Chawnshang Chang Lab
Dr. Chawnshang Chang()
George Hoyt Whipple Distinguished Professor of Pathology, Urology and Radiation Oncology
Dr. Chang's research focuses on the Androgen Receptor (AR) (Chang, et al, Science, 1988) and three Nuclear Orphan Receptors TR2 (Chang, et al, BBRC, 1988); TR3 (Chang, et al, ASBMB, 1989) and TR4 (Chang, et al, PNAS, 1994)] he isolated from human testis. The successful cloning of the AR cDNA (Chang, et al, Science, 1988) represents the landmark discovery in the Androgen-AR field, in that it enabled the elucidation of the pathophysiological mechanisms of many androgen-AR related diseases. Here are examples:
- Kennedy's (SBMA) neuron disease: The availability of the complete AR sequence quickly led to finding that SBMA patients have mutated AR sequences with longer poly glutamine (polyQ) regions thus permitted this mutated AR to interact with other proteins (coregulators), forming a nuclear aggregation that interrupted neuronal functioning. In 1996, Dr. Chang's team isolated the first AR coregulator (PNAS, 1996), and from there, they screened the first anti-AR compound (ASC-J9) that interrupted the interaction between the AR coregulator(s) and the AR leading to AR protein degradation. Testing in mice proved that ASC-J9 could improve SBMA disease symptoms markedly by decreasing the AR-polyQ aggregations. Moreover, SBMA mice treated with ASC-J9 retained normal sexual function and fertility (Yang et al, and Chang, Nature Medicine, 2007). This continual effort from cloning AR, to isolation and characterizing of AR coregulators, to finding a compound to provide better treatment for SBMA, truly represents an idea of from the bench to the bedside.
- Prostate Cancer: Androgen deprivation therapy (ADT) with medical/surgical castration has remained as the standard treatment of advanced prostate cancer for the past 70 years. Yet, most tumors eventually recur and patients die. Cloning the AR (Chang, et al, Science, 1988) and generation AR antibodies (Chang, et al, Endocrinology, 1989) allowed clinicians to monitor the AR status of processing prostate tumors, finding that classic ADT failed to eliminate the prostate AR. Classic ADT failed to eliminate the prostate AR and tumor recur, subsequent findings suggest the reason can be (a) AR functions differentially in different prostate cells: suppressor in epitheial basal cells; survivor in epithelial luminal cells and proliferators in stromal cells (Niu et al and Chang PNAS 2008) Since classic ADT target systemic androgen and not specific to prostate cells with AR positive roles, it should fail. (b) In addition to classic androgens (T and DIH), prostate AR can be also activated by non-androgens, such as estrogens (Yeh, et al and Chang, PNAS, 1998), the antiandrogen flutamide (Yeh, Miyamoto and Chang, Lancet, 1997), and delta 5-androstenedione (Miyamoto, et al and Chang, PNAS, 1998). These findings led to investigating new therapeutic approaches which targeted the AR (and not androgens, as current ADT standardly does.). The results from early animal tests which targeted the AR by either ASC-J9 or AR-siRNA showed the suppression of tumor progression of prostate cancers. In summary, from cloning AR (Chang et al. Science 1988) to develop ASC-J9 to target AR in selective cells (Yang et al and Chang, Nat. Med. 2007) the 20 years continue AR studies in Dr. Chang¹s lab not only advance our understanding the AR function in prostate, may also lead to develop better therapeutic approaches to battle prostate cancer
- Testicular Feminization Syndrome (Tfm): Cloning of the AR and AR coregulators led to the discovery of various AR mutations (Mowszowicz et al, and Chang, Mol. Endo.1993) and unconventional hormonal pathways (estrogen-AR-AR coregulators, Yeh, et al and Chang, PNAS, 1998) in Tfm patients. Successful screening of AR mutations in Tfm families and development of special ligand(s) which interact and activate with mutated AR may help reduce Tfm disease' symptoms
- Female AR-related diseases: The successful generation of the first cell-specific knockout AR mouse (Yeh, et al and Chang, PNAS, 2002) allowed Dr. Chang's Lab to develop the first female animal without a functional AR. Later on, using these mice, Dr. Chang's Lab found that the AR plays an important role in female breast development and breast cancer progression (Yeh et al, and Chang, JEM, 2003) as well as fertility and folliculogenesis (Hu et al, and Chang, PNAS, 2004). These findings opened a new field for studying the AR's role(s) in female health and diseases.
- Other AR-related diseases: Using cell-specific knockout mice and the anti-AR compound, ASC-J9, Dr. Chang's Lab was also able to dissect new pathophysiological mechanisms of several other AR related diseases and physiological processes, such as bladder cancer (Miyamoto et al, and Chang, JNCI, 2007), male fertility and spermatogenesis (Chang et al, PNAS, 2004), liver cancer (Ma et al, Gastroenterology, 2004), and wound healing (Chang et al, JCI, 2009). These newly dissected mechanisms may then help us develop better therapeutic approaches for these AR related diseases and impaired processes.
- The discovery of TR2/TR4 orphan nuclear receptors: TR2 represents the first identified orphan receptor (without counting RXR) in the nuclear receptor superfamily (Chang et al, BBRC, 1988). The natural ligand(s) of these "receptors" remain unidentified. Over 90% of published papers related to TR2/TR4 have come from Dr. Chang's Lab, TR2/TR4 are master regulators of many bio-physiological functions. Knockout of TR2 and/or TR4 results in accelerated aging, abnormal metabolism and insulin sensitivity, and fertility and neurological dysfunctions (Collins et al and Chang, PNAS, 2004; Chen et al and Chang, MCB, 2005). Several compounds that can modulate kinase activity can modulate TR2/TR4 transactivation. Continued research on TR2/TR4 in the future may provide a new target for drug development to treat or prevent many "disease" processes, such as aging, diabetes, and neuro-dysfunctions.
In summary, Dr. Chang's Lab has been responsible for many key discoveries and developing several essential reagents for studying AR. Today, more than 700 laboratories are utilizing AR-related reagents (such as AR-cDNA, AR-antibodies, AR-siRNA, AR-5'-promoter reporter, AR-coregulators, AR knockout mice, and the anti-AR ASC-J9) generated in Dr. Chang's Lab. The whole AR field has received far-reaching benefits from the discoveries made by Dr. Chang and his co-workers.
- The Introduction of the Taiwanese Osteoporosis Society President's Award for Dr. Chawnshang Chang
- National Taiwan University, Agriculture Chemistry, BS, 1978
- Taiwan Army Chemical School (ROTC), Taiwan, Chemistry, Lieutenant, 1980
- University of Chicago, Chicago, Illinois, Biochemistry and Molecular Biology, Ph.D., 1985
- University of Chicago, Chicago, Illinois, Molecular Endocrinology Postdoc, 1988
- Professional and Academic Experience:
- 1988-90 Assistant Professor and Director, Urology Research Labs, Dept. of Surgery/Urology and Ben May Institute, University of Chicago, Chicago, IL
- 1990-00 Assistant Professor (90-93), Associate Professor (93-96), Professor (96-97). Visiting Professor (97-00), Director, Tissue & Blood Bank (90-97). Departments of Human Oncology and Medicine and UW Comprehensive Cancer Center, University of Wisconsin, Madison, WI
- 1996-98 Visiting Professor, Department of Urology, Osaka University, Osaka, Japan
- 1998- Visiting Professor, Oncology Institute, Xiamen University, Xiamen, China
- 1998 - Visiting Professor & Director of Andrology Lab, Dept. of Urology, Beijing Univ., China
- 1999 - Visiting Professor, Reproductive Medicine Institute, Chang Gung University, Taiwan
- 1999 - Visiting Professor, National Taiwan Univ., Taiwan
- 1997 - Director, George Whipple Laboratory for Cancer Research, University of Rochester, Rochester, NY
- 1997 - Director, Urology Research Center, University of Rochester, Rochester, NY
- 1997 - Director, Molecular Oncology Graduate Program. University of Rochester, Rochester, NY
- 1997 - George Whipple Distinguished Professor, Departments of Pathology, Urology, Radiation Oncology and Biochemistry, and The Cancer Center, University of Rochester, Rochester, NY
- 2000 - Founder, AndroScience Corporation, San Diego, CA.
- 2002 - Visiting Professor, Wuhan University, Wuhan, China.
- 2003 - Visiting Professor, Tiamjin Medical University, Tianjin, China.
- 2004 - Visiting Professor, Taipei Medical University, Taipei, Taiwan.
- Honors and Awards:
- 1988 The Ayerst Award for Outstanding Young Endocrinologist from the Endocrine Society
- 1989 Andrew Melon Award for Outstanding Young Faculty in USA from Andrew Melon Foundation
- 1990 Outstanding Young Investigator Award from Cancer Research Foundation
- 1991 The Milheim Award for Excellence in Cancer Research from Milheim Foundation
- 1991-94 American Cancer Society Junior Professorship in Cancer Research
- 1995-97 Blowity-Ridgeway Award in Andrology from Blowity-Ridgeway Foundation
- 1993-99 CapCure Award (6 times) for Excellence in Prostate Cancer Research
- 1997 Award with Honorary Fellow from The Japan Society of Andrology (The 2nd Non-Japanese ever awarded such honor)
- 1998 George Hoyt Whipple Lecture, University of Rochester, Rochester, NY
- 1998 Jiepimg Wu Award, for Outstanding Achievement in Urology (The highest honor for Chinese-Medical Researcher). Beijing, China.
- 1999 President Award for Outstanding Urology Research, The highest honor from The Urology Association of Taiwan for the Contribution in Androgen Receptor and Prostate Cancer.
- 1999 Davey Memorial Award for Outstanding Cancer research, University of Rochester.
- 1999 Scholar of the Year, The highest honor from The Taiwanese Osteoporosis Association for Outstanding Contribution in Sex hormones and Osteoporosis.
- 2001 The Taiwanese Osteoporosis Society President's Award
- 2002 Dr. S.T.Huang-Chan memorial Lecture/Award, University of Hong Kong
- 2002 Dr. Chien-Tien Hsu Memorial Lecture/Award at Taiwan Annual OBGYN Meeting
- 2003 Who's Who in America.
- 2003 The president Award from Taiwanese Association of Andrology
- 2009 - The Chang Jiang Scholar Endowed Chair Award-China
- 1988-present Patents: 9 patents including AR gene/AR knockout mice/AR Coregulators / Anti-AR drugs / TR2&4 Nuclear Receptors.
- 1988-present Invited Speaker: 99 International Symposia and 292 Universities/Institutes (1988-present)
- Research Projects Ongoing:
- Title I: "Non-AR mediated DHT-promoted Bladder Cancer initiation and progression" Agency: NIH. R01CA155477 Years 1-5 (2011-2016). P.I.: Chawnshang Chang, Ph.D.
- Title II: "Stromal AR Roles in Prostate Hyperplasia and Cancer" Agency: NIH. R01CA156700 Years 1-5 (2011-2016). P.I.: Chawnshang Chang, Ph.D.
- Lab members