UPMC Hillman Cancer Center

Timothy Burns, MD, PHD

Timothy Burns
Assistant Professor of Medicine


Contact Information

Contact Information

Hillman Cancer Center Suite 2.18
5117 Centre Avenue
Pittsburgh, PA 15232

Phone: 412-623-7877
Email: burnstf@upmc.edu
Fax: 412-623-7768

Administrative Assistant
Name: Carm Campbell
Phone: 412-623-7770
Email: campbellcm@upmc.edu
Fax: 412-623-7768

Research Keywords

Research Keywords

Mutant KRAS; oncogenes; non-small cell lung carcinoma; lung cancer; TWIST1; chemoresistance; Hsp90 inhibitors; targeted cancer therapies; acquired resistance; brain metastases

Research Summary

Research Summary


TWIST1 Signaling

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.

Selected Publications

Selected Publications

  • Ancevski Hunter K, Friedland DM, Villaruz LC, Burns TF. First-line osimertinib in patients with treatment-naive somatic or germline EGFR T790M-mutant metastatic NSCLC. J Thorac Oncol. 2018 Jan;13(1):e3-e5. PubMed Link
  • Yochum ZA, Cades J, Mazzacurati L, Neumann NM, Khetarpal SK, Chatterjee S, Wang H, Attar MA, Huang EH, Chatley SN, Nugent K, Somasundaram A, Engh JA, Ewald AJ, Cho YJ, Rudin CM, Tran PT, Burns TF. A first-in-class TWIST1 inhibitor with activity in oncogene-driven lung cancer. Mol Cancer Res. 2017 Dec;15(12):1764-1776. PubMed Link
  • Chatterjee S, Huang EH, Christie I, Burns TF. Reactivation of the p90RSK-CDC25C pathway leads to bypass of the ganetespib induced G2/M arrest and mediates acquired resistance to ganetespib in KRAS mutant NSCLC. Mol Cancer Ther. 2017 Aug;16(8):1658-1668. PubMed Link
    Shared Resources Used: AF, CF
  • Chatterjee S, Huang EH, Christie I, Kurland BF, Burns TF. Acquired resistance to the Hsp90 inhibitor, ganetespib in KRAS mutant NSCLC is mediated via reactivation of the ERK-p90RSK-mTOR signaling network. Mol Cancer Ther. 2017. 16(5):793-804. PubMed Link
    Shared Resources Used: AF, CF
  • Somasundaram A, Burns TF. The next generation of immunotherapy: keeping lung cancer in check. J Hematol Oncol. 2017;10(1):87 PubMed Link
  • Chatterjee S, Bhattacharya S, Socinski MA, Burns TF. HSP90 inhibitors in lung cancer: promise still unfulfilled. Clin Adv Hematol Oncol. 2016 May;14(5):346-56. PubMed Link
  • Bhattacharya S, Socinski MA, Burns TF. KRAS mutant lung cancer: progress thus far on an elusive therapeutic target. Clin Transl Med. 2015;4(1):35. PubMed Link
  • Somasundaram A, Socinski MA, Burns TF. Personalized treatment of EGFR mutant and ALK-positive patients in NSCLC. Expert Opin Pharmacother. 2014 Dec;15(18):2693-708. PubMed Link
  • Burns TF, Dobromilskaya I, Murphy SC, Gajula RP, Thiyagarajan S, Chatley SN, Aziz K, Cho YJ, Tran PT, Rudin CM. Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer. Mol Cancer Res 2013 Apr; 11(4):329-38. PubMed Link
  • Tran PT*, Shroff EH*, Burns TF*, Thiyagarajan S, Das ST, Zabuawala T, Chen J, Cho YJ, Luong R, Tamayo P, Salih T, Aziz K, Adam SJ, Vicent S, Nielsen CH, Withofs N, Sweet-Cordero A, Gambhir SS, Rudin CM, Felsher DW. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis. PLoS Genet. 2012;8(5):e1002650. PubMed Link

See all pubs (Pubmed)

Collaborations

Collaborations

Current Internal Collaborators

Christopher Bakkenist, PhD
Development of ATR/ATM inhibitors for lung cancer
Member - Molecular and Cellular Cancer Biology Program (MCCBP)

Sanja Dacic, MD, PhD
Role of TWIST1 in oncogene-driven NSCLC; Role of the HGF-MET-TWIST1 pathway in lung brain metastases
Member - Lung Cancer Program (LCP)

Hannah Rabinowich, PhD
Mechanisms of acquired resistance to Hsp90 inhibitors and other targeted therapies
Member - Cancer Immunology Program (CIP)

Laura Stabile, PhD
Role of TWIST1 in MET-driven NSCLC; Role of the HGF-MET-TWIST1 pathway in lung brain metastases; Role of anti-estrogens in overcoming resistance to immunotherapy in NSCLC
Member - Lung Cancer Program (LCP)

Current External Collaborators

Andres Ewald, PhD
Development of TWIST1 inhibitors
Johns Hopkins University

Charles Rudin, MD, PhD
Development of TWIST1 inhibitors
Memorial Sloan Kettering Cancer Center

Phuoc Tran, MD, PhD
Role of TWIST1 in EGFR-mutant NSCLC; Development of TWIST1 inhibitors
Johns Hopkins University

Shared Resource Usage

Shared Resource Usage

  • Animal Facility
  • Biostatistics Facility
  • Cytometry Facility
  • In Vivo Imaging Facility
  • Tissue and Research Pathology Services

Affiliated Graduate Programs

Affiliated Graduate Programs

  • Molecular Pharmacology

Department Website









Last modified: 2/2/18