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Timothy Burns

Timothy Burns

Program: Cancer Biology

412-623-7877 burnstf@upmc.edu Hillman Cancer Center Suite 2.18
5117 Centre Avenue
Pittsburgh PA
Summary

Lung cancer is the leading cause of cancer death in the United States and worldwide. Recent advances in the treatment of non-small cell lung carcinoma (NSCLC) have come from recognition that NSCLC is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms. This paradigm is typified by the recent progress made in the treatment of patients with EGFR-mutant and EML4-ALK translocation-driven adenocarcinomas of the lung with tyrosine kinase inhibitors targeting these oncogenes. Unfortunately, little progress has been made in the treatment of patients with the most frequently observed driver oncogene, mutant KRAS. KRAS is mutated in approximately 25% of all NSCLC, and patients with this mutation have an increased risk of recurrence in early stage disease and have a worse prognosis with metastatic disease. My research and clinical interests revolve around the development of targeted therapies for KRAS-mutant NSCLC as well as novel strategies to overcome resistance to targeted therapies for EGFR-mutant and MET-altered NSCLC. The first line of research in my laboratory focuses on the role of the epithelial'mesenchymal transition transcription factor TWIST1 in oncogene-driven NSCLC. We have demonstrated the TWIST1 is essential for lung tumorigenesis for several key oncogenic drivers including KRAS mutant, EGFR mutant and MET mutant/amplified NSCLC. Furthermore, we have demonstrated that TWIST1 overexpression leads to resistance to EGFR and MET targeted therapies. We are currently examining the mechanism(s) through which this occurs and developing therapeutic combinations to overcome this resistance. Furthermore, we are exploring whether targeting the HGF-MET-TWIST1 pathway can be an effective strategy for preventing or treating lung brain metastases. Importantly, we have developed a novel TWIST1 inhibitor which serves a tool compound for our therapeutic studies and serves as the basis for our current drug screening efforts in order to develop a TWIST1 inhibitor that we can translate to the clinic. The second line of research in my lab focuses on studying the mechanisms of resistance to the Hsp90 inhibitor, ganetespib in KRAS-mutant NSCLC so that we can use to develop a rationally designed Hsp90 inhibitor combination for the clinic which can prevent or overcome resistance. Of note, we have recently demonstrated that the ERK-p90RSK-CDC25C pathway plays a key role in resistance to Hsp90 inhibitors through bypass of a G2/M checkpoint. These data suggest that the combination of an ERK inhibitor with an Hsp90 inhibitor maybe effective in KRAS mutant NSCLC and we hope to test this combination in early phase trials soon.

Research Interests and Keywords
  • acquired resistance
  • brain metastases
  • chemoresistance
  • Hsp90 inhibitors
  • Lung Cancer
  • Mutant KRAS
  • non-small cell lung carcinoma
  • Oncogenes
  • targeted cancer therapies
  • TWIST1
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