Michael J. Spinella, PHD
Associate Professor of Pharmacology & Toxicology
Pharmacology & Toxicology
Albany Medical College, PHD 1992
Norris Cotton Cancer Center
Pharmacology and Toxicology Graduate Program
Program in Experimental and Molecular Medicine
Dept. of Pharmacology and Toxicology
Geisel School of Medicine
Lebanon NH 03756
Office: Rubin 605
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.
A New Cancer Therapeutic Target
Alex’s Lemonade Stand
DNA methylation inhibitor therapy for testicular germ cell tumors.
DoD Investigator-Initiated Research Award
Molecular mechanisms of DNA methylation inhibition therapy for testicular cancer in adolescents
Retinoid tumor differentiation mechanisms
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.
G0S2 Suppresses Oncogenic Transformation by Repressing a MYC-Regulated Transcriptional Program.
Epigenetic Targeting of Platinum Resistant Testicular Cancer.
All-trans-retinoic acid antagonizes the Hedgehog pathway by inducing patched.
Headway and hurdles in the clinical development of dietary phytochemicals for cancer therapy and prevention: lessons learned from vitamin A derivatives.
Serine/threonine kinase 17A is a novel candidate for therapeutic targeting in glioblastoma.
Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation.
Modulation of clock gene expression by the transcriptional coregulator receptor interacting protein 140 (RIP140).
Serine/threonine kinase 17A is a novel p53 target gene and modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells.