UPMC Hillman Cancer Center

Preclinical Drug Discovery and Development

PX-866CTP investigators are focused on the pre-clinical discovery, design, and development of novel agents and/or combination regimens for cancer therapy. New molecules discovered in CTP laboratories that are directed against a range of interesting and novel targets are in various stages of drug development; while some of these agents are in early in vitro testing, others have moved on to in vivo model systems, and several are being tested in early phase clinical trials.

Selected Publications

  • Hyperactivation of signal transducer and activator of transcription 3 (STAT3) has been linked to tumorigenesis in most malignancies, including head and neck squamous cell carcinoma. Intravenous delivery of a chemically modified cyclic STAT3 decoy oligonucleotide with improved serum and thermal stability demonstrated antitumor efficacy in conjunction with downmodulation of STAT3 target gene expression such as cyclin D1 and Bcl-X(L) in a mouse model of head and neck squamous cell carcinoma. Recent findings suggest a lack of toxicity of intravenous administration of a cyclic STAT3 decoy oligonucleotide, with comparable antitumor effects at two dose levels investigated. (Sen et. al., Mol Med. 2014 Mar 18;20:46-56.)
  • Profilin-1 (Pfn-1) is a ubiquitously expressed actin-binding protein that is essential for normal cell proliferation and migration. In breast cancer and several other adenocarcinomas, Pfn-1 expression is downregulated when compared to normal tissues. A multiplexed phenotypic screen was performed to identify compounds that inhibit cell motility through upregulation of Pfn-1. Two bona fide inducers of Pfn-1, purvalanol and tyrphostin A9, were identified, illustrating the utility of the high-content cell motility assay to discover novel targeted anti-migratory agents by integrating functional phenotypic analyses with target-specific readouts in a single assay platform. (Joy et. al., PLoS One. 2014 Feb 10;9(2):e88350.)
  • The myeloid cell leukemia-1 (MCL1) gene encodes antiapoptotic Mcl-1(L) and proapoptotic Mcl-1(S) proteins. In cancer, the Mcl-1(L)/Mcl-1(S) ratio is very high, accounting for the antiapoptotic nature of cancer cells. As such, reducing this ratio can render the cancer cells prone to apoptosis. The Mcl-1(L)/Mcl-1(S) ratio is determined in the alternative pre-mRNA splicing step that is regulated by splicing factor 3B1 (SF3B1). A recent study showed that meayamycin B, a potent inhibitor of SF3B1, reversed the dominant isoform from Mcl-1(L) to Mcl-1(S) at the mRNA and protein levels. The resulting proapoptotic cellular environment was further exploited; when meayamycin B was combined with Bcl-x(L) inhibitor ABT-737, the combination treatment triggered apoptosis in non-small cell lung cancer A549 and H1299 cells that were otherwise resistant to ABT-737. These results demonstrate that perturbation of the MCL1 splicing with small molecule inhibitors of SF3B1 provides a means to sensitize cancer cells toward Bcl-x(L) inhibitors. (Gao and Koide. ACS Chem Biol. 2013 May 17;8(5):895-900.)
  • PEGylated lipopeptide surfactants carrying drug-interactive motifs specific for a peptide-nitroxide antioxidant, JP4-039, were designed and constructed to facilitate the solubilization of this drug candidate as micelles and emulsion nanoparticles. This process can be extended to the design and development of new lipidic and polymeric systems for improved in vivo delivery of anticancer agents (Gao et. al., Mol Pharm. 2013 Jan 7;10(1):187-98.)

Members

Beumer, Jan-Hendrik, PharmD, PhD
Pharmaceutical Sciences
Li, Song, MD, PhD
Pharmaceutical Sciences
Boyiadzis, Michael, MD
Medicine
Parikh, Rahul, MD, PhD
Medicine
Curran, Dennis, PhD
Chemistry
Premkumar, Daniel, PhD
Neurological Surgery
Chu, Edward, MD
Medicine
Schmitz, John, PhD
Medicine
Deiters, Alexander, PhD
Chemistry
Schurdak, Mark, PhD
Computational and Systems Biology
Eiseman, Julie, PhD
Pharmacology & Chemical Biology
Sun, Dandan, MD, PhD
Neurology
Freeman, Bruce, PhD
Pharmacology & Chemical Biology
Taylor, D. Lansing, PhD
Computational and Systems Biology
Islam, Kabirul, PhD
Chemistry
Vogt, Andreas, PhD
Computational and Systems Biology
Jiang, Yu, PhD
Pharmacology & Chemical Biology
Wang, Qiming, PhD
Pharmacology & Chemical Biology
Johnston, Paul, PhD
Pharmaceutical Sciences
Wipf, Peter, PhD
Chemistry
Kagan, Valerian, PhD, DSc
Environmental & Occupational Health
Xie, Wen, MD, PhD
Pharmaceutical Sciences
Koide, Kazunori, PhD
Chemistry
Xie, Xiang-Qun, PhD, MBA
Pharmaceutical Sciences
Lagasse, Eric, PharmD, PhD
Pathology
Zeng, Dexing, PhD
Radiology