Laboratory of Molecular Design
Department of Biochemistry & Molecular Biology
Genetic Diagnosis and Therapy of Cancer
Cancer covers a broad spectrum of diseases, in every tissue of the body. Tissues are composed of cells, which normally grow slowly, under the tight control of a network of regulatory genes. The slow accumulation of activating mutations in growth genes, and inactivating mutations in suppressor genes, eventually allows a cell to grow out of control. Relapse is due to the development of resistant cells, rather than the escape of sensitive cells, suggesting the need for new approaches to treatment of the disease.
This laboratory is developing sequence-specific oligonucleotides against cancer genes and neurological genes for use as diagnostics and therapeutics. The cancer gene mRNAs being studied include the CCND1, MYCC, HER2, IGF1R, and KRAS2 in breast cancer, pancreas cancer, prostate cancer, colon cancer, and lung cancer.
In a new direction, we have begun to knock down two microRNAs, miR-17 and miR-21, which are overexpressed in triple negative breast cancer cells. Micro RNA precursor duplexes were thought to include an active guide strand and an inactive passenger strand. However, we discovered passenger strand activity in triple negative breast cancer cells, when anti-miR-17-3p depressed PTEN and PDCD4 protein, instead of raising them. Nuclease-resistant sequences complementary to miR-17 or miR-21 might interdict breast cancer cell growth.
The neurological genes being studied include MAOA mRNA and D2DR mRNA in certain brain cells that react strongly to cocaine. We are developing mRNA imaging agents to visualize and quantitate those two neural mRNAs in vivo. Similarly, we are developing mRNA imaging agents that target the NLGN4Y mRNA, which might be implicated in the development of autism spectrum disorders, when overexpressed. Finally, we have designed PNA sequences targeting HTT mRNA, for PET imaging of the efficacy of antisense therapy in Huntington's disease.
To move our approaches into the clinic, we must identify the most efficacious antisense and siRNA target sequences, their mechanisms and physiological effects. We must design and synthesize potent DNA and RNA analogs capable of surviving in the bloodstream following administration must be synthesized, and we must determine their structures.
To see active cancer gene mRNAs from outside the body, we synthesize peptide analogs that enable receptor-specific uptake and mRNA hybridization of peptide nucleic acids (PNA). By adding a radionuclide chelator to one end of a PNA-peptide, we can radioimage cancerous or precancerous regions by single photon emission computed tomography (SPECT) or positron emission tomography (PET). By using a branched dendrimer PNA-peptide with multiple chelators to bind gadolinium, we can see cancer gene mRNA by magnetic resonance imaging (MRI). By using twin near infrared fluorophores on the ends of a stemless PNA molecular beacon, we can see cancer gene mRNA by near infrared fluorescence (NIRF).
To translate mRNA imaging into clinical cancer management, we have licensed the breast and lung indications to Molecular Targeting Technologies, our collaborators on the NIH KRAS2 grant shown below.
Three-dimensional touch-and-feel molecular modeling and surgical simulation are being integrated with our genetic imaging scans. This study includes touch-and-feel simulations of the kinetic pathway of ligand docking with macromolecules in order to cull out kinetically unfavorable ligand designs.
- Jin, Y.-Y., Andrade, J., Simone, N. L., and Wickstrom, E. (2014) Micro ribonucleic acid passenger strand activity? PLoS One 9(1) under revision.
- Sonar, M. V., Wampole, M. E., Jin, Y.-Y., Chen, C.-P., Thakur, M. L., and Wickstrom, E. (2014) Fluorescence detection of KRAS2 mRNA hybridization in lung cancer cells with PNA-peptides containing an internal thiazole orange. Bioconjugate Chemistry 25(9):1697-1708. (Pubmed)
- Jin, L., Lim, M., Zhao, S., Sano, Y., Simone, B. A., Savage, J. E., Wickstrom, E., Camphausen, K., Pestell, R.G., and Simone, N. L. (2014) The metastatic potential of triple negative breast cancer is decreased via caloric restriction-mediated reduction of the miR-17~92 cluster. Breast Cancer Research and Treatment 146(1):41-50. (Pubmed)
- Khosravi, F., King, B., Rai, S., Kloecker, G., Wickstrom, E., and Panchapakesan, B. (2013) Nanotube devices for digital profiling: A focus on cancer biomarkers and circulating tumor cells. IEEE Nanotechnology Magazine 7(4):20-26. (Scopus)
- Paudyal, B., Zhang, K., Chen, C.-P., Mehta, N., Wampole, M. E., Mitchell, E. P., Gray, B. D., Mattis, J. A., Pak, K.-Y., Thakur, M. L., and Wickstrom, E. (2013) Determining efficacy of breast cancer therapy by PET imaging of HER2 mRNA. Nuclear Medicine and Biology 40(8):994-999. (Pubmed)
- Sanders, J. M., Wampole, M. E., Chen, C.-P., Sethi, D., Singh, A., Dupradeau, F.Y., Wang, F., Gray, B.D., Thakur, M. L., and Wickstrom, E. (2013) Effects of hypoxanthine substitution in peptide nucleic acids targeting KRAS2 oncogenic mRNA molecules: theory and experiment. Journal of Physical Chemistry B 117(39):11584–11595. (Pubmed)
- Wampole, M.E., Kairys, J. C., Mitchell, E. P., Ankeny, M. L., Thakur, M. L., and Wickstrom, E. (2013) Consistent surgeon evaluations of three-dimensional rendering of PET/CT scans of the abdomen of a patient with a ductal pancreatic mass. PLoS One 8(9):e75237 (Pubmed)
- Olejniczak, A.B., Kierzek, R., Wickstrom, E., and Lesnikowski, Z. J. (2013) Synthesis, physicochemical and biochemical studies of anti-IRS-1 oligonucleotides containing carborane and/or metallacarborane modification. Journal of Organometallic Chemistry 747:201-210. (abstract)
- Thakur, M.L., Zhang, K., Berger, A., Cavanaugh, B., Kim, S., Channappa, C., Frangos, A.J., Dascenzo, C., Wickstrom, E., and Intenzo, C.M. (2013) Targeting genomic biomarkers for PET/PEM imaging of breast cancer. Journal of Nuclear Medicine 54:(7):1019-1025. (Pubmed)
- Sanders, J. M., Wampole, M. E., Thakur, M. L., and Wickstrom, E. (2013) Molecular determinants of epidermal growth factor binding: a molecular dynamics study. PLoS One 8(1):e54136. (abstract)
- Opitz, A.W., Czymmek, K.J., Wickstrom, E., and Wagner, N.J. (2013) Uptake, efflux, and mass transfer coefficient of fluorescent PAMAM dendrimers into pancreatic cancer cells. Biochimica et Biophysica Acta - Biomembranes, 1828(2) 294–301. (Pubmed)
- Sethi, D., Thakur, M. L., and Wickstrom, E. (2012) Receptor-specific peptides for targeting of liposomal, polymeric, and dendrimeric nanoparticles in cancer diagnosis and therapy. Current Molecular Imaging 1(1):3-11. (Abstract)
- Sethi, D., Chen, C.-P., Jing, R.-Y., Thakur, M. L., and Wickstrom, E. (2012) Fluorescent peptide-PNA chimeras for imaging monoamine oxidase A mRNA in neuronal cells. Bioconjugate Chemistry 23(2):158-163. (Pubmed)
- Thakur, M. L., Zhang, K., Paudyal, B., Devakumar, D., Covarrubias, M., Chen, C.-P., Gray, B. D., Wickstrom, E., and Pak, K.-Y. (2012) Targeting apoptosis for optical imaging of infection. Molecular Imaging and Biology 14(2):163-171. (Pubmed)
- Wickstrom, E., Chen, C.-P., Devadhas, D., Wampole, M., Jin, Y.-Y., Sanders, J. M., Kairys, J. C., Ankeny, M. L., Hu, R., Barner, K. E., Steiner, K. V., and Thakur, M. L. (2011) Three dimensional projection environment for molecular design and surgical simulation. Studies in Health Technologies and Informatics 163:691-695. (Pubmed)
- Chen, C.-P., and Wickstrom, E. (2010) Daptomycin-tetraethyleneglycol-bisphosphonate-Ti6Al4V foils resist Staphylococcus aureus colonization. Bioconjugate Chemistry 21(11):1978–1986. (Pubmed)
- Opitz, A.W., Thakur, M.L., Wickstrom, E., and Wagner, N.J. (2010) Physiologically based pharmacokinetics of molecular imaging nanoparticles for mRNA detection determined in tumor-bearing mice. Oligonucleotides 20(3):117-125. (Pubmed)
- Amirkhanov, N.V., Zhang, K., Aruva, M. R., Thakur, M.L., and Wickstrom, E. (2010) Imaging human pancreas cancer xenografts by targeting mutant KRAS2 mRNA with [111In]DO3An-poly(diamidopropanoyl)m-KRAS2 PNA-D(Cys-Ser-Lys-Cys) nanoparticles. Bioconjugate Chemistry 21(4):731-40. (Pubmed)
- Thakur, M. L., Zhang, K., Devadhas, D., Pestell, R.G., and Wickstrom, E. (2010) Imaging spontaneous MMTVneu transgenic mammary tumors: Targeting metabolic activity versus genetic products. Journal of Nuclear Medicine 51(1):106-111. (Pubmed)
- Wickstrom, E., and Thakur, M. L. (2010) Genetic and molecular approaches to imaging breast cancer. In: Sauter, E. R., and Daly, M. B., eds., Breast Cancer Risk Reduction and Early Detection, Springer, Boston, Chap. 9, 163-182. (Abstract)
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- NIH 1 R01 CA157372-02 $2,252,751, VPAC1 Receptor-Targeted PET Imaging of Prostate Cancer, Mathew Thakur, PI, Eric Wickstrom, co-I, 20% effort, 1 May 2012-30 Apr 2016, second year direct costs $393,876 (Abstract)
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