PROJECT SUMMARY/ABSTRACT
Osteosarcoma (OS), the most common malignant bone tumor in humans and dogs, shares several features in
both species including clinical presentation and molecular alterations. Despite numerous efforts there have been
no improvements in disease outcome for either species in the past three decades: 30% of people and 90% of
dogs still die of metastasis. While some approaches have shown promise in the setting of microscopic disease,
in both species, macroscopic metastasis exhibits inherent resistance to multiple agents (kinase inhibitors,
chemotherapy, immunotherapy, among others). I recently characterized the canine OS genome 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 trial efforts suggest
that contemporary approaches to therapeutic advancement such as kinase inhibitors and immune checkpoint
blockade will likely have limited clinical impact, necessitating the development of innovative therapeutic
strategies. 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. In previous work, I found that loss of MCT1 or MCT4 function in OS cells decreases basal and compensatory
glycolysis, cellular proliferation and invasive capacity. I also showed 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. Building on these data, I will by leverage a comparative cross-
species approach to first define regulatory circuits that support aerobic glycolysis mediated by MCT1/MCT4 in
OS and then identify and validate therapeutic vulnerabilities related to MCT control of cellular metabolism. I
hypothesize that in OS cells, sustained MCT1/MCT4 expression is driven by constitutive STAT3/FOXM1
activation and increased MYC copy number, thereby promoting aerobic glycolysis. I further predict that
loss of MCT1/MCT4 through genetic manipulation or targeted inhibitors will impair tumor growth in vivo,
and that this can be maximized through rational drug combination. To accomplish this, I will first
characterize the transcriptional regulation of MCT1/MCT4 in OS using a combination of ChIP-sequencing,
bisulfite sequencing and 4C/ChiA-PET analysis. Xenograft studies in mice will complement in vitro analyses to
assess how loss of MCT1/4 function affects OS metabolic profile, tumor phenotype and tumor growth. Lastly, I
will use a zebrafish model to screen select agents for synthetic lethality with MCT blockade, then validate findings
in mice. The rich research environment afforded by Tufts University and its partners ensures access to resources
and expertise necessary for completion of the proposed work. My training in veterinary oncology, clinical trials
and genetics along with guidance from my mentoring team with expertise in genomics, bioinformatics, animal
models and translational oncology make me well positioned for successful transition to independence.