Dr. Chawnshang Chang ()

A. Research Contribution:

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:

1. 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.

2. 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 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. Moreover, these prostate cancer ARs can be 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, liver cancers (Chang et al, manuscript in preparation) and bladder cancers (Miyamoto, et al, and Chang, JNCI, 2007). The past 20 years' of AR research in Dr. Chang's Lab not only helped us to better understand the AR roles in prostate cancer progression, but are also likely to lead to the development of better therapeutic approaches for prostate cancer and other malignancies.

3. 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

4. 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.

5. 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 (Chang et al, manuscript submitted), and wound healing (Chang et al, manuscript in preparation). 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.

 

B. Academic CV:

 

1. The Introduction of the Taiwanese Osteoporosis Society President's Award for Dr. Chawnshang Chang (click for detailed information)

2. Education:

1. National Taiwan University, Agriculture Chemistry, BS, 1978
2. Taiwan Army Chemical School (ROTC), Taiwan, Chemistry, Lieutenant, 1980
3. University of Chicago, Chicago, Illinois, Biochemistry and Molecular Biology, Ph.D., 1985
4. University of Chicago, Chicago, Illinois, Molecular Endocrinology Postdoc, 1988

3. Professional and Academic Experience:

1. 1988-90 Assistant Professor and Director, Urology Research Labs, Dept. of Surgery/Urology and Ben May Institute, University of Chicago, Chicago, IL
2. 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
3. 1996-98 Visiting Professor, Department of Urology, Osaka University, Osaka, Japan
4. 1998- Visiting Professor, Oncology Institute, Xiamen University, Xiamen, China
5. 1998- Visiting Professor & Director of Andrology Lab, Dept. of Urology, Beijing Medical Univ., China
6. 1999- Director and Adjunct Professor, Reproductive Medicine Institute, Chang Gung University, Taiwan
7. 1999- Director and Adjunct Professor, Steroid Hormone Research Center, National Taiwan Univ., Taiwan
8. 1997- Director, George Whipple Laboratory for Cancer Research, University of Rochester, Rochester, NY
9. 1997- Director, Urology Research Center, University of Rochester, Rochester, NY
10. 1997- Director, Molecular Oncology Graduate Program. University of Rochester, Rochester, NY
11. 1997- George Whipple Distinguished Professor, Departments of Pathology, Urology, Radiation Oncology and Biochemistry, and The Cancer Center, University of Rochester, Rochester, NY
12. 2000- Founder, AndroScience Corporation. San Diego, CA.

4. Honors and Awards:

1. 1988 The Ayerst Award for Outstanding Young Endocrinologist from the Endocrine Society
2. 1989 Andrew Melon Award for Outstanding Young Faculty in USA from Andrew Melon Foundation
3. 1990 Outstanding Young Investigator Award from Cancer Research Foundation
4. 1991 The Milheim Award for Excellence in Cancer Research from Milheim Foundation
5. 1991-94 American Cancer Society Junior Professorship in Cancer Research
6. 1995-97 Blowity-Ridgeway Award in Andrology from Blowity-Ridgeway Foundation
7. 1993-99 CapCure Award (6 times) for Excellence in Prostate Cancer Research
8. 1997 Award with Honorary Fellow from The Japan Society of Andrology (The 2nd Non-Japanese ever awarded such honor)
9. 1998 George Hoyt Whipple Lecture, University of Rochester, Rochester, NY
10. 1998 Jiepimg Wu Award, for Outstanding Achievement in Urology (The highest honor for Chinese-Medical Researcher). Beijing, China.
11. 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.
12. 1999 Davey Memorial Award for Outstanding Cancer research, University of Rochester.
13. 1999 Scholar of the Year, The highest honor from The Taiwanese Osteoporosis Association for Outstanding Contribution in Sex hormones and Osteoporosis.
14. Dr. S.T.Huang-Chan memorial Lecture/Award, University of Hong Kong./Dr. Chien-Tien Hsu Memorial Lecture/Award at 2002 Annual meeting of OBGYN,/ WhoÕs Who in America.

15. The Taiwanese Osteoporosis Society President's Award

5. Grant and Publication Review:

1. 1995- Associate Editor, Frontiers in Bioscience.
2. 1999- Member of Editorial Board, Endocrine.
3. 1999- Member of Editorial Board, The Prostate Journal
4. 1994-01 NIH Study Section: Ad Hoc & Regular Member at Biochemical Endocrinology
5. 1992-96 VA Merit Grant Oncology Study Section
6. 1993-95 NIH Prostate SPORE P50 Center Grant; and NIH PO1 Core Grant
7. 1993- ARMY Breast Cancer Grant Pathology Study Section
8. 1992-98 Medical Research Council of Canada and Dutch Cancer Society Grant;
9. 1998- NIH Research Centers in Minority Institutes Core Grant 1996-99 Taiwan CRC Biomedical Sciences Project and Taiwan National Science Council Grant
10. 1990- Reviewer in PNAS/JBC/Mol. Endo/Cancer Research and 16 other peer-reviewed journals Invited Speaker: 47 International Symposia and 188 Universities/Institutes (1988-present)

6. Research Projects Ongoing or Completed During the Last 3 Years:

6a: Current Funded Projects-4 RO1 grants

1. Title I: "Androgen Receptor in B cell Development and Functions" Agency: NIH. RO1-DK73414 Years 1-4 (03/01/07-12/31/10). P.I.: Chawnshang Chang, Ph.D. The goals of this project are to study the mechanism through which AR regulates B cells.
2. Title II: "Androgen Receptor Roles in Liver Cancer Incidence and Progression" Agency: NIH. RO1-CA122295 Years 1-5 (07/01/07-5/31/12). P.I.: Chawnshang Chang, Ph.D. The goals of this project are to study the role of AR in development and growth of HCC and explore the feasibility of targeting AR for treatment of HCC.
3. Title III: "Loss of Androgen Receptor Promotes Metastatic Cancer" Agency: NIH. RO1-CA122840-01A2 Years 1-5 (09/21/07-7/31/12). P.I.: Chawnshang Chang, Ph.D. The goals of this project are to study the role of AR in prostate cancer metastasis.
4. Title IV: "New Mice Models for Studies of Androgen Receptor in Prostate Cancer" Agency: NIH/ NCI. RO1-CA1273300-01A1 Years 1-5 (01/01/08-12/31/12). P.I.: Chawnshang Chang, Ph.D. The goals of this project are to study the role of AR in prostate carcinogenesis.

6b: Funded Projects During the Past Three Years

1. Title I: "PTEN Tumor Suppressor in Breast Cancer" (10% effort) Agency: ARMY/Breast Program; Idea Award, Years 1-3 (06/01/01-05/31/04). P.I.: Chawnshang Chang, Ph.D. The goals of this project are to study the role of PTEN in breast cancer.
2. Title II: "TR4 Orphan Receptor in Testis" (12% effort) Agency: NIH/NIDDK; RO1-DK56984, Years 1-4 (01/01/01-12/31/04). P.I.: Chawnshang Chang, Ph.D. The goals of this project are to study the associated proteins that may modulate TR4 function.
3. Title III: "Suppression of AR Transactivation by AKT Kinase" (10% effort) Agency: ARMY/Prostate Program; Idea Award, Years 1-3 (01/01/02-12/31/04). P.I.: C. Chang, Ph.D. The goals of this project are to study the mechanism of Akt signal pathway.
4. Title IV:"Induction of AR Transactivation by DHT vs E2" (12% effort) Agency: NIH/NIDDK; RO1-DK60905, Years 1-4 (09/30/01-08/31/05). P.I.: Chawnshang Chang, Ph.D. The goal of this project is to dissect the differences between E2 and DHT for AR transactivation.
5. Title V: "AR in prostate and cancer and bone" (15 % effort) Agency: NIH/NCI; RO1-CA103006, Years 1-3 (09/01/03-08/31/06). P.I.: Chawnshang Chang, Ph.D. The goal of this project is to study how AR influences bone metastasis.
6. Title VI: "Single and Double Knockout of TR2 and TR4 Receptors" (15 % effort) Agency: NIH/NIDDK; RO1-DK63212, Years 1-5 (02/01/03-01/31/07). P.I.: Chawnshang Chang, Ph.D. The goal of this project is to knock out TR2 and TR4 gene for the study of phenotype change involving TR2/4.
7. TitleVII"Suppression of AR by PTEN in prostate cancer" (12% effort) Agency: NIH/NIDDK; RO1-DK/CA60948, Years 1-5 (09/01/02-08/31/07). P.I.: Chawnshang Chang, Ph.D. The goal of this project is to dissect the molecular mechanism of PTEN in the prostate carcinogenesis.
8. Title VIII: "Knockout AR in prostate" (10% effort) Agency: DOD; Idea Award, Years 1-3 (05/01/04-04/30/07). P.I.: Chawnshang Chang, Ph.D. The goals of this project are to study prostate function after lost AR.
9. Title IX: "New Therapy of SBMA" Agency: ADD Foundation. Award Year (07/01/06-06/30/08). P.I.: Chawnshang Chang, Ph.D.
10. In addition to the grants listed above, Dr. Chang is involved in antiandrogen mechanism study funded by NIH- STTR ($25,000) via AndroScience (5% effort, 09/01/02-08/31/03)

7. Current ongoing projects:

1.	Generation and characterization of individual tissue-specific knockout mouse to study AR in vivo functions in (a) prostate/breast/liver/bladder cancers, (b) immune system, (c) male& female fertility, (d) baldness/acne and (e) brain-neuron.
2.	Study how AR can function as either proliferator, survivor and suppressor in individual prostate cancer cell.
3.	Purification/crystallization of AR and AR coregulators and their use in screening antiandrogens.
4.	How can we identify T- or DHT-specific target genes and develop T- or DHT- specific antiandrogens?
5.	Development of new Anti-AR compounds via interruption the interaction between AR and AR Coregulators.

For the orphan nuclear TR2/TR3/TR4 receptors that our Lab cloned, we will concentrate on the following topics:

1.	Identifying new ligands/activators for TR2/TR3/TR4.
2.	Finding physiological roles of these ligands/hormones in proliferation, differentiation, and apoptosis.
3.	Studying the potential role of these ligands/hormones in resistance to radiation and chemo-therapeutic drugs
4.	Studying the bi-directional regulation between orphan receptors and (a) brain neuro-systems, (b) vitamin A and D systems, and (c) p53 tumor suppressors.
5.	Studying TR2/TR4 physiological roles in TR2/TR4 knock-out mice and in TR2/TR4-overexpressing transgenic mice.

In summary, by combining basic and clinical studies of androgen receptors and orphan nuclear receptors, we hope to develop a better understanding of androgen mechanisms and produce better antiandrogens leading to more effective drug therapies in the near future.

8. Publications

Click here for detail .