Michael J. Spinella, Ph.D.
Associate Professor of Pharmacology & Toxicology
Pharmacology & Toxicology
Albany Medical College, PHD 1992
SUNY - Oswego, BA 1985
Norris Cotton Cancer Center
Pharmacology and Toxicology Graduate Program
Program in Experimental and Molecular Medicine
Dept. of Pharmacology and Toxicology
Dartmouth Medical School
Hanover NH 03755
Office: Vail 504A
Research Interest: Molecular Targets of Cancer Therapy
Research projects in Dr. Spinella's laboratory are focused on identification of mechanistic links between stem cell pluripotency and cancer and the identification of downstream genes and pathways that are induced during chemotherapy that either kill tumors or in other instances lead to their resistance.
Dr. Spinella's research addresses the interplay between the differentiation status of human tumor cells and chemotherapy response. A model system is pluripotent human embryonal carcinoma which are the stem cells of testicular cancer and differentiate along a neuronal pathway associated with growth suppression in response to retinoic acid (RA). RA binds and activates the retinoic acid receptor family of transcription factors and in this way regulates the expression of critical target genes. Using de novo screening approaches like microarray analysis, we have identified novel RA target genes and are in the process of characterizing these genes for their importance in mediating the therapeutic effects of RA. Further we are testing the hypothesis that several of the genes down-regulated by RA, and required to maintain the pluripotent context of these cells, are also responsible for the high cure rates seen in testicular cancer patients treated with conventional chemotherapy (see below).
A second focus in the laboratory relates to the interesting clinical finding that testicular cancer is one of the few human solid tumor that can be cured with high success (~90%) with conventional chemotherapy even when widely metastatic. We have shown through further microarray studies that the master tumor suppressor and transcription factor, p53 is hyperactivated in testicular cancer cells in response to the chemotherapy agent cisplatin and in the process have identified several novel p53 target genes. We are in the process of validating these p53 targets and assessing their importance in the curative response of testicular cancer to therapy. These studies will also expand the known biologic activities of the p53 gene, which is a critical tumor suppressor of all cancers.
A general theme of the lab is then to assess whether therapeutic targets activated in the testicular cancer context can mediate curative responses when targeted more directly and efficiently in other tumor types that are not currently curable, for example lung and brain cancers.
Rotations and Thesis Projects:
1. Determine the importance of DNMT3B as a therapeutic target in testicular cancer and the mechanism responsible for the hypersensitivity of testicular cancer to demethylation agents.
2. Determine the role and mechanism of action of novel p53 target genes during chemotherapy responses in testicular cancer and other solid tumors.
3. Determine the role of novel RA target genes in the induction of differentiation and growth suppression in human embryonal carcinoma and other tumors.
PR093629 DOD Investigator-Initiated Research Award
Molecular Mechanisms of DNA Methylation Inhibition Therapy for Testicular Cancer in Adolescents
R01CA111422 Cyclin D as a Retinoid Molecular Target
Prouty Grant - A strategy for Targeting Pluripotent Cancer Stem Cells
Pharmacology 215; Medical Pharmacology
PEMM 126; Cancer Biology
PEMM 133; Pharmacology of Drug Development (Course Director)
Dr. Spinella obtained is Ph.D. in Biochemistry from the Albany Medical College in 1992. He received postdoctoral training at the Massey Cancer Center and in the Department of Medicine at the Medical College of Virginia and advanced training in Molecular Oncology as a Research Associate in the Department of Medicine and in the Molecular Pharmacology and Therapeutics Program at the Memorial Sloan Kettering Cancer Center. In 1998, Dr. Spinella joined the faculty at Dartmouth Medical School as Assistant Professor in the Department of Pharmacology and Toxicology.
Curtin JC, Spinella MJ. p53 in human embryonal carcinoma: identification of a transferable, transcriptional repression domain in the N-terminal region of p53. Oncogene. 2005 Feb 24;24(9):1481-90. (view details on MedLine)
White KA, Yore MM, Deng D, Spinella MJ. Limiting effects of RIP140 in estrogen signaling: potential mediation of anti-estrogenic effects of retinoic acid. J Biol Chem. 2005 Mar 4;280(9):7829-35. Epub 2005 Jan 4. (view details on MedLine)
Kerley-Hamilton JS, Pike AM, Li N, DiRenzo J, Spinella MJ. A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma. Oncogene. 2005 Sep 8;24(40):6090-100. (view details on MedLine)
Giuliano CJ, Kerley-Hamilton JS, Bee T, Freemantle SJ, Manickaratnam R, Dmitrovsky E, Spinella MJ. Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochim Biophys Acta. 2005 Oct 15;1731(1):48-56. Epub 2005 Sep 1. (view details on MedLine)
Giuliano CJ, Freemantle SJ, Spinella MJ. Testicular germ cell tumors: a paradigm for the successful treatment of solid tumor stem cells. Curr. Cancer Therapy Reviews 2:255-270, 2006.
Heim KC, White KA, Deng D, Tomlinson CR, Moore JH, Freemantle SJ, Spinella MJ. Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells. Mol Cancer. 2007 Sep 19;6:57. (view details on MedLine)
Kerley-Hamilton JS, Pike AM, Hutchinson JA, Freemantle SJ, Spinella MJ. The direct p53 target gene, FLJ11259/DRAM, is a member of a novel family of transmembrane proteins. Biochim Biophys Acta. 2007 Apr;1769(4):209-19. Epub 2007 Feb 22. (view details on MedLine)
Heim KC, Gamsby JJ, Hever MP, Freemantle SJ, Loros JJ, Dunlap JC, Spinella MJ. Retinoic acid mediates long-paced oscillations in retinoid receptor activity: evidence for a potential role for RIP140. PLoS One. 2009 Oct 28;4(10):e7639. (view details on MedLine)
Beyrouthy MJ, Garner KM, Hever MP, Freemantle SJ, Eastman A, Dmitrovsky E, Spinella MJ. High DNA methyltransferase 3B expression mediates 5-aza-deoxycytidine hypersensitivity in testicular germ cell tumors. Cancer Res. 2009 Dec 15;69(24):9360-6. Epub . (view details on MedLine)
Mao P, Hever MP, Niemaszyk LM, Haghkerdar JM, Yanco EG, Desai D, Beyrouthy MJ,Kerley-Hamilton JS, Freemantle SJ, Spinella MJ. Serine/threonine kinase 17A is a novel p53 target gene and modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells. J Biol Chem. 2011 Apr 13. [Epub ahead of print] (view details on MedLine)