Previously Funded Research

Timothy Burns, MD, PhD

University of Pittsburgh

Research Project:

Targeting glycolysis in MET altered lung cancer brain metastases

Summary:

Lung adenocarcinoma (LUAD) has the highest incidence of brain metastases (BM) with almost 40% of lung cancer patients developing BM during the course of their disease. As there are no targeted therapies for the treatment of LUAD-BM, the development of novel treatments to effectively prevent and treat LUAD-BM is urgently needed to improve patient survival. Our preliminary studies suggest that alterations in the MET gene are selected for in metastatic lesions to the brain, and that the MET pathway may be a therapeutic target for LUAD-BM. In this project, we will define the metabolic vulnerabilities of MET altered NSCLC BM and provide the preclinical rationale to test whether metabolic inhibitors could be effective in a significant subset of LUAD BM patients (~20%) in the clinic.

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Final report:
The original aim of the grant was to define metabolic dependencies of MET altered non-small cell lung cancer (NSCLC). Dr. Burns used cell lines and mouse models to define the proteins that regulate metabolic pathways in MET altered lung cancer in the presence and absence of MET inhibitors and what happens at the time of resistance. Hexokinase 2 (HK2) is one of the proteins that changes expression and appears to be MET dependent. This occurs also in MET driven acquired resistance in EGFR driven cancers. Glutamine and glucose deprivation as well as glycolytic inhibitors have been used to evaluate this approach to control cancer cell growth.

The researcher has found that MET induces glycolysis through TWIST1-dependent transcriptional regulation of HK2 and that this TWIST1-HK2 pathway is upregulated at the time of MET TKI resistance. Glycolytic inhibition is effective in a context dependent manner at the time of MET TKI resistance (in vitro vs. ex vivo) validating the value of the ex vivo model. Finally, he has shown that glycolytic inhibition may be effective for other oncogenic drivers (EGFR mutant NSCLC) when MET amplification is the etiology of acquired TKI resistance. The researcher has demonstrated the importance of MET in brain metastases and has found that glycolytic inhibition may play a role in the treatment of this special site of disease.

Impact:
This work represents a novel approach to developing new strategies for the treatment of MET-driven NSCLC whether the MET alterations are de novo, the result of the development of resistance to treatment, or whether they occur as a resistance mechanism in oncogene-driven cancers such as EGFRmut+ NSCLC. This is a great area of need, that is “overcoming resistance.” Although this represents early data, there is potential for application of these findings in clinical trials. Another potentially important outcome is the use of this treatment approach in the management of brain metastases which is another great area of need.