Targeted Therapeutics work when they strike at the vulnerabilities of cancer cells. A logical mode of attack, common to traditional chemotherapeutic agents, is to hinder the ability of cancer cells to successfully replicate their genome. These drugs can be either cytostatic or cytotoxic, but generally work to halt the successful production of more cancer cells independent of the unique molecular alterations that first enabled carcinogenesis or contributed to disease progression. An example familiar to veterinary medicine is lomustine (CCNU), an alkylating nitrosourea, often used to treat canine mast cell tumors, among other cancers. This drug cross-links DNA and RNA making cells unable to repair damaged DNA before they are stimulated to divide (4) and this causes cell death.
One issue with this approach is the inevitable development of drug resistance. The dormant nature of some cancer cells, expression of multidrug-resistance proteins and other mechanisms that enable cancer cells to avoid cell death, all contribute to emergence of drug refractory cancer. In some cancers there are gene expression and genomic changes that can predict response to DNA damaging agents (this information can also be provided through FidoCure), but, because all cells in the body depend on DNA and RNA integrity, generally this approach is akin to a non-specific attack, much like surgery or radiation therapy.
A second therapeutic approach is to attack “unique” cancer vulnerabilities. Each cancer cell harbors an array of genetic changes, some of which contribute directly to the cancer phenotype. Targeting specific proteins produced as a result of these genome alterations can have profound effects on cancer proliferation and survival. An example of a targeted drug familiar to veterinary medicine is toceranib, marketed by Zoetis, Inc. as Palladia®. Like lomustine, it can be used to treat canine mast cell tumors. However, toceranib is a small molecule inhibitor of transmembrane receptor tyrosine kinases (RTKs) that regulate cell proliferation and viability. Two RTKs inhibited by toceranib play important roles in the tumor vasculature. These are vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). A third RTK, which may be the important target in mast cell malignancy, is called c-Kit (KIT). KIT was first identified as the cellular homolog of the feline sarcoma viral oncogene, v-kit but another alias is mast cell growth factor (MGF). It has long been known that KIT is hyper-activated by mutation in some canine mast cell tumors.
The One Health Company offers a comprehensive molecular diagnostic platform that can be used to rapidly identify clinically informative molecular events. The platform includes both DNA-based and RNA-based molecular profiling. We use cutting-edge genome analysis to measure the mutational landscape of tumor DNA. In addition, our platform includes the option for comprehensive RNA analysis to enable identification of differentially expressed genes and/or the expression of gene-fusion products that may be associated with sensitivity or resistance to therapeutics in The One Health Company’s pharmacopeia. This comprehensive approach provides the maximum breadth of information for our canine patients by incorporating known cancer genotype/phenotype associations into any drug recommendations given to your veterinary practice. As more and more information become available to us regarding canine cancer genomes, including that from our growing database, our dynamic platform and expert team will work to maximize biomarker coverage in our assays to deliver as much information as possible to guide veterinarians in the clinical management of their canine patients.
Biomarkers help predict whether or not a drug will work for a patient. For example, in human non-small cell lung cancer, it was found that patient tumors that responded to the drug erlotinib, all harbored activating mutation in the epidermal growth factor receptor (EGFR). Although the drug was designed as a wildtype EGFR inhibitor, mutant EGFR tumors are particularly dependent on the constitutively activated EGFR signal. Activating mutation in EGFR is therefore the biomarker that guides the decision to treat a human patient with this drug. The One Health genomic panel incorporates next-generation sequencing (NGS) and advanced molecular profiling technology to test for DNA and RNA biomarkers. They are linked through annotated levels of evidence, to clinical outcomes and drug response. The presence of biomarkers helps to guide the veterinarian in designing the optimal management strategy, including selection of appropriate treatment, for their canine patient. The information we provide should be used in conjunction with histology, physical examination, history and staging to optimize treatment.
Access to Knowledge
A search using the phrase “targeted therapy” at the U.S. National Library of Medicine’s Pubmed portal (https://www.ncbi.nlm.nih.gov/pubmed/) will reveal close to 150 thousand distinct citations. The targeted medicine field is large and continuously evolving, making information difficult to find. In addition, finding information specific to veterinary medicine can be difficult and time consuming. For example, hemangiosarcomas, common in veterinary oncology, are not common in humans. It may be difficult to find data concerning toxicities, therapies and/or complications that may arise in canines. The One Health Company has already begun accumulating and analyzing information collected from the veterinary oncology community. This includes information regarding toxicities, drug dosage, efficacy and ease of owner delivery to the patient. When combined with the continued accrual of deeply annotated genomic and outcomes data from hundreds and eventually thousands of canine cancer patients, these integrated data will facilitate a transformation in veterinary oncology equivalent to that which has been ongoing in human oncology since the genomics revolution of the early 2000s.