Alexzander A. A. Asea, Ph.D.
Department of Pathology and Laboratory Medicine
1901 South 1st Street, Bldg. 205
Temple, Texas 76508
Education and Post-Graduate Training
Dr. Alexzander Asea received his PhD in Medical Microbiology and Immunology from the University of Gothenburg, Sweden, where his studies helped form the basis for clinical trials of combined immunotherapy with histamine and interleukin-2 in metastatic melanoma and high-risk acute myelogenous leukemia (AML). Dr. Asea went on to perform postdoctoral training at the University of Miami School of Medicine and the Dana-Farber Cancer Institute and Harvard Medical School.
In 2002, Dr. Asea was appointed the Deputy Director, Center for Molecular Stress Response at Boston University School of Medicine and the Boston Medical Center. Dr. Asea was recruited in 2005 to Scott & White Hospital and the Texas A&M Health Science Center College of Medicine as the Effie and Wofford Cain Centennial Endowed Chair in Clinical Pathology and Director, Division of Investigative Pathology.
Dr. Asea's research interests center on the role of heat shock proteins in human disease. His initial observations studying the effect of heat shock proteins on human monocytes lead to a paradigm shift in our understanding of the role of heat shock proteins. Thus, heat shock proteins previously known to be an intracellular molecular chaperone, can be found in the extracellular milieu where it has regulatory effects on immunocompetent cells (Fig 1). Additional discoveries including the recent finding that surface expression of heat shock proteins differentially regulate tumor growth and metastasis, and that silencing these proteins eliminates the migration capability of the highly metastatic breast adenocarcinoma in vitro and in vivo, has opened a new front in the fight against cancer.
Fig 1. Model for stress-induced release of Hsp72 into the circulation. Stress can either induce cell death by activating the death pathway or activate the cellular stress response, which stimulates synthesis of intracellular Hsp72 known to inhibit cell death. Increased intracellular Hsp72 is expressed on the surface of cells and becomes a target for NK cell cytotoxicity. Intracellular Hsp72 is subsequently released into the extracellular milieu within exosomes and enters the circulation. Circulating extracellular Hsp72 (eHsp72) binds to APC and stimulates the chaperokine effect; cytokine, chemokine and reactive oxygen species release. In addition, peptides chaperoned by eHsp72 are processed and presented in the context of the MHC class I to stimulate specific CTL responses. Psychological stress and exercise induce the release of eHsp72 into the circulation by a hitherto unknown tissue or organ.
Dr. Asea has received numerous honors, awards and grant funding for his studies from the federal government, industry, and private foundations. He currently has 2 patents, over 80 scientific publications, books and reviews in the field of cancer research. Dr. Asea is the editor of the book series Heat Shock Proteins (Springer Publications) and currently the Biology & Chemistry Counselor for the Society of Thermal Medicine, a scientific society focused on combining hyperthermia and radiation with current therapies for curing cancer and other human diseases.
Breast Cancer Program
Combined Hyperthermia plus Radiotherapy for the Eradication of Triple-Negative Breast Cancer (TNBC): Cancer stem cells (CSC) possess the ability to give rise to all cell types found in a particular cancer, and are therefore tumorigenic causing relapse and metastasis by giving rise to new tumors. Breast tumors from African-American and Hispanic women often lack the human epidermal growth factor receptor 2, estrogen receptor and progesterone receptor, termed triple-negative breast cancer (TNBC), creating a phenotype and disease quite distinct from that seen in Caucasian women. TNBC are extremely aggressive and generally insensitive to most available hormonal or targeted therapeutic agents. In collaboration with Dr Sunil Krishnan (MD Anderson), we will study the role of heat shock proteins during the regression of TNBC-CSC in female mice in response to radiotherapy plus hyperthermia generated non-invasively optically activated gold nanoshells.
Vaccine Development: Recently, novel therapeutic strategies like hyperthermia and heat shock protein (HSP)-based cancer therapies are in various stages of clinical trials and show great potential. One caveat is that the size of the tumor is a limiting factor to whether there will be enough tumor-derived HSP preparation to complete the scheduled treatment. To overcome this problem, we have developed heat shock protein (HSP)-vaccines by fusing HSP with antigenic peptides relevant to breast cancer including MUC-1 and ErbB2.
Treatment of Established Tumors: RNA interference (RNAi) is a mechanism that inhibits gene expression at the stage of translation or by hindering the transcription of specific genes. RNAi targets include RNA from viruses and transposons (significant for some forms of innate immune response), and also plays a role in regulating development and genome maintenance. Small interfering RNA strands (siRNA) are key to the RNAi process, and have complementary nucleotide sequences to the targeted RNA strand. Specific RNAi pathway proteins are guided by the siRNA to the targeted messenger RNA (mRNA), where they "cleave" the target, breaking it down into smaller portions that can no longer be translated into protein. We have constructed a HSP-based siRNA which targets and selectively silences the expression of a specific sequence in both murine Hsp25 and human Hsp27, and effectively stops the growth of established tumors. This is an effective tool for drug development and the elucidation of anti-tumor mechanisms.
Prostate Cancer Program
Heat shock proteins (HSP) play key roles in the stress response and immune modulation. We hypothesized that radiation (RT) induces extracellular release of Hsp70 from tumors with resultant increased pro-inflammatory cytokines and stimulation of immune effector mechanisms designed to kill tumors. In collaboration with Dr Hurwitz (Harvard Medical School), we are studying the role of circulating HSPs in patients undergoing RT for prostate cancer with or without hormonal therapy (ADT).
Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK. 2000. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nature Medicine 6: 435-442
Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK. 2002. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277: 15028-15034
Bausero MA, Page DT, Osinaga E, Asea A. 2004. Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis. Tumour Biol. 25: 243-251
Bausero MA, Gastpar R, Multhoff G, Asea A. 2005. Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J. Immunol. 175: 2900-2912
Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G. 2005. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 65: 5238-5247
Bausero MA, Bharti A, Page DT, Perez KD, Eng JW, Ordonez SL, Asea EE, Jantschitsch C, Kindas-Muegge I, Ciocca D, Asea A. 2006. Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell. Tumour Biol. 27: 17-26
Asea A. 2006. Release of heat shock proteins: passive vs active release mechanisms. In Heat Shock Proteins: Potent Mediators of Inflammation and Immunity, ed. A Asea, A DeMaio. Dordrecht, The Netherlands: Springer
Bausero MA, Asea A. 2007. Role of Hsp25/27 in metastatic spread of cancer cells. In Heat Shock Proteins in Cancer, ed. SK Calderwood, D Ciocca, pp. 131-140. Dordrecht, The Netherlands.: Springer
Asea A. 2008. Hsp70: a chaperokine. Novartis Found Symp 291: 173-179; discussion 179-183, 221-174
Singh NK, Rao P, Asea A. 2008. Silencing of metastasis-associated gene 1 (mta1) stimulates Hsp70 cellular release and neurite extension in neuroblastoma cells. In Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection, ed. A Asea, IR Brown, pp. 273-282. Dordrecht, The Netherlands: Springer
Asea A. 2008. Heat shock proteins and toll-like receptors. Handb. Exp. Pharmacol. 183: 111-127
Ortega E, Hinchado MD, Martin-Cordero L, Asea A. 2009. The effect of stress-inducible extracellular Hsp72 on human neutrophil chemotaxis: a role during acute intense exercise. Stress 12: 240-249
Kaur P, Asea A. 2009. Toll-like receptors and infectious diseases: role of heat shock proteins. In Heat Shock Proteins in Infectious Disease, ed. SK Calderwood, AG Pockley, G Santoro. Dordrecht, The Netherlands: Springer, Nov 3. [Epub ahead of print]
Zheng H, Nagaraja GM, Kaur P, Asea EE, Asea A. 2009. Chaperokine function of recombinant Hsp70 produced in insect cells using a baculovirus expression system is intact. J. Biol. Chem. Oct 27. [Epub ahead of print]