even parallel human survival analyses [81,82 ]. Because of these striking similarities, canine osteosarcoma is gaining fast attention as a valid clinical model for the human disease [83,84], and more effort should be put in setting up drug trials with canine patients, as an important clinical surrogate to start human clinical trials. ...
