William A. Maltese, Ph.D.
|William Anthony Maltese, Ph.D.
Professor and Chairman
Biochemistry and Cancer Biology
Current research centers on the roles of Ras-related GTPases in intracellular trafficking
and signaling pathways that regulate unconventional forms of cell death. Recent studies
have established that activated forms of the Ras oncogene trigger a form of non-apoptotic
cell death instead of cell proliferation in glioblastoma cells. This novel form of
cell death, termed “methuosis”, involves severe cytoplasmic vacuolization that begins
with hyperstimulation of macropinocytosis (vesicular uptake of extracellular fluid)
and disruptions of endocytic trafficking. The Rac1 and Arf6 GTPases have been identified
as key downstream mediators of this novel effect of Ras. Current studies focus on
further defining the molecular mechanisms underlying methuosis, and determining if
manipulation of the relevant pathways can be exploited in a therapeutic context to
impede the growth of gliomas and breast carcinomas in vivo. In this regard, unique
chemical compounds related to a class of molecules termed chalcones have been found
to stimulate a methuosis phenotype similar to that caused by activated Ras. Ongoing
studies are aimed at modifying the structures of these molecules to optimize their
potency and stability, with the long range goal of evaluating their therapeutic potential
in tumor models. A major objective is to identify the molecular targets of the methuosis-inducing
compounds. Collaborations have also been established with experts in bioengineering
and nanoparticle development to explore the possibility of packaging the new compounds
in nanoparticles containing tumor-homing peptides. The goal of these studies is to
promote tumor-specific uptake of the drugs in brain tumors and breast cancers while
minimizing toxicity to normal tissues.
Member of the mentoring faculty for the Biomedical Sciences Graduate Program (Cancer Biology track)
Ph.D. 1977 Syracuse University, Syracuse, NY
B.S. 1972 St. Francis College, Brooklyn, NY
RECENT ACADEMIC APPOINTMENTS:
1999-present Professor and Chairman, Biochemistry & Cancer Biology, University of Toledo Health Science Campus (formerly Medical University of Ohio)
1997-1999 Professor of Cellular & Molecular Physiology, Penn. State University, College of Medicine
1996-1997 Senior Scientist Geisinger Clinic, Weis Center for Research
1987-1995 Staff Scientist Geisinger Clinic, Weis Center for Research
1981-1987 Assistant Professor of Neurology, Columbia University, College of Physicians & Surgeons
1980-1981 Research Assistant Professor of Pediatrics, Washington University, College of Medicine
1977-1979 Postdoctoral Trainee, Washington University, College of Medicine
Maltese, W.A., and Overmeyer, J.H. (2014) Methuosis: Nonapoptotic cell death associated with vacuolization of macropinosome and endosome compartments. Am. J. Pathol. 184:1630-1642.
Trabbic, C.J., Dietsch, H.M., Alexander, E.M., Nagy, P.I., Robinson, M.W., Overmeyer, J.H., Maltese, W.A., and Erhardt, P.W. (2014) Differential induction of cytoplasmic vacuolization and methuosis by novel 2-indolyl-substituted pyridinylpropenones. ACS Med. Chem. Lett. 5:73-77.
Robinson, M.W., Overmeyer, J.H., Young. A.M., Erhardt P.W. and Maltese, W.A. (2012) Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel
type of non-apoptotic cell death. J. Med. Chem. 55:1940-1956.
Wilson, E.N., Bristol, M.D., Di, X.L., Maltese, W.A., Koterba, K., Beckman, M.J. and Gewirtz, D.A. (2011) A switch between cytoprotective and cytotoxic autophagy in the radiosensitization of breast tumor cells by chloroquine and vitamin D. Hormones Cancer 2:272-285.
Overmeyer, J.H., Young, A.M., Bhanot, H. and Maltese, W.A. (2011) A Chalcone-related small molecule that induces methuosis, a novel form of non-apoptotic cell death, in glioblastoma cells. Mol. Cancer 10:69.
Overmeyer, J.H., and Maltese, W.A. (2011) Death pathways triggered by activated Ras in cancer cells. Frontiers Biosci. 16:1693-1713.
Bhanot, H., Young, A.M., Overmeyer, J.H. and Maltese, W.A. (2010) Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6. Mol. Cancer Res. 8:1358-1374.
Kaul, A., and Maltese, W.A. (2009) Killing of cancer cells by the photoactivatable protein kinase C inhibitor, calphostin C, involves induction of endoplasmic reticulum stress. Neoplasia 11:823-834.
Alam, G., Cui, H., Shi, H., Yang, L., Ding, J., Mao, L., Maltese, W.A. and Ding, H-F. (2009) MYCN promotes the expansion of Phox2B-positive neuronal progenitors to drive neuroblastoma development. Am. J. Path.175:856-866.
Overmeyer, J.H., Kaul, A., Johnson, E.E., and Maltese, W.A. (2008) Active Ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis. Mol. Cancer Res.6:965-977.
Kaul, A., Overmeyer, J.H., and Maltese, W.A. (2007) Activated Ras induces cytoplasmic vacuolation and non-apoptotic cell death in glioblastoma cells via novel effector pathways. Cell. Signalling19:1034-1043.
Johnson, E.E., Overmeyer, J.H., Gunning, W.T. and Maltese, W.A. (2006) Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes. J. Cell Sci.119:1219-1232.
Zeng, X., Overmeyer, J.H., and Maltese, W.A. (2006) Functional specificity of the mammalian Beclin-Vps34 PI 3-Kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J. Cell Sci.119:259-270.
Overmeyer, J.H., and Maltese, W.A. (2005) Tyrosine phosphorylation of Rab proteins. Methods in Enzymology 403:194-202.
Ding, J.D., Soule, G., Overmeyer, J.H., and Maltese, W.A. (2003) Tyrosine phosphorylation of the Rab24 GTPase in cultured mammalian cells. Biochem. Biophys. Res. Commun.312:670-675.
Maltese, W.A., Soule, G., Gunning, W., Calomeni, E. and Alexander, B. (2002) Mutant Rab24 GTPase is targeted to nuclear inclusions. BMC Cell Biology3:25-42.
Overmeyer, J.H., Wilson, A.L., and Maltese, W.A. (2001) Membrane targeting of a Rab GTPase that fails to associate with Rab escort protein (REP) or guanine nucleotide dissociation inhibitor. J. Biol. Chem.276:20379-20386.
Maltese, W.A., Wilson, S., Tan, Y., Suomensaari, S., Sinha, S., Barbour, R., and McConlogure, L. (2001) Retention of the Alzheimer's beta-amyloid precursor protein fragment C99 in the endoplasmic reticulum prevents formation of the amyloid beta-peptide. J. Biol. Chem.276:20267-20279.
Erdman, R.A., and Maltese, W.A. (2001) Different Rab GTPases associate preferentially with alpha or beta GDP-dissociation inhibitors. Biochem. Biophys. Res. Commun.282:4-9.
Erdman, R.A., Shellenberger, K.E., Overmeyer, J.H., and Maltese, W.A. (2000) Rab24 is an atypical member of the Rab GTPase family. J. Biol. Chem.275:3848-3856.