William A. Maltese, Ph.D.
|William Anthony Maltese, Ph.D.
Professor and Chairman
Biochemistry and Cancer Biology
McMaster Endowed Chair of Biochemistry and Cancer Biology
Our current research centers on the molecular and cellular characterization of novel forms of non-apoptotic cell death and the development of novel anti-cancer agents designed to induce these forms of cell death in brain tumors. Our past studies established that ectopic expression of activated forms of the Ras or Rac GTPases in glioblastoma and other types of cancer cells can trigger a unique form of cell death which we termed "methuosis". This form of cell death begins with the accumulation of numerous large cytoplasmic vacuoles that arise because of dysfunctional trafficking of macropinosomes and endosomes (vesicles that bring extracellular fluid into the cell). Ultimately the metabolic activity of the cell is compromised and the membrane ruptures. In more recent studies, we have collaborated with medicinal chemists in the Center for Drug Design and Development to identify unique chemical compounds (indole-based chalcones) that stimulate a methuosis phenotype, very similar to that caused by activated Ras. Ongoing studies are aimed at 1) identifying the specific molecular targets of the methuosis-inducing compounds and 2) modifying the structures of these molecules to optimize their potency, pharmacokinetic properties and transport across the blood-brain barrier. The therapeutic potential of the lead compounds will be evaluated in preclinical brain tumor models. To facilitate tumor-specific drug uptake and minimize toxicity to normal tissues, efforts are also underway to develop prodrugs consisting of tumor-homing peptides tethered to our lead compounds. Finally, as an offshoot of our recent structure-activity studies, we have discovered that minor structural modifications of our methuosis-inducing compounds can radically alter their biological activity, leading to a new class of microtubule disruptors that can cause cell death by mitotic catastrophe. Efforts are underway to define the mechanism of action of these compounds and to determine if they may have therapeutic advantages over existing microtubule-targeted chemotherapeutic agents.
|Examples of extreme vacuolization of micropinosomes associated with non-apoptotic cell death (methuosis) in U251 glioblastoma cells. Panels a and b show phase contrast and electron microscopy images of a stable U251 cell line in which overexpression of H-Ras (G12V) was induced for a period of 4 days (reprinted with permission from Overmeyer et al., 2008). Similar images of U251 cells treated with indolyl chalcone, MIPP, were obtained after 3 days (c) or 2 days (d) of drug treatment (reprinted with permission from Overmeyer et al., 2011).|
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.