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Elucidating the therapeutic utility of targeting metabolic dependencies in osteosarcoma

阐明针对骨肉瘤代谢依赖性的治疗效用

基本信息

批准号：
10360455
负责人：
Heather Lynn Gardner
金额：
$ 12.63万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360455
关键词：
Address Adolescent Affect Amputation Animal Disease Models Animal Model Binding Bioinformatics Canis familiaris Cell Proliferation Cell membrane Cells ChIP-seq Chemicals Chromatin Conformation Capture and Sequencing Chromatin Interaction Analysis by Paired-End Tag Sequencing Clinical Clinical Trials Comparative Genomic Analysis Complement Data Dependence Development Disease Disease Outcome Down-Regulation Doxorubicin Drug Combinations Ensure Environment Exhibits FOXM1 gene Future Gene Expression Profile Genetic Transcription Genome Genomics Glutaminase Glycolysis Growth Human Immune checkpoint inhibitor Immune response Immunosuppression Immunotherapeutic agent Immunotherapy Impairment In Vitro Lactic acid Link Long Term Survivorship Malignant Bone Neoplasm Mediating Mediator of activation protein Medical Genetics Mentors Metabolic Metabolic Pathway Metabolism Metastatic Osteosarcoma Metastatic to Microscopic Modeling Molecular Mus Mutation Neoplasm Metastasis Nutrient Operative Surgical Procedures Pathway interactions Persons Phenotype Phosphotransferases Positioning Attribute Primary Neoplasm Recording of previous events Refractory Regulation Research Resistance Resources STAT3 gene Scientist Somatic Mutation Therapeutic Training Transcriptional Regulation Tumor Immunity Universities Variant Work Xenograft procedure Zebrafish aerobic glycolysis arginase bisulfite sequencing cancer cell cancer clinical trial cancer genome cell growth chemotherapy clinical development clinical translation comparative design flexibility genetic manipulation immune checkpoint blockade in vivo inhibitor innovation kinase inhibitor knockout gene loss of function metabolic profile mouse model neoplastic cell osteosarcoma programs skills small molecule inhibitor targeted agent therapeutic target translational oncology tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

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.

项目总结/文摘