Laboratory of Molecular Design
Department of Biochemistry & Molecular Biology
Genetic Diagnosis and Therapy of Cancer

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  • Eric Wickstrom, Ph.D., Professor
    215-955-4578 fax: 215-955-4580
  • Chang-Po Chen, Ph.D., Research Associate
    215-955-0828
  • Matthew E. Wampole, Ph.D., Postdoctoral Research Fellow
    215-955-1361
  • Yuan-Yuan Jin, B.S., Graduate Student
    215-955-1361
  • Jeffrey M. Sanders, B.S., Graduate Student
    215-955-1361
  • John Miscenich, M.B.A., Volunteer Administrator
    215-955-4579

Research Focus:

RHI       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 cancer gene-specific oligonucleotides and siRNAs against cancer genes in the signal transduction pathway for use as diagnostics and therapeutics for cancers. The biological systems being studied include the CCND1, EGFR, HER2, IGF1R, and KRAS2 cancer genes in breast cancer, ovarian cancer, pancreas cancer, prostate cancer, colon cancer, lymphoma, and lung cancer. 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.
nano       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).
      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 genetic 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 to react strongly to cocaine. We are developing genetic imaging agents to visualize and quantitate those two neural mRNAs in vivo.
      We can destroy IRS1 cancer gene mRNA in breast cancer cells and MKP1, BIM, and BCL2 cancer gene mRNAs in acute lymphoblastic leukemia cells with short interfering RNA (siRNA) sequences. We can stop KRAS2 cancer gene mRNA production in pancreas cancer cells with PNA-peptide sequences. We also use negatively charged PNA to turn off cancer gene orthologs in zebrafish.
van       Cancer cells begin to slough off into the bloodstream as a tumor becomes malignant. We are developing noninvasive detection of circulating tumor cells with monoclonal antibodies adsorbed to single wall carbon nanotube junctions. This approach will be especially useful for underserved communities.
      Infections that develop on medical implants inflict great damage. We can stop infections before they start by covalently bonding therapeutics, such as antibiotics, chemotherapeutics, peptides, or oligonucleotides, to titanium and other implant materials via flexible, hydrophilic spacers.


Recent Publications:

  1. 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, in press. (Abstract)
  2. 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, in press. (Pubmed)
  3. 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)
  4. Chen, C.-P., and Wickstrom, E. (2010) Daptomycin-tetraethyleneglycol-bisphosphonate-Ti6Al4V foils resist Staphylococcus aureus colonization. Bioconjugate Chemistry 21(11):1978–1986. (Pubmed)
  5. 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)
  6. 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)
  7. 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)
  8. 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)
  9. Mukherjee, A., Wickstrom, E., and Thakur, M. L. (2009) Imaging oncogene expression. European Journal of Radiology 70(2):265-273. (Pubmed)
  10. Shao, N., Wickstrom, E., and Panchapakesan, B. (2008) Nanotube-antibody biosensor arrays for detection of circulating breast cancer cells. Nanotechnology 19:465101 (11 pp). (Abstract)
  11. Antoci, V., Jr., Adams, C. S., Parvizi, J., Davidson, H. M., Composto, R. J., Freeman, T. A., Wickstrom, E., Ducheyne, P., Jungkind, D., Shapiro, I. M., and Hickok, N. J. (2008) The inhibition of Staphylococcus epidermidis biofilm formation by vancomycin-modified titanium alloy and implications for the treatment of periprosthetic infection. Biomaterials 29(35):4684–4690. (Pubmed)
  12. Zhang, C.-M., Liu, C.-P., Christian, T., Gamper, H., Rozenski, J., Randolph, J.B., Wickstrom, E., Cooperman, B.S., and Hou, Y.-M. (2008) Pyrrolo-C as a molecular probe for monitoring conformations of the tRNA 3' end. RNA 14(10):2245-2253. (Pubmed)
  13. Amirkhanov, N.V., Dimitrov, I., Opitz, A.W., Zhang, K., Lackey, J.P., Cardi, C.A., Wagner, N.J., Lai, S., Thakur, M.L., and Wickstrom, E. (2008) Design of (Gd-DO3A)n-polydiamidopropanoate-peptide nucleic acid-D(Cys-Ser-Lys-Cys) magnetic resonance contrast agents. Biopolymers 89(12):1061-1076. (Pubmed)
  14. Tian, X., Michal, A.M., Li, P., Wolfe, H.R., Waldman, S.A., and Wickstrom, E. (2008) STa peptide analogs for probing guanylyl cyclase C. Peptide Science 90(5):713-723. (Pubmed)
  15. Millar, H.J., Nemeth, J.A., McCabe, F.L., Pikounis, B., and Wickstrom, E. (2008) Circulating human interleukin-8 as an indicator of cancer progesssion in a human non-small cell lung carcinoma model. Cancer Epidemiology, Biomarkers & Prevention 17(8):2180-2187. (Pubmed)
  16. Zhang, K., Aruva, M. R., Shanthly, N., Cardi, C. A., Rattan, S., Patel, C., Kim, C., McCue, P. A., Wickstrom, E., and Thakur, M. L. (2008) PET imaging of VPAC1 expression in experimental and spontaneous prostate cancer. Journal of Nuclear Medicine 49(1):112-121. (Pubmed)
  17. Cesarone, G., Edugupanti, O.M., Chen, C.-P., and Wickstrom, E. (2007) Insulin receptor substrate 1 knockdown in human MCF7 estrogen receptor-positive breast cancer cells by nuclease-resistant IRS1 siRNA conjugated to a disulfide-bridged D-peptide analog of insulin-like growth factor 1. Bioconjugate Chemistry 18(6):1831-1840. (Pubmed)
  18. Tian, X., Aruva, M. R., Zhang, K., Cardi, C. A., Thakur, M. L., and Wickstrom, E. (2007) PET imaging of CCND1 mRNA in human MCF7 estrogen receptor-positive breast cancer xenografts with an oncogene-specific [64Cu]DO3A-PNA-IGF1 analog radiohybridization probe. Journal of Nuclear Medicine 48(10):1699-1707. (Pubmed)
  19. Chen, C.-P., Zeiger, A.R., and Wickstrom, E. (2007) Bactericidal activity of extended 9-glycyl-amido-minocyclines. Bioorganic & Medicinal Chemistry Letters 17(23):6558-6562. (Pubmed)
  20. Zhang, K., Aruva, M.R., Shanthly, N., Cardi, C.A., Patel, C.A., Rattan, S., Cesarone, G., Wickstrom, E., and Thakur, M.L. (2007) Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) receptor specific peptide analogues for PET imaging of breast cancer: In vitro/in vivo evaluation. Regulatory Peptides 144(1-3):91-100. (Pubmed)
  21. Yakubov, L.A., Rogachev, V.A., Likhacheva, A.C., Bogachev, S.S., Sebeleva, T.E., Shilov, A.G., Baiborodin, S.I., Petrova, N.A., Mechetina, L.V., Shurdov, M.A., and Wickstrom, E. (2007) Natural human gene correction by small extracellular genomic DNA fragments. Cell Cycle 6(18):2293-2301. (Pubmed)
  22. Chakrabarti, A., Zhang, K., Aruva, M.R., Cardi, C.A., Opitz, A.W., Wagner, N.J., Thakur, M.L., and Wickstrom, E. (2007) Radiohybridization PET imaging of KRAS G12D mRNA expression in human pancreas cancer xenografts with [64Cu]DO3A-peptide nucleic acid-peptide nanoparticles. Cancer Biology & Therapy 6(6):948-956. (Pubmed)
  23. Shao, N., Lu, S., Wickstrom, E., and Panchapakesan, B. (2007) Integrated molecular targeting of IGF1R and Her2 surface receptors and destruction of breast cancer cells using single wall carbon nanotubes. Nanotechnology 18(31):315101 (9 pp). (Abstract)
  24. Duffy, K. T. and Wickstrom, E. (2007) Zebrafish tp53 knockdown extends the survival of irradiated zebrafish embryos more effectively than the p53 inhibitor pifithrin-alpha. Cancer Biology and Therapy 6(5):675-678. (Pubmed)
  25. Antoci, V., Jr., King, S. B., Jose, B., Parvizi, J., Zeiger, A. R., Wickstrom, E., Freeman, T. A., Composto, R. J., Ducheyne, P., Shapiro, I. M., Hickok, N. J., and Adams, C. S. (2007) Vancomycin covalently bonded to titanium alloy prevents bacterial colonization. Journal of Orthopaedic Research 25(7):858-866. (Pubmed)
  26. Panchapakesan, B., and Wickstrom, E. (2007) Nanotechnology for sensing, imaging, and treating cancer. Surgical Oncology Clinics of North America 16:293-305. (Abstract)
  27. Edupuganti, O.P., Antoci, V., Jr., King, S.B., Jose, B., Adams, C.S., Parvizi, J., Shapiro, I.M., Zeiger, A.R., Hickok, N.J., and Wickstrom, E. (2007) Vancomycin covalently bound to Ti6Al4V pins provides longterm inhibition of Staphylococcus aureus colonization. Bioorganic & Medicinal Chemistry Letters 17(10):2692-2696. (Pubmed)
  28. Tian, X., Chakrabarti, A., Amirkhanov, N., Aruva, M. R., Zhang, K., Cardi, C. A., Lai, S., Thakur, M. L., and Wickstrom, E. (2007) Receptor-mediated internalization of chelator-PNA-peptide hybridization probes for radioimaging and magnetic resonance imaging of oncogene mRNAs in tumours. Biochemical Society Transactions, 35(Feb):72-76. (Pubmed)
  29. Teker, K., Wickstrom, E., and Panchapakesan, B. (2006) Biomolecular tuning of electronic transport properties of carbon nanotubes via antibody functionalization. IEEE Sensors Journal 6(12):1422-1428. (Abstract)
  30. McAleer, M. F., Duffy, K. T., Davidson, W. R., Kari, G., Dicker, A. P., Rodeck, U., and Wickstrom, E. (2006) Antisense inhibition of cyclin D1 expression is equivalent to flavopiridol for radiosensitization of zebrafish embryos. International Journal of Radiation Oncology, Biology, Physics 66(2):546-551. (Pubmed)
  31. Quadros, M. R. D., Connelly, S., Kari, C., Abrams, M. T., Wickstrom, E., and Rodeck, U. (2006) EGFR-dependent downregulation of Bim in epithelial cells requires MAPK and PKC-delta activities. Cancer Biology and Therapy 5(5):498-504. (Pubmed)
  32. Wickstrom, E., Thakur, M. L., and Sauter, E. R. (2006) Radiolabeled peptide nucleic acid oncogene probes conjugated to receptor-specific peptide analogs. In Janson, C. G., and During, M. J., eds., Peptide Nucleic Acids, Morpholinos, and Related Antisense Biomolecules, Molecular Biology Intelligence Unit, Landes Bioscience/Kluwer Academic/Plenum Publishers, New York, Chap. 5, 59-86. (Abstract)
  33. Cesarone, G., Garofalo, C., Abrams, M. T., Igoucheva, O., Alexeev, V., Yoon, K., Surmacz, E., and Wickstrom, E. (2006) Specific reduction of insulin receptor substrate 1 (IRS-1) expression in MCF7 cells by RNA interference enhances tamoxifen-mediated cell death. Journal of Cellular Biochemistry 98(2):440-450. (Pubmed)
  34. Wickstrom, E., and Thakur, M. L. (2006) Imaging cancer gene activity in patients from outside the body. Biotechnology Healthcare 2:45-48. (Abstract)
  35. Panchapakesan, B., Cesarone, G., Lu, S., Teker, K., and Wickstrom, E. (2005) Conductivity sensing of breast cancer cells by carbon nanotubes coated with monoclonal antibodies against IGF1 receptor. NanoBiotechnology 1(4):353-360. (Abstract)
  36. Efimov, V., Chakhmakhcheva, O., and Wickstrom, E. (2005) Synthesis and application of negatively charged PNA analogues. Nucleosides, Nucleotides, and Nucleic Acids 24(10):1853-1874. (Pubmed)
  37. Teker, K., Sirdeshmukh, R., Sivakumar, K., Lu, S., Wickstrom, E., Wang, H.-N., Vo-Dinh, T., and Panchapakesan, B. (2005) Applications of carbon nanotubes for cancer research. NanoBiotechnology 1(2):171-182. (Abstract)
  38. Panchapakesan, B., Lu, S., Sivakumar, K., Teker, K., Cesarone, G., and Wickstrom, E. (2005) Single wall carbon nanotube nanobomb agents for killing breast cancer cells. NanoBiotechnology 1(2):133-140. (Abstract)
  39. Tian, X., Chakrabarti, A., Amirkhanov, N., Aruva, M., Zhang, K., Mathew, B., Cardi, C., Qin, W., Sauter, E. R., Thakur, M. L., and Wickstrom, E. (2005) External imaging of CCND1, MYC and KRAS oncogene mRNAs with tumor-targeted radionuclide-PNA-peptide chimeras. In El-Deiry, W., ed., Tumor Progression and Therapeutic Resistance, Annals of the New York Academy of Sciences, 1059:106-144. (Pubmed)
  40. Tian, X., Aruva, M. R., Wolfe, H. R., Qin, W., Sauter, E. R., Thakur, M. L., Waldman, S. A., and Wickstrom, E. (2005) Tumor-targeting peptide-PNA-peptide chimeras for imaging overexpressed oncogene mRNAs Nucleosides, Nucleotides, and Nucleic Acids 24:1085-1091. (Pubmed)
  41. Amirkhanov, N. V. and Wickstrom, E. (2005) Synthesis of novel polydiamidopropanoate dendrimer PNA-peptide chimeras for non-invasive magnetic resonance imaging of cancer. Nucleosides, Nucleotides, and Nucleic Acids 24:423-426. (Pubmed)
  42. Chakrabarti, A., Aruva, M. R., Sajankila, S. P., Thakur, M. L., and Wickstrom, E. (2005) Synthesis of novel PNA-peptide chimera for non-invasive imaging of cancer. Nucleosides, Nucleotides, and Nucleic Acids 24:409-414. (Pubmed)
  43. Jose, B., Antoci, V., Jr., Zeiger, A. R., Wickstrom, E., and Hickok, N. J. (2005) Vancomycin covalently bonded to titanium beads kills Staphylococcus aureus. Chemistry & Biology 12(9):1041-1048. (Pubmed)
  44. Duffy, K. T., McAleer, M. F., Davidson, W. R., Kari, L., Kari, C., Liu, C.-G., Farber, S. A., Cheng, K. C., Mest, J. R., Wickstrom, E., Dicker, A. P., and Rodeck, U. (2005) Coordinate control of cell cycle regulatory genes in zebrafish development tested by cyclin D1 knockdown with morpholino phosphorodiamidates and hydroxyprolyl-phosphono peptide nucleic acids. Nucleic Acids Research 33(15):4914–4921. (Full text)
  45. Abrams, M. T., Robertson, N. M., Litwack, G., and Wickstrom, E. (2005) Evaluation of glucocorticoid sensitivity in 697 pre-B acute lymphoblastic leukemia cells after overexpression or silencing of MAP kinase phosphatase-1. Journal of Cancer Research and Clinical Oncology 131(6):347-354. (Pubmed)
  46. Tian, X., Aruva, M. R., Qin, W., Zhu, W., Sauter, E. R., Thakur, M. L., and Wickstrom, E. (2005) Noninvasive molecular imaging of MYC mRNA expression in human breast cancer xenografts with a [99mTc]peptide-PNA-peptide chimera. Bioconjugate Chemistry 16(1):70-79. (Pubmed)
  47. Abrams, M. T., Robertson, N. M., Yoon, K., and Wickstrom, E. (2004) Inhibition of glucocorticoid sensitivity by RNA interference against BIM in acute lymphoblastic leukemia cells. Journal of Biological Chemistry 279(53):55809-55817. (Pubmed)
  48. Tian, X., Aruva, M. R., Qin, W., Zhu, W., Duffy, K. T., Sauter, E. R., Thakur, M. L., and Wickstrom, E. (2004) External imaging of CCND1 cancer gene activity in experimental human breast cancer xenografts with [99mTc]peptide-PNA-peptide chimeras. Journal of Nuclear Medicine 45(12):2070-2082. (Pubmed)

Research Support:

  1. NIH 1 R01 CA148565-02 $2,485,137, PET Imaging of KRAS2 Activation to Guide EGFR Targeting in Cancer Therapy, Eric Wickstrom, contact co-PI, Mathew Thakur, co-PI, Edith Mitchell, co-PI, 15% effort, 1 Jul 2010-30 Apr 2014, second year direct costs $442,412 (Abstract)
  2. NIH 1 R44 CA136306-03, $385,321, Radiohybridization Imaging of HER2 Oncogene to Detect Breast Cancer, Koon Yan Pak, co-PI, Brian Gray, co-PI, Mathew Thakur, co-PI, Eric Wickstrom, co-PI, 8% effort, 1 Sep 2008-31 Aug 2012, current year direct costs: $118,843 (Abstract)
  3. NIH 1 R21 DA027746-02, $309,000, Neuronal mRNA PET Imaging, Eric Wickstrom, PI, 5% effort, 1 Sep 2009-29 Feb 2012, current year direct costs $100,000 (Abstract)
  4. Delaware Health Sciences Alliance, $75,000, NLGN4Y Gene Dosage Effects in Human and Cellular Models for Autism, Judith Ross, PI, Eric Wickstrom, co-I, 1 Nov 2011-30 Apr 2013, current year direct costs $50,000 (Abstract)
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