Photo of Samuel D. Rabkin,  PhD

Samuel D. Rabkin, PhD

Massachusetts General Hospital

Massachusetts General Hospital


rabkin@mgh.harvard.edu

Samuel D. Rabkin, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Thomas A. Pappas Professor of Neurosciences, Neurosurgery, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Research in my laboratory centers on the application of herpes simplex virus (HSV) vectors for cancer therapy and gene delivery to cells of the nervous system. Replication-competent oncolytic HSV vectors are being developed that target tumor cells for destruction, yet are non-pathogenic to normal tissue. The virus constructs are examined in various mouse tumor models (human xenografts, syngeneic implants (subcutaneous, intracranial, orthotopic) and transgenic mice) for efficacy and mechanism of action, their safety evaluated, and finally tested in clinical trials. A number of different vector strategies are being pursued: (i) viral gene mutations that are complemented by the cancer cell phenotype; (ii) transcriptionally targeted vectors using tumor cell-specific regulatory regions to drive ICP4 expression; and (iii) "armed" oncolytic vectors that express anti-cancer transgenes (immune-modulatory and anti-angiogenic). Current areas of interest include: immunotherapy using oncolytic HSV as 'in situ' cancer vaccines, oncolytic HSV-dendritic cell interactions, cancer stem-like (tumor-initiating) cells in tumors of the nervous system.

Publications

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  • Nigim F, Cavanaugh J, Patel AP, Curry WT, Esaki S, Kasper EM, Chi AS, Louis DN, Martuza RL, Rabkin SD, Wakimoto H. Targeting Hypoxia-Inducible Factor 1留 in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment. J Neuropathol Exp Neurol 2015; 74:710-22. PubMed
  • Wang JN, Xu LH, Zeng WG, Hu P, Rabkin SD, Liu RR. Treatment of human thyroid carcinoma cells with the g47delta oncolytic herpes simplex virus. Asian Pac. J. Cancer Prev. 2015; 16:1241-5. PubMed
  • Lu L, Saha D, Martuza RL, Rabkin SD, Wakimoto H. Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma. J. Neurooncol. 2014. PubMed
  • Antoszczyk S, Spyra M, Mautner VF, Kurtz A, Stemmer-Rachamimov AO, Martuza RL, Rabkin SD. Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus. 2014. PubMed
  • Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek AK, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 2014; 157:580-94. PubMed
  • Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res 2014; 2:295-300. PubMed
  • Ning J, Wakimoto H, Rabkin SD. Immunovirotherapy for glioblastoma. Cell Cycle 2014; 13:175-6. PubMed
  • Wang J, Xu L, Zeng W, Hu P, Zeng M, Rabkin SD, Liu R. Treatment of human hepatocellular carcinoma by the oncolytic herpes simplex virus G47delta. Cancer Cell Int 2014; 14:83. PubMed
  • Cheema TA, Fecci PE, Ning J, Rabkin SD. Immunovirotherapy for the treatment of glioblastoma. Oncoimmunology 2014; 3:e27218. PubMed
  • Cheema TA, Wakimoto H, Fecci PE, Ning J, Kuroda T, Jeyaretna DS, Martuza RL, Rabkin SD. Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci U S A 2013; 110:12006-11. PubMed
  • Zhang W, Fulci G, Wakimoto H, Cheema TA, Buhrman JS, Jeyaretna DS, Stemmer Rachamimov AO, Rabkin SD, Martuza RL. Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models. Neoplasia 2013; 15:591-9. PubMed
  • Rheinbay E, Suvà ML, Gillespie SM, Wakimoto H, Patel AP, Shahid M, Oksuz O, Rabkin SD, Martuza RL, Rivera MN, Louis DN, Kasif S, Chi AS, Bernstein BE. An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep 2013; 3:1567-79. PubMed
  • Murphy AM, Rabkin SD. Current status of gene therapy for brain tumors. Transl Res 2013; 161:339-54. PubMed
  • Kanai R, Rabkin SD. Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors. CNS Oncol 2013; 2:129-142. PubMed
  • Tamura K, Wakimoto H, Agarwal AS, Rabkin SD, Bhere D, Martuza RL, Kuroda T, Kasmieh R, Shah K. Multimechanistic tumor targeted oncolytic virus overcomes resistance in brain tumors. Mol Ther 2013; 21:68-77. PubMed
  • Barnard Z, Wakimoto H, Zaupa C, Patel AP, Klehm J, Martuza RL, Rabkin SD, Curry WT. Expression of FMS-like tyrosine kinase 3 ligand by oncolytic herpes simplex virus type I prolongs survival in mice bearing established syngeneic intracranial malignant glioma. Neurosurgery 2012; 71:741-8; discussion 748. PubMed
  • Kanai R, Zaupa C, Sgubin D, Antoszczyk SJ, Martuza RL, Wakimoto H, Rabkin SD. Effect of 粒34.5 Deletions on Oncolytic Herpes Simplex Virus Activity in Brain Tumors. J Virol 2012; 86:4420-31. PubMed
  • Sgubin D, Wakimoto H, Kanai R, Rabkin SD, Martuza RL. Oncolytic herpes simplex virus counteracts the hypoxia-induced modulation of glioblastoma stem-like cells. Stem Cells Transl Med 2012; 1:322-32. PubMed
  • Wang J, Hu P, Zeng M, Rabkin SD, Liu R. Oncolytic herpes simplex virus treatment of metastatic breast cancer. Int J Oncol 2012; 40:757-63. PubMed
  • Wakimoto H, Mohapatra G, Kanai R, Curry WT, Yip S, Nitta M, Patel AP, Barnard ZR, Stemmer-Rachamimov AO, Louis DN, Martuza RL, Rabkin SD. Maintenance of primary tumor phenotype and genotype in glioblastoma stem cells. 2012; 14:132-44. PubMed
  • Kanai R, Rabkin SD, Yip S, Sgubin D, Zaupa CM, Hirose Y, Louis DN, Wakimoto H, Martuza RL. Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells. Journal of the National Cancer Institute 2012; 104:42-55. PubMed
  • Castelo-Branco P, Passer BJ, Buhrman JS, Antoszczyk S, Marinelli M, Zaupa C, Rabkin SD, Martuza RL. Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer. Gene Ther 2010; 17:805-10. PubMed
  • Passer BJ, Cheema T, Zhou B, Wakimoto H, Zaupa C, Razmjoo M, Sarte J, Wu S, Wu CL, Noah JW, Li Q, Buolamwini JK, Yen Y, Rabkin SD, Martuza RL. Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication. Cancer Res 2010; 70:3890-5. PubMed
  • Kanai R, Wakimoto H, Cheema T, Rabkin SD. Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer? Future Oncol 2010; 6:619-34. PubMed
  • Maguire CA, Gianni D, Meijer DH, Shaket LA, Wakimoto H, Rabkin SD, Gao G, Sena-Esteves M. Directed evolution of adeno-associated virus for glioma cell transduction. J. Neurooncol. 2010; 96:337-47. PubMed
  • Passer BJ, Castelo-Branco P, Buhrman JS, Varghese S, Rabkin SD, Martuza RL. Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells. Cancer Gene Ther 2009; 16:551-60. PubMed
  • Wakimoto H,Kesari S,Farrell CJ,Curry WT Jr,Zaupa C,Aghi M,Kuroda T,Stemmer-Rachamimov A,Shah K,Liu TC,Jeyaretna DS,Debasitis J,Pruszak J,Martuza RL,Rabkin SD. Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res 2009; 69:3472-81. PubMed
  • Aghi MK,Liu TC,Rabkin S,Martuza RL. Hypoxia enhances the replication of oncolytic herpes simplex virus. Mol Ther 2008; 17:51-6. PubMed
  • Farrell CJ,Zaupa C,Barnard Z,Maley J,Martuza RL,Rabkin SD,Curry WT Jr. Combination immunotherapy for tumors via sequential intratumoral injections of oncolytic herpes simplex virus 1 and immature dendritic cells. Clin Cancer Res 2008; 14:7711-6. PubMed
  • Farassati F,Pan W,Yamoutpour F,Henke S,Piedra M,Frahm S,Al-Tawil S,Mangrum WI,Parada LF,Rabkin SD,Martuza RL,Kurtz A. Ras signaling influences permissiveness of malignant peripheral nerve sheath tumor cells to oncolytic herpes. Am J Pathol 2008; 173:1861-72. PubMed
  • Liu TC, Castelo-Branco P, Rabkin SD, Martuza RL. Trichostatin A and Oncolytic HSV Combination Therapy Shows Enhanced Antitumoral and Antiangiogenic Effects. Mol Ther 2008; 16:1041-7. PubMed
  • Liu TC, Wakimoto H, Martuza RL, Rabkin SD. Herpes simplex virus Us3(-) mutant as oncolytic strategy and synergizes with phosphatidylinositol 3-kinase-Akt targeting molecular therapeutics. Clin Cancer Res 2007; 13:5897-902. PubMed
  • Varghese S, Rabkin SD, Nielsen GP, MacGarvey U, Liu R, Martuza RL. Systemic therapy of spontaneous prostate cancer in transgenic mice with oncolytic herpes simplex viruses. Cancer Res 2007; 67:9371-9. PubMed
  • Prabhakar S, Messerli SM, Stemmer-Rachamimov AO, Liu TC, Rabkin S, Martuza R, Breakefield XO. Treatment of Implantable NF2 Schwannoma Tumor Models with Oncolytic Herpes Simplex Virus G47Delta. Cancer Gene Ther 2007; 14:460-7. PubMed
  • Aghi M, Rabkin SD, Martuza RL. Angiogenic response caused by oncolytic herpes simplex virus-induced reduced thrombospondin expression can be prevented by specific viral mutations or by administering a thrombospondin-derived peptide. Cancer Res 2007; 67:440-4. PubMed
  • Jeyaretna DS, Rabkin SD, Martuza RL. Oncolytic herpes simplex virus therapy for peripheral nerve tumors. Neurosurg Focus 2007; 22:E4. PubMed
  • Liu TC, Zhang T, Fukuhara H, Kuroda T, Todo T, Martuza RL, Rabkin SD, Kurtz A. Oncolytic HSV armed with platelet factor 4, an antiangiogenic agent, shows enhanced efficacy. Mol Ther 2006; 14:789-97. PubMed
  • Liu TC, Zhang T, Fukuhara H, Kuroda T, Todo T, Canron X, Bikfalvi A, Martuza RL, Kurtz A, Rabkin SD. Dominant-negative fibroblast growth factor receptor expression enhances antitumoral potency of oncolytic herpes simplex virus in neural tumors. Clin Cancer Res 2006; 12:6791-9. PubMed
  • Kuroda T, Rabkin SD, Martuza RL. Effective treatment of tumors with strong beta-catenin/T-cell factor activity by transcriptionally targeted oncolytic herpes simplex virus vector. Cancer Res 2006; 66:10127-35. PubMed
  • Varghese S, Rabkin SD, Liu R, Nielsen PG, Ipe T, Martuza RL. Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther 2005; 13:253-65. PubMed
  • Kuroda T, Martuza RL, Todo T, Rabkin SD. Flip-Flop HSV-BAC: bacterial artificial chromosome based system for rapid generation of recombinant herpes simplex virus vectors using two independent site-specific recombinases. BMC Biotechnol 2006; 6:40. PubMed
  • Liu R, Martuza RL, Rabkin SD. Intracarotid delivery of oncolytic HSV vector G47Delta to metastatic breast cancer in the brain. Gene Ther 2005; 12:647-54. PubMed
  • Liu R, Varghese S, Rabkin SD. Oncolytic herpes simplex virus vector therapy of breast cancer in C3(1)/SV40 T-antigen transgenic mice. Cancer Res 2005; 65:1532-40. PubMed
  • Varghese S, Rabkin SD. Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther 2003; 9:967-78. PubMed
  • Sundaresan P, Hunter WD, Martuza RL, Rabkin SD. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J Virol 2000; 74:3832-41. PubMed
  • Castelo-Branco P, Passer BJ, Buhrman JS, Antoszczyk S, Marinelli M, Zaupa C, Rabkin SD, Martuza . An oncolytic herpes simplex virus armed with a xenogeneic homologue of prostatic acid phosphatase enhances anti-tumor efficacy in prostate cancer Gene Ther 2010.
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