University of Pittsburgh Cancer Institute (UPCI)

New Therapeutic Targets and Rational Combinations of
Targeted Therapies

Targeted therapies LCP investigators are defining the molecular pathways that contribute to the development and progression of lung malignancies, and strive to translate their findings into novel therapeutics to improve clinical outcomes for lung cancer patients. Since traditional chemotherapy has proven to be of limited effectiveness for treating lung cancer, LCP members are exploring innovative targeted and combination therapies in clinical trials at the Lung Cancer Specialty Care Center (LCSCC) of UPCI and UPMC CancerCenter.

Selected Publications

  • Although anatomic segmentectomy has been considered a compromised procedure by many surgeons, recent retrospective, single-institution series have demonstrated tumor recurrence and patient survival rates that approximate those achieved by lobectomy. In a large propensity-matched comparison, lobectomy was associated with modestly increased freedom from recurrence and overall survival, but the differences were not statistically significant. (Landreneau et. al, J Clin Oncol. 2014 Aug 10;32(23):2449-55.)
  • To determine whether Gramicidin S (GS)-nitroxide, JP4-039, esophageal radiation protection protected lung tumors in a transgenic model, LoxP-Stoop-LoxP Kristen Rat Sarcoma Viral oncogene (LSL-K-RAS) mice were administered intra-tracheal- CRE recombinase, bilateral lung tumors were confirmed at 11 weeks, then thoracic irradiation was delivered. Results indicated that intraesophageal radioprotective small-molecule antioxidant therapy protects normal tissue but not tumor tissue in mice with transgenic lung tumors. (Epperly et. al., In Vivo. 2014 Jul-Aug;28(4):435-40.)
  • LCP researchers found that SUV(max) appears to be a statistically and clinically significant independent prognostic marker for progression-free survival in patients with stage I non-small cell lung cancer treated with stereotactic body radiation therapy. (Horne et. al., Radiat Oncol. 2014 Jan 30;9:41.)
  • A large fraction of non-small cell lung cancers (NSCLC) are dependent on defined oncogenic driver mutations. Although targeted agents exist for EGFR- and EML4-ALK-driven NSCLCs, no therapies target the most frequently found driver mutation, KRAS. LCP members showed that silencing of TWIST1 in KRAS-mutant human NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or, in some cases, apoptosis. Similar effects were observed in EGFR mutation-driven and c-Met-amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was independent of p53 or p16 mutational status and did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 resulted in significant growth inhibition of KRAS-mutant, EGFR-mutant, and c-Met-amplified NSCLCs. Remarkably, inducible silencing of TWIST1 resulted in significant growth inhibition of established KRAS-mutant tumors. Together these findings suggest that silencing of TWIST1 in oncogene driver-dependent NSCLCs represents a novel and promising therapeutic strategy. (Burns et. al., Mol Cancer Res. 2013 Apr;11(4):329-38.)

Members

Burns, Timothy, MD, PhD
Medicine
Luketich, James, MD
Surgery
Christie, Neil, MD
Surgery
Pennathur, Arjun, MD
Surgery
Dacic, Sanja, MD, PhD
Pathology
Reilly, John, MD
Medicine
Deutsch, Melvin, MD
Radiation Oncology
Schuchert, Matthew, MD
Cardiothoracic Surgery
Dhir, Rajiv, MD
Pathology
Sciurba, Frank, MD
Medicine
Epperly, Michael, PhD
Radiation Oncology
Shapiro, Steven, MD
Medicine
Gladwin, Mark, MD
Medicine
Socinski, Mark, MD
Medicine
Greenberger, Joel, MD
Radiation Oncology
Stabile, Laura, PhD
Pharmacology & Chemical Biology
Herman, James, MD
Medicine
Villaruz, Liza, MD
Medicine
Levina, Vera, PhD
Medicine