Targeting Tumor Metabolism May Hold Therapeutic Promise
Despite three decades of effort, outcomes for patients with osteosarcoma (OS) have remained largely unchanged; while 70% experience long term survival, metastatic disease is extremely resistant to treatment, with only 10-30% of patients living beyond 5 years. Interestingly, OS is the most common primary bone tumor in dogs, with over 25,000 new cases/year. In both species, survival times have remained unchanged, and 30% of people and 90% of dogs still die of metastasis. Multiple lines of evidence suggest that canine OS exhibits a similar biology to its human counterpart including anatomic location/clinical presentation, development of chemotherapy-resistant metastases, and altered expression/activation of oncogenes and tumor suppressor genes. Consequently, canine OS is frequently used as a natural model of the human disease.
Over the past 3 decades, numerous clinical trials have been undertaken in both dogs and people with OS to address chemotherapy resistant metastatic disease, with essentially no improvements in outcomes. Given this lack of progress, substantial effort has been directed at dissecting the genomic landscapes of human and canine OS with the goal of identifying new therapeutic vulnerabilities. Dr. Heather Gardner, a graduate student in the London laboratory, recently characterized the canine OS genome using whole genome, whole exome and RNA sequencing, and found that as with human OS, the somatic mutational load is low, copy number aberrations/structural variants predominate, and no clear molecular drivers are evident. These data, along with a history of failed clinical efforts necessitate the development of innovative therapeutic strategies in order to improve outcomes for patients with OS.
Altered tumor metabolism has recently received substantial attention as a therapeutic vulnerability in several tumors. A distinguishing feature of cancer cells is their ability to undergo aerobic glycolysis, allowing them to thrive in a variety of microenvironments. Monocarboxylate transporters (MCTs) are key facilitators of this, moving lactic acid across the plasma membrane, and are critical for growth and metastasis of glycolytic tumors, such as OS. Heather Gardner, DVM, a Genetics PhD student working in the London lab focuses on credentialing MCTs as therapeutic targets in OS and identifying mechanisms of synthetic lethality. Her work demonstrates that loss of MCT1 or MCT4 function in OS cells decreases basal and compensatory glycolysis, cellular proliferation and invasive capacity. She has also shown that MCT4 is a direct transcriptional target of STAT3 and FOXM1, both of which exhibit constitutive activation in OS, supporting a link between MCT4/STAT3/FOXM1 and aerobic glycolysis. However, despite impressive activity in vitro, blockade of MCT function alone in mouse tumor models tends to induce stasis rather than tumor regression, indicating that rational drug combinations may be needed to maximize the effect of MCT inhibition. Therefore, building upon her previous work, Dr. Gardner is currently exploring synthetic lethal combinations for in vivo translation in OS, by defining their transcriptional and functional regulation, assessing how loss of function modulates tumor genotype and phenotype and then leveraging these data to interrogate rational therapeutic combinations in vivo. Together studies will create a blueprint for clinical trials in pet dogs with OS, prior to subsequent translation in people.
Gardner HL, Sivaprakasam K, Briones N, Zismann V, Perdigones N, Drenner K, Facista S, Richholt R, Liang W, Aldrich J, Trent JM, Shields PG, Robinson N, Johnson J, Lana S, Houghton P, Fenger J, Lorch G, Janeway KA, London CA, Hendricks WPD. 2019. Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun Bio. 2:226. Abstract