Steven S. Rosenfeld MD, Ph.D.
Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Department of Cancer Biology
Clinical investigations of glioma therapeutics, cell motility, tumor invasion, molecular motors in tumor biology, novel therapeutic approaches, animal models of glioma
The focus of our laboratory is on the role of molecular motors in driving the malignant phenotype of glioblastoma, by enabling glioma cells to grow and invade through the mechanically challenging environment that constitutes brain white matter and cortex. We have shown that four members of the myosin superfamily of molecular motors serve specific needs in the biology of gliomas, and therefore represent novel targets for the development of therapeutics that could block tumor dispersion and growth. The work on these myosin family members is organized around three projects:
In the first project, we are examining how myosins IIA and IIB enable glioma cells to maneuver through the small intercellular spaces found in brain white matter and cortex, and tune glioma responsiveness to the stiffness of the microenvironment in which they migrate and grow. This work involves time lapse microscopy measurements of tumor cell migration in situ in brain, as well as studies of glioma migratory and proliferative behavior on synthetic substrates and matrices with defined spatial and mechanical properties. Hand-in-hand with these studies are experiments examining the efficacy of myosin II-targeting therapeutics administered in rodent models of glioma.
In the second project, we are examining how myosins Vb and VI are needed to sensitize glioma cells to extracellular growth factors, including PDGF and EGF. Knockdown of either myosin Vb or VI blunts downstream signaling by these growth factors, and we are now investigating how suppression of these motors affects tumor dispersion and growth in pre-clinical models of glioma.
The third project involves examining the role of myosin X in glioma chemotaxis. This myosin isoform is upregulated nearly 20-fold in human glioblastomas of the mesenchymal phenotype, and is responsible for formation of filopodia. Studies of myosin X knockdown on glioma migration through microfabricated porous substrates are being correlated with effects on glioma dispersion in pre-clinical models of glioma.
As a neuro-oncologist in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, I am ultimately interested in applying these investigations into the design of new approaches to the treatment of anaplastic gliomas in humans.
Dropcho, E.J., Rosenfeld, S.S., Morawetz, R.B., Vitek, J., Gorum, T., Gillespie, G.Y., Mahaley, M.S., Glantz, M., Bell, S., Brothers, M., and Schold, S.C. (1992) “Pre-Radiation Intracarotid Cisplatin Treatment of Newly Diagnosed Anaplastic Gliomas." J. Clin. Oncology, 10,452-458.
Sweeney, H.L., Rosenfeld, S.S., Brown, F., Faust, L., Smith, J., Xing, J., Stein, L., and Sellers, J. (1998) “Kinetic Tuning of Myosin via a Flexible Loop Adjacent to the Nucleotide Binding Pocket” J. Biol. Chem., 273, 6262-6270.
Dropcho, E.J., Rosenfeld, S.S., Vitek, J., Guthrie, B.L., and Morawetz, R.B. (1998) Phase II Study of Intracarotid or Selective Intracerebral Infusion of Cisplatin for Treatment of Recurrent Anaplastic Gliomas. J. Neuro-Oncology, 36, 191-198.
Gillespie, G.Y., Soroceanu, L., Manning, T., Gladson, C.L.,and Rosenfeld, S.S. (1999) “Glioma Migration Can Be Blocked By Non-Toxic Inhibitors Of Myosin II” Cancer Research, 59, 2076-2082.
Xing, J., Wriggers, W., Jefferson, G.M., Stein, R., Cheung, H.C., and Rosenfeld, S.S. (2000) “Kinesin Has Three Nucleotide-Dependent Conformations—Implications for Strain-Dependent Release” J. Biol. Chem. 275, 35413-35423.
Cairncross G. Swinnen L. Bayer R., Rosenfeld S. Salzman D. Paleologos N. Kaminer L. Forsyth P. Stewart D. Peterson K. Hu W. Macdonald D. Ramsay D. Smith A. Oligodendroglioma Study Group (2000). "Myeloablative chemotherapy for recurrent aggressive oligodendroglioma." Neuro-Oncology. 2:114-119.
Steven S. Rosenfeld, Jun Xing, Geraldine M. Jefferson, Herbert C. Cheung, and Peter H. King (2002) "Measuring Kinesin's First Step" J. Biol. Chem, 277: 36731-36739.
Steven S. Rosenfeld, Polly Fordyce, Geraldine M. Jefferson, Peter H. King, and Steven M. Block. (2003) “Stepping and Stretching: How Kinesin Uses Internal Strain To Walk Processively” J. Biol. Chem. 278: 18550-18556.
Steven S. Rosenfeld, Jun Xing, Li-Qiong Chen, and H. Lee Sweeney (2003) “Myosin IIB Is Unconventionally Conventional” J. Biol. Chem, 278, 27449-27455.
Steven S. Rosenfeld, and H. Lee Sweeney (2004) “A Model of Myosin V Processivity” J. Biol. Chem., 279, 40100-40111.
Rosenfeld SS. Xing J. Jefferson GM. King PH. Docking and rolling, a model of how the mitotic motor Eg5 works. (2005) Journal of Biological Chemistry. 280, 35684-95,
Abrey LE. Childs BH. Paleologos N. Kaminer L. Rosenfeld S. Salzman D. Finlay JL. Gardner S. Peterson K. Hu W. Swinnen L. Bayer R. Forsyth P. Stewart D. Smith AM. Macdonald DR. Weaver S. Ramsay DA. Nimer SD. DeAngelis LM. Cairncross JG. (2006) High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma: long-term follow-up. Neuro-Oncology. 8, 183-8.
Maliga Z. Xing J. Cheung H. Juszczak LJ. Friedman JM. Rosenfeld SS. (2006) A pathway of structural changes produced by monastrol binding to Eg5. Journal of Biological Chemistry. 281:7977-82.
Mamelak AN. Rosenfeld S. Bucholz R. Raubitschek A. Nabors LB. Fiveash JB. Shen S. Khazaeli MB. Colcher D. Liu A. Osman M. Guthrie B. Schade-Bijur S. Hablitz DM. Alvarez VL. Gonda MA. (2006) Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. Journal of Clinical Oncology. 24, 3644-50.
H. Lee Sweeney, Hyokeun Park, Alan B. Zong, Zhaohui Yang, Paul R. Selvin, and Steven S. Rosenfeld (2007) How Myosin VI Coordinates its Heads During Processive Movement. EMBO J. 26, 2682-2692.
Nabors LB. Mikkelsen T. Rosenfeld SS. Hochberg F. Akella NS. Fisher JD. Cloud GA. Zhang Y. Carson K. Wittemer SM. Colevas AD. Grossman SA. (2007) Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma Journal of Clinical Oncology. 25,1651-1657.
Shah GD. Silver JS. Rosenfeld SS. Gavrilovic IT. Abrey LE. Lassman AB. (2007) Myelosuppression in patients benefiting from imatinib with hydroxyurea for recurrent malignant gliomas. Journal of Neuro-Oncology. 85, 217-222. Yardimci H. van Duffelen M. Mao Y. Rosenfeld SS. Selvin PR. (2008) The mitotic kinesin CENP-E is a processive transport motor. Proc. Nat. Acad. Sci. USA. 105, 6016-6021.
Beadle C. Assanah MC. Monzo P. Vallee R. Rosenfeld SS. Canoll P. (2008) The role of myosin II in glioma invasion of the brain. Molecular Biology of the Cell. 19, 3357-3368.
Erdal Toprak, Ahmet Yildiz, Melinda Tonks Hoffman, Steven S. Rosenfeld, and Paul R. Selvin (2009) Why kinesin is so processive PNAS,106, 2717-12722.
Rosenfeld SS. van Duffelen M. Behnke-Parks WM. Beadle C. Corrreia J. Xing J. (2009). The ATPase cycle of the mitotic motor CENP-E. Journal of Biological Chemistry. 284, 32858-68..
Surasak Phuphanich, Jeffrey G. Supko, Kathryn A. Carson, Stuart A. Grossman, L. Burt Nabors, Tom Mikkelsen, Glenn Lesser, Steve Rosenfeld, Serena Desideri, Jeffrey J. Olson (2010) Phase 1 Clinical Trial of Bortezomib in Adults with Recurrent Malignant Glioma. J. Neuro-Oncology, 100, 95-103.
William M. Behnke-Parks Steven S. Rosenfeld (2011) Loop L5 Acts as a Conformational Latch in the Mitotic Kinesin Eg5. Journal of Biological Chemistry, 286, 5242-5253.
Sanja Ivkovic, Christopher Beadle, Kristin Swanson, Peter Canoll, and Steven Rosenfeld (2011) Direct Inhibition Of Myosin II Effectively Blocks Glioma Invasion In The Presence Of Multiple Motogens. Under review, Molecular Biology of the Cell.
Jeffrey N. Bruce, Robert L. Fine, Peter Canoll, Jonathan Yun, Benjamin C. Kennedy, Steven S. Rosenfeld, Stephen A. Sands, Krishna Surapaneni, Rose Lai, Candix L. Yanes, Emilia Bagiella, Robert L. DeLaPaz (2011) Regression of Recurrent Malignant Gliomas with Convection-Enhanced Delivery of Topotecan. Neurosurgery, in press.
Liang Lei, Adam M. Sonabend, Paolo Guarnieri, Craig Soderquist, Thomas Ludwig, Steven Rosenfeld, Jeffrey Bruce, and Peter Canoll (2011) Novel Glioblastoma Models Reveal the Connection between Adult Glial the Proneural Phenotype. PLoS ONE 6(5): e20041.