Laboratory of Molecular Design
Department of Biochemistry & Molecular Biology
Genetic Diagnosis and Therapy of Cancer
- Eric Wickstrom, Ph.D., Professor
- Yuan-Yuan Jin, Ph.D., Visiting Scientist
- Vilas Desai, Ph.D., Research Associate
- Prabhakar U. Pawar, Ph.D., Postdoctoral Fellow
- Kaitlyn Uhrick, M.S., PhD Student
- Jason Mazzatenta, M.S., Visiting Scientist
- Joshua Kovich, B.S., PhD Student
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-17-5p depressed PTEN and PDCD4 protein, instead of raising them. Nuclease-resistant sequences that specifically block miR-17 or miR-21 might interdict triple negative breast cancer cell growth.
To translate microRNA blockade into clinical cancer management, TJU has licensed our technology to Bound Therapeutics LLC.
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 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 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 see cancer gene mRNA by near infrared fluorescence (NIRF).
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.
Both the RNA imaging approach and the virtual reality approach are being applied to the problem of varying levels of 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.
- Tripathi, S., Kean, R., Bongiorno, E., Hooper, D.C., Jin, Y.-Y., Wickstrom, E., McCue, P.A., and Thakur, M.L. (2019) Targeting VPAC1 receptors for imaging glioblastoma. Molecular Imaging in Biology Jun 18. doi: 10.1007/s11307-019-01388-5. (Pubmed)
- Kumar, P., Tripathi, S., Chen, C.-P, Wickstrom, E., and Thakur, M.L. (2019) Evaluating Ga-68 peptide conjugates for targeting VPAC receptors: Stability and pharmacokinetics. Molecular Imaging in Biology 21:(1):130-139. (Pubmed)
- Oh, E., Liu, Y., Sonar, M. V., Merry, D. E., and Wickstrom, E. (2018) Fluorescence imaging of huntingtin mRNA knockdown. Bioconjugate Chemistry 29(4):1276-1282. (Pubmed)
- Chen, C.-P., Jing, R.-Y., and Wickstrom, E. (2017) Covalent attachment of daptomycin to Ti6Al4V alloy surfaces by a thioether linkage to inhibit colonization by Staphylococcus aureus. ACS Omega 2:1645-1652. (Pubmed)
- Trabulsi, E.J., Tripathi, S., Solomides, C., Wickstrom, E., Gomella, L.G., and Thakur, M.L. (2017) Development of a voided urine assay for detecting prostate cancer noninvasively: a pilot study. British Journal of Urology International 119(6):885-895. (Pubmed)
- Khosravi, F., Trainor, P., Lambert, G., Kloecker, G., Wickstrom, E., Rai, S.N., and Panchapakesan, B. (2016) Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube-CTC-chip. Nanotechnology 27(444):44LT03 (18pp). (Pubmed)
- Kumar, P., Tripathi, S., Chen, C.-P., Mehta, N., Paudyal, B., Wickstrom, E., and Thakur, M.L. (2016) Evaluation of a PACAP peptide analog labeled with 68Ga using two different chelating agents. Cancer Biotherapy and Radiopharmaceuticals 31(1):29-36. (Pubmed)
- Khosravi, F., Trainor, P., Rai, S., Kloecker, G., Wickstrom, E., and Panchapakesan, B. (2016) Label-free capture of breast cancer cells spiked in buffy coats using carbon nanotube antibody micro-arrays. Nanotechnology 27(13):13LT02, doi:10.1088/0957-4484/27/13/13LT02. (Pubmed)
- Jin, Y.-Y., Andrade, J., and Wickstrom, E. (2015) Non-specific blocking of miR-17-5p guide strand in triple negative breast cancer cells by amplifying passenger strand activity. PLoS One 10(12):e0142574. (Pubmed)
- Wickstrom, E. (2015) DNA and RNA derivatives to optimize distribution and delivery. Adv Drug Deliv Rev. 87:25-34. (Pubmed)
- 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)
- Bound Therapeutics Pilot, $493,696, Triple Negative Breast Cancer Therapy by microRNA Blockade, Eric Wickstrom, PI, 01 Mar 2016-30 Jun 2021, current year direct costs $108,579 (Abstract)
- NIH 1 R41 CA 235707-01A1, $299,774, microRNA-21 Blockade of Triple Negative Breast Cancer, Eric Wickstrom, PI, 15 Jun 2019-31 May 2020, first year direct costs $258,309 (Abstract)
- KOP Therapeutics, $714,000, Product Development for Cancer Therapy Targeting an Unrecognized Oncogene mRNA, Eric Wickstrom and Mathew Thakur, PIs, 50% effort each, 24 Oct 2019-23 Oct 2020, first year direct costs $460,000 (Abstract)
- CHDI Foundation A14615, $662,687, Huntingtin mRNA PET Imaging to Quantify Therapeutic Efficacy, Eric Wickstrom and Mathew Thakur, PIs, 10% effort each, 01 Feb 2020-31 Jan 2022, first year direct costs $282,488 (Abstract)
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- Jin, Y.-Y., Andrade, J., and Wickstrom, E. (2015) Non-specific blocking of miR-17-5p guide strand in triple negative breast cancer cells by amplifying passenger strand activity. PLoS One 10(12):e0142574 (open source)
miR-17-5p guide strand blocker: 5�-dACCTGCACTGTAAGCACTTTG-3�
miR-17-3p passenger strand blocker: 5'-dTACAAGTGCCTTCACTGCAG-3�
miR-21-5p guide strand blocker: 5'-dCAACATCAGTCTGATAAGCT-3�