A variety of research projects from members of the UACC are highlighted below
Therapeutic Development Program - Developing Unique Anti-Cancer Targets
Brown, R. V., Danford, F. L., Gokhale, V., Hurley, L. H., & Brooks, T. A. (2011). Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex. The Journal of Biological Chemistry, 286:(47), 41018–41027.
- Surface Plasmon Resonance (SPR) is a direct method for studying binding interactions in real time without labels.
- The PSR’s Biacore T100 SPR Biosensor was used to confirm that GQC-05, a molecule from the NCI Compound Library, selectively binds to a G-quadruplex area on a promoter region of the myc gene (MYC G4).
- Biotinylated MYCpu41 oligomer was captured on a streptavidin chip. The quindoline derivatives, GQC-Qi (known to bind MYC G4) or GQC-05, were passed over the chip surfaces at varying concentrations, and the change in refractive index at the surface was monitored.
- MYC G4-binding affinity for GQC-05 (dissociation constant, KD) was calculated by plotting response vs. small molecule concentration.
- These results demonstrate how SPR can be used to effectively screen novel anti-cancer drug candidates.
Cancer Biology Program - Developing New Methods to Quantify Neuropeptides Associated with Pain Receptors
Laude, N. D., Meske, D. S., Kramer, C. L., Lemister, E., Navratilova, E., Porreca F., Heien, M. L. (2015). Quantification of Endogenous Opioid Peptide Dynamics in the Anterior Cingulate Cortex by Online-Preservation Microdialysis, Manuscript Submitted to Nature Scientific Reports.
- Mapping the dynamic changes of endogenous opioid peptides (EOPs) in specific brain circuits is needed to assess their roles in chronic pain conditions common in some human cancers – Better management of cancer pain.
- Nick Laude, a graduate student trained by PSR scientists, developed a method to detect (EOPs) at attomole levels from in vivo microdialysis-obtained CNS fluid.
- First ever quantitative LC-MS measurements of enkephalins in the anterior cingulate cortex.
- Reliable electrospray ionization by a chip-based source, combined with the high resolution and accurate mass analysis by the LTQ-Orbitrap mass spectrometer, were essential to the success of this analysis.
Cancer Biology Program - Identifying Chemopreventive Natural Products and Elucidating their Mechanisms of Action
Radkakrishnan, V. M., Kojs, P., Young, G., Ramalingam, R., Jagadish, B., Mash, E. A., Martinez, J. D., Ghishan, F. K., Kiela, P. R. (2014). pTyr421 Cortactin Is Overexpressed in Colon Cancer and Is Dephosphorylated by Curcumin: Involvement of Non-Receptor Type 1 Protein Tyrosine Phosphatase (PTPN1). PLoS One, 9(1): e85796.
- Cortactin (CTTN) is a direct target of curcumin in colorectal cancer cells. CTTN, first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in-cell motility and invasion. The phosphorylated form of cortactin (pTyr421) is required for cancer cell motility and invasion.
- The PSR was able to use a global proteomics approach to show that CTTN was a direct curcumin target in colorectal cancer cells. Curcumin is a natural compound with promising chemopreventive and chemosensitizing effects.
- Collectively, the data from this study suggested that curcumin is an activator of Non-Receptor Type 1 Protein Tyrosine Phosphatase and can reduce cell motility in colon cancer via dephosphorylation of pTyr421-CTTN. This finding could be exploited for novel and individualized treatment (precision medicine) in colon cancer.
Cancer Prevention and Control Program - Are Biodiesel Emissions Safer than Diesel Emissions in Underground Mines?
Mehus A.A., Reed R.J., Lee V.S., Littau S.R., Hu C., Lutz E.A., Burgess J.L. (2015). Comparison of Acute Health Effects From Exposures to Diesel and Biodiesel Fuel Emissions. Journal of Occupational and Environmental Medicine, 57(7):705-12,
- Forty eight subjects were exposed to vehicle exhaust in an underground mine, alternating the use of diesel (diesel emissions are a known carcinogen) with a 75% biodiesel/25% diesel blend fuel, sputum and plasma were collected.
- The PSR depleted albumin and 11 other highly abundant proteins by affinity chromatography to allow detection of potential biomarkers that may be in lower concentrations.
- Proteins were enzymatically digested into peptides, and analyzed in triplicate by LC-MS/MS on the LTQ Orbitrap Velos. A total of 848 sputum and 407 plasma proteins were identified and quantified.
- 42 and 32 novel candidate biomarkers were selected in sputum and plasma, respectively. Demonstrates CPC research and outreach that may lead to lowering the risk of cancer in miners.