UPMC Hillman Cancer Center

Mechanisms of Action of Anticancer Agents

Laboratory ResearchCTP researchers are evaluating a variety of key cancer cell signaling mechanisms, and the way in which anticancer drugs may be working to target specific molecules and pathways within cancer cells. These molecular targets include nuclear and cellular matrix proteins, transcription factors, growth factors, kinase receptors and other transmembrane proteins, and hormone and hormone receptors, among others.

Selected Publications

  • One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue, CTP members sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. This study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. (Gough et. al., PLoS One. 2014 Jul 18;9(7):e102678.)
  • Protein kinase D (PKD) signaling plays a critical role in the regulation of DNA synthesis, proliferation, cell survival, adhesion, invasion/migration, motility, and angiogenesis. CTP members discovered that PKD2 was the dominant isoform expressed in human colon cancer cells, and that suppression of PKD using the small molecule inhibitors CRT0066101 and kb-NB142-70 resulted in low micromolar in vitro antiproliferative activity against multiple human colorectal cancer cell lines. Daily administration of CRT0066101 resulted in significant inhibition of tumor growth in HCT116 xenograft nude mice. Taken together, these studies show that PKD plays a significant role in mediating growth signaling in colorectal cancer and may represent a novel chemotherapeutic target for the treatment of colorectal cancer. (Wei et. al., Mol Cancer Ther. 2014 May;13(5):1130-41.)
  • The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G(2) arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. CTP members have now determined that the ATR-CHEK1 pathway is upregulated in a subset of oral squamous cell carcinoma (OSCC) with distal 11q loss and loss of the G(1) phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G(2) checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR-CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC. (Parikh et. al., Genes Chromosomes Cancer. 2014 Jan;53(1):25-37.)
  • Mammalian target of rapamycin (mTOR) has been suggested as a crucial modulator of tumor biology. Expression of mTOR and the effect of mTOR inhibition in cancer stem-like cells isolated from three human metastatic CRCs (CoCSCs) was evaluated. CoCSCs exhibited a strong mTOR complex 2 (mTORC2) expression, and a rare expression of mTOR complex 1 (mTORC1). This latter correlated with differentiation, being expressed in CoCSC-derived xenografts. The apoptosis-inducing mTOR inhibitor Torin-1 hindered growth, motility, invasion, and survival of CoCSCs in vitro, and suppressed tumor growth in vivo with a concomitant reduction in vessel formation. Torin-1 also affected the expression of markers for cell proliferation, angio-/lympho-genesis, and stemness in vivo. Importantly, Torin-1 did not affect the survival of normal colon stem cells in vivo, suggesting its selectivity towards cancer cells. (Francipane et. al., Oncotarget. 2013 Nov;4(11):1948-62.)

Members

Amankulor, Nduka, MD
Neurological Surgery
Pollack, Ian, MD
Neurological Surgery
Beumer, Jan-Hendrik, PharmD, PhD
Pharmaceutical Sciences
Schmitz, John, PhD
Medicine
Chu, Edward, MD
Medicine
Schurdak, Mark, PhD
Computational and Systems Biology
Duensing, Anette, MD
Pathology
Sen, Malabika, PhD
Medicine
Eiseman, Julie, PhD
Pharmacology & Chemical Biology
Taylor, D. Lansing, PhD
Computational and Systems Biology
Freeman, Bruce, PhD
Pharmacology & Chemical Biology
Vogt, Andreas, PhD
Computational and Systems Biology
Jocaobson, Rebecca Crowley, MD
Biomedical Informatics (DBMI)
Wang, Qiming, PhD
Pharmacology & Chemical Biology
Kagan, Valerian, PhD, DSc
Environmental & Occupational Health
Wipf, Peter, PhD
Chemistry
Lagasse, Eric, PharmD, PhD
Pathology