Member, Cell Stress Biology
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo NY 14263
Telephone: (716) 845-3147
Fax: (716) 845-8899
E-mail: john.subjeck@roswellpark.org

Professor
Molecular & Cellular Biophysics and Biochemistry
Roswell Park Graduate Division
University at Buffalo

Dr. John R. Subjeck joined the staff of Roswell Park Cancer Institute (RPCI) in 1979, as a Cancer Research Scientist, Division of Radiation Biology, Department of Radiation Medicine. He was appointed Member in the Departments of Cell Stress Biology and Molecular and Cellular Biology in 1999, and is also a Professor of the Molecular & Cellular Biophysics and Biochemistry Roswell Park Graduate Division, University at Buffalo (UB).

Dr. Subjeck earned his doctoral degree in Biophysical Sciences, UB School of Medicine & Biomedical Sciences in 1974. He completed a postdoctoral fellowship in Experimental Pathology at RPCI in 1977. From 1977-1979, Dr. Subjeck specialized in Hyperthermia as a Research Affiliate in Medical Physics in the Division of Radiation Biology at RPCI. He is certified by the American Board of Radiology in Therapeutic Radiological Physics.

Dr. Subjeck’s research interests focus on heat shock/stress proteins and their use as anti-cancer vaccines. 

Projects
Heat Shock Proteins as Cancer vaccines and the use of hyperthermia as an adjuvant.

Stress proteins are known to play essential roles in normal cellular functions and are involved in numerous pathways involving protein processing and interactions. They protect cells from a variety of protein and cellular damaging environments at the molecular, cellular and organismal levels. Several of the stress proteins have come under intense scrutiny.

However, from the earliest studies, major stress proteins known as hsp110 (in the cytoplasm) and grp170 (in the endoplasmic reticulum) were observed, but studies of their structure and function were not undertaken. Cloning of these proteins in this laboratory indicated that they are related to one another and are also "distant" relatives of the intensively studied hsp70 family. They are found in every eucaryotic cell examined, yeast to man. It is our overall goal to determine the functions of these ubiquitous stress proteins and how they compare to and interact with the hsp70s as well as other molecular chaperones. Our studies show that both hsp110 and grp170 are highly efficient peptide chain binding proteins and form complexes with other full length proteins under heat shock conditions.

Secondly, we are studying hsp110 and grp170 and their interaction with the immune response and as potential cancer vaccines.

Progress

We have shown that vaccination with hsp110 or grp170 biochemically purified from Meth A fibrosarcoma caused complete regression of this tumor in mice. Since clinical use of "heat shock vaccine therapy" to-date has been using another heat shock protein and limited by the quantity of hsp/grp which can be purified from a human tumor (surgical) specimen, we have carried out characterization of hsp110 and grp170 as recombinant protein based vaccines. These studies are founded in our understanding of the structural/molecular chaperoning properties of hsp110 and grp170 and the mechanisms of interaction of hsp110/grp170 with cells of the immune system. Recent data indicate that these recombinant, molecular-targeted vaccines elicit powerful and specific anti-tumor CTL responses against the tumor protein antigen that are chaperoned by hsp110 or grp170. Current studies focus on 1) Mechanism of hsp110 and grp170 interactions with antigen presenting on cells and 2) On translation of this novel anti-cancer vaccine approach into the clinic to treat melanoma and other cancers.

Key Publications

• Wang XY, Chen X, Manjili MH, Repasky E, Henderson R, Subjeck J. Targeted immunotherapy using reconstituted chaperone complexes of heat shock protein 110 and melanoma-associated antigen gp100. Cancer Res., 15;63(10): 2553-60, 2003.
• Manjili MH, Wang XY, Chen X, Martin T, Repasky E, Henderson R, Subjeck J. HSP110- HER-2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice. J. Immunol. 171(8):4054-4061, 2003.
• Park J, Easton D, MacDonald I, Chen X, Wang XY, Subjeck J. The chaperoning properties of mouse grp170, a member of the third family of hsp70 related proteins. Biochemistry, 42(50):14893-14902, 2003.
• Manjili MH, Wang XY, MacDonald IJ, Arnouk H, Yang GY, Pritchard MT, Subjeck J. Cancer immunotherapy and heat-shock proteins: promises and challenges. Expert Opin Biol Ther., 4(3):363-73, 2004.
• Park JE, Facciponte J, Chen X, MacDonald I, Repasky EA, Manjili MH, Wang XY, Subjeck J.  Chaperoning function of stress protein grp170, a member of the hsp70 superfamily, is responsible for its immunoadjuvant activity. Cancer Res, 2006; 66(2):1161-1168.
•  Wang XY, Arnouk H, Chen X, Kazim L, Repasky EA, Subjeck J.  Extracellular targeting of endoplasmic reticulum chaperone glucose-regulated protein 170 enhances tumor immunity to a poorly immunogenic melanoma. J Immunol, 2006; 177(3):1543-1541.
•  Kim HL, Wang XY, Segal B, Subjeck J. Hsp110 and Grp170, relatives of the HSP70 superfamily, and their applications in the therapy of cancer and infectious diseases. Research Signpost, Heat Shock Proteins in Biology and Medicine. 2006; (Eds. J. Radons and G. Multhoff).
•  Facciponte J, Wang, XY, Subjeck J. Hsp110 and Grp170, members of the Hsp70 superfamily, bind to scavenger receptor-A and scavenger receptor expressed by endothelial cells-I . Eur. J. Immunol, 2007; 37(8): 2268-79.
•  Gao P, Sun X, Chen X, Wang Y, Foster BA, Subjeck J, Fisher PB, Wang XY. Secretable chaperone    Grp170 enhances therapeutic activity of a novel tumor suppressor, mda-7/IL-24. Cancer Res. 2008 May 15; 68(10):3890-8.