Department of Experimental Therapeutics, Division of Cancer Medicine
About Rugang Zhang
Dr. Zhang received his Ph.D. in Cell Biology from the Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Science. His postdoctoral training came from the Institute for Cancer Research, Fox Chase Cancer Center, where he later became an Assistant Professor. He joined The Wistar Institute as an Associate Professor in 2012, was promoted to Professor in 2015 and later became holder of the Christopher M. Davis Endowed Professor & Leader, Immunology, Microenvironment and Metastasis Program. He assumed various leadership roles during his time at Wistar and was appointed Deputy Director in 2017. He joined The University of Texas MD Anderson Cancer Center as a Professor and Chair of Department of Experimental Therapeutics in 2023.
Dr. Zhang is committed to finding a cure for epithelial ovarian cancer, the most lethal gynecological malignancy in the developed world. In addition, he investigates the aging process of normal mammalian cells and its role in both tissue aging and cancer development for the discovery of therapeutic applications.
Present Title & Affiliation
Professor, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Department Chair, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
The Zhang laboratory studies ovarian cancer biology with the goal of developing novel therapeutic approaches to combat the disease with precision. In particular, the lab investigates how alterations in epigenetics— or the heritable changes that affects gene expression without alterations in the underlying DNA sequence—contribute to epithelial ovarian cancer. The ultimate goal of this line of investigation is to leverage these newly gained mechanistic insights for developing new therapeutics in a personalized manner based on one’s unique genetic and/or pathway signatures.
The Zhang laboratory also investigates the mechanisms that underlie aging in normal mammalian cells and how this process is implicated in tissue aging or evaded by tumor cells during malignant transformation. In particular, the lab focuses on epigenetic and metabolic pathways that regulate the aging process. The overarching goal for identifying such mechanisms is the development of novel strategies to promote healthy aging and combat cancer.
EPIGENETICS OF EPITHELIAL OVARIAN CANCER
A major discovery in recent cancer genome-wide sequencing is the identification of significant genetic changes in chromatin-modifying genes. However, despite great strides in identifying the various epigenetic enzymes/factors involved in cancer, the translational application of these findings in cancer intervention remains to be explored. The Zhang lab will pursue these issues in the coming years by focusing on the epigenetic SWItch/Sucrose Non-Fermentable (SWI/SNF) and PP2A complexes as proof of principles in the context of ovarian cancer.
a) Mechanism-guided therapeutic strategies for genetic alterations that affect the SWI/SNF chromatin remodeling complex in epithelial ovarian cancer (such as ARID1A mutation in clear cell and endometrioid subtypes of ovarian cancer, and CARM1 amplification/overexpression in high-grade serous ovarian cancer).
b) Epigenetic approaches to chemotherapy resistance and cancer stemness in epithelial ovarian cancer.
c) Epigenetic approaches to primer for and/or synergize with immunological therapy in epithelial ovarian cancer.
d) PARP inhibitors resistance mechanism and approaches to sensitizing BRCA-proficient ovarian cancer to PARP inhibitors.
e) Epigenetic and immunological approaches to mutations in subunits of the PP2A complex (e.g., PPP2R1A) in ovarian and endometrial cancers.
EPIGENETIC AND METABOLIC BASIS OF CELLULAR SENESCENCE
Cellular senescence is a state of stable cell growth arrest that is accompanied by drastic molecular and phenotypic changes. Cellular senescence is a major contributor to tissue aging and plays a context-dependent role in tumor development. For example, cellular senescence is tumor suppressive and overcoming the senescence-associated cell growth arrest is a necessary step during cell transformation. In contrast to its tumor suppressive function, senescent cells can also promote cancer by acquiring a secretory phenotype and create a pro-tumorigenic microenvironment. The biological process of cellular senescence represents an ideal paradigm to examine the role of the DNA damage response, epigenetically determined chromatin structure, and metabolic reprogramming during tissue aging and cancer development.
a) Chromatin basis of the senescence-associated secretory phenotype.
b) Targeting senescence-associated metabolic vulnerability to develop cancer therapeutics.
c) Targeting senescence-associated immunological vulnerability to develop cancer therapeutics.
Education & Training
|2002||Chinese Academy of Sciences, Institute of Biochemistry and Cell Biology, Shanghai, CHN, PHD, Molecular and Cellular Biology|
|1997||Anhui Normal University, Anhui, CHN, BS, Biology|
|2003-2008||Postdoctoral Associate, Fox Chase Cancer Center, Philadelphia, PA|
|2002-2003||Postdoctoral Fellow, University of Pennsylvania, Philadelphia, PA|
- Hao X, Shiromoto Y, Sakurai M, Towers M, Zhang Q, Wu S, Havas A, Wang L, Berger S, Adams PD, Tian B, Nishikura K, Kossenkov AV, Liu P, Zhang R. ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16INK4a levels. Nat Cell Biol 24(8):1202-1210, 2022. e-Pub 2022. PMID: 35851616.
- Liu H, Lin J, Zhou W, Moses R, Dai Z, Kossenkov AV, Drapkin R, Bitler BG, Karakashev S, Zhang R. KDM5A Inhibits Antitumor Immune Responses Through Downregulation of the Antigen-Presentation Pathway in Ovarian Cancer. Cancer Immunol Res 10(8):1028-1038, 2022. PMID: 35726891.
- Lin J, Guo D, Liu H, Zhou W, Wang C, Müller I, Kossenkov AV, Drapkin R, Bitler BG, Helin K, Zhang R. The SETDB1-TRIM28 Complex Suppresses Antitumor Immunity. Cancer Immunol Res 9(12):1413-1424, 2021. PMID: 34848497.
- Zundell JA, Fukumoto T, Lin J, Fatkhudinov N, Nacarelli T, Kossenkov AV, Liu Q, Cassel J, Hu CA, Wu S, Zhang R. Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant Ovarian Cancers. Cancer Res 81(20):5325-5335, 2021. e-Pub 2021. PMID: 34548333.
- Lin J, Liu H, Fukumoto T, Zundell J, Yan Q, Tang CA, Wu S, Zhou W, Guo D, Karakashev S, Hu CA, Sarma K, Kossenkov AV, Zhang R. Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer. Nat Commun 12(1):5321, 2021. e-Pub 2021. PMID: 34493732.
- Liu P, Li F, Lin J, Fukumoto T, Nacarelli T, Hao X, Kossenkov AV, Simon MC, Zhang R. m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype. Nat Cell Biol 23(4):355-365, 2021. e-Pub 2021. PMID: 33795874.
- Wu S, Fukumoto T, Lin J, Nacarelli T, Wang Y, Ong D, Liu H, Fatkhutdinov N, Zundell JA, Karakashev S, Zhou W, Schwartz LE, Tang HY, Drapkin R, Liu Q, Huntsman DG, Kossenkov AV, Speicher DW, Schug ZT, Van Dang C, Zhang R. Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma. Nat Cancer 2(2):189-200, 2021. e-Pub 2021. PMID: 34085048.
- Karakashev S, Fukumoto T, Zhao B, Lin J, Wu S, Fatkhutdinov N, Park PH, Semenova G, Jean S, Cadungog MG, Borowsky ME, Kossenkov AV, Liu Q, Zhang R. EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition. Cancer Cell 37(2):157-167.e6, 2020. e-Pub 2020. PMID: 32004442.
- Nacarelli T, Fukumoto T, Zundell JA, Fatkhutdinov N, Jean S, Cadungog MG, Borowsky ME, Zhang R. NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer. Cancer Res 80(4):890-900, 2020. e-Pub 2019. PMID: 31857293.
- Zhao B, Liu P, Fukumoto T, Nacarelli T, Fatkhutdinov N, Wu S, Lin J, Aird KM, Tang HY, Liu Q, Speicher DW, Zhang R. Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence. Nat Commun 11(1):908, 2020. e-Pub 2020. PMID: 32075966.
- Iwasaki O, Tanizawa H, Kim KD, Kossenkov A, Nacarelli T, Tashiro S, Majumdar S, Showe LC, Zhang R, Noma KI. Involvement of condensin in cellular senescence through gene regulation and compartmental reorganization. Nat Commun 10(1):5688, 2019. e-Pub 2019. PMID: 31831736.
- Fukumoto T, Fatkhutdinov N, Zundell JA, Tcyganov EN, Nacarelli T, Karakashev S, Wu S, Liu Q, Gabrilovich DI, Zhang R. HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer. Cancer Res 79(21):5482-5489, 2019. e-Pub 2019. PMID: 31311810.
- Zhao B, Lin J, Rong L, Wu S, Deng Z, Fatkhutdinov N, Zundell J, Fukumoto T, Liu Q, Kossenkov A, Jean S, Cadungog MG, Borowsky ME, Drapkin R, Lieberman PM, Abate-Shen CT, Zhang R. ARID1A promotes genomic stability through protecting telomere cohesion. Nat Commun 10(1):4067, 2019. e-Pub 2019. PMID: 31492885.
- Fukumoto T, Zhu H, Nacarelli T, Karakashev S, Fatkhutdinov N, Wu S, Liu P, Kossenkov AV, Showe LC, Jean S, Zhang L, Zhang R. N6-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance. Cancer Res 79(11):2812-2820, 2019. e-Pub 2019. PMID: 30967398.
- Wu S, Fatkhutdinov N, Rosin L, Luppino JM, Iwasaki O, Tanizawa H, Tang HY, Kossenkov AV, Gardini A, Noma KI, Speicher DW, Joyce EF, Zhang R. ARID1A spatially partitions interphase chromosomes. Sci Adv 5(5):eaaw5294, 2019. e-Pub 2019. PMID: 31131328.
- Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, Aird KM, Iwasaki O, Kossenkov AV, Schultz D, Noma KI, Baur JA, Schug Z, Tang HY, Speicher DW, David G, Zhang R. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol 21(3):397-407, 2019. e-Pub 2019. PMID: 30778219.
- Wu S, Fatkhutdinov N, Fukumoto T, Bitler BG, Park PH, Kossenkov AV, Trizzino M, Tang HY, Zhang L, Gardini A, Speicher DW, Zhang R. SWI/SNF catalytic subunits' switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells. Nat Commun 9(1):4116, 2018. e-Pub 2018. PMID: 30297712.
- Fukumoto T, Park PH, Wu S, Fatkhutdinov N, Karakashev S, Nacarelli T, Kossenkov AV, Speicher DW, Jean S, Zhang L, Wang TL, Shih IM, Conejo-Garcia JR, Bitler BG, Zhang R. Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer. Cell Rep 22(13):3393-3400, 2018. PMID: 29590609.
- Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park PH, Lee JH, Kossenkov AV, Gaonkar KS, Yan H, Drapkin R, Conejo-Garcia JR, Speicher DW, Ordog T, Zhang R. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun 9(1):631, 2018. e-Pub 2018. PMID: 29434212.
- Karakashev S, Zhu H, Yokoyama Y, Zhao B, Fatkhutdinov N, Kossenkov AV, Wilson AJ, Simpkins F, Speicher D, Khabele D, Bitler BG, Zhang R. BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer. Cell Rep 21(12):3398-3405, 2017. PMID: 29262321.
- Bitler BG, Wu S, Park PH, Hai Y, Aird KM, Wang Y, Zhai Y, Kossenkov AV, Vara-Ailor A, Rauscher FJ, Zou W, Speicher DW, Huntsman DG, Conejo-Garcia JR, Cho KR, Christianson DW, Zhang R. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19(8):962-973, 2017. e-Pub 2017. PMID: 28737768.
- Stephen TL, Payne KK, Chaurio RA, Allegrezza MJ, Zhu H, Perez-Sanz J, Perales-Puchalt A, Nguyen JM, Vara-Ailor AE, Eruslanov EB, Borowsky ME, Zhang R, Laufer TM, Conejo-Garcia JR. SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells. Immunity 46(1):51-64, 2017. PMID: 28099864.
- Svoronos N, Perales-Puchalt A, Allegrezza MJ, Rutkowski MR, Payne KK, Tesone AJ, Nguyen JM, Curiel TJ, Cadungog MG, Singhal S, Eruslanov EB, Zhang P, Tchou J, Zhang R, Conejo-Garcia JR. Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells. Cancer Discov 7(1):72-85, 2017. e-Pub 2016. PMID: 27694385.
- Yokoyama Y, Zhu H, Lee JH, Kossenkov AV, Wu SY, Wickramasinghe JM, Yin X, Palozola KC, Gardini A, Showe LC, Zaret KS, Liu Q, Speicher D, Conejo-Garcia JR, Bradner JE, Zhang Z, Sood AK, Ordog T, Bitler BG, Zhang R. BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer. Cancer Res 76(21):6320-6330, 2016. PMID: 27803105.
- Aird KM, Iwasaki O, Kossenkov AV, Tanizawa H, Fatkhutdinov N, Bitler BG, Le L, Alicea G, Yang TL, Johnson FB, Noma KI, Zhang R. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol 215(3):325-334, 2016. e-Pub 2016. PMID: 27799366.
- Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG, Allegrezza MJ, Yokoyama Y, Kossenkov AV, Bradner JE, Conejo-Garcia JR, Zhang R. BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression. Cell Rep 16(11):2829-2837, 2016. PMID: 27626654.
- Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, Schultz DC, Liu Q, Shih IeM, Conejo-Garcia JR, Speicher DW, Zhang R. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 21(3):231-8, 2015. e-Pub 2015. PMID: 25686104.
- Zhou W, Liu H, Yuan Z, Zundell J, Towers M, Lin J, Lombardi S, Nie H, Murphy B, Yang T, Wang C, Liao L, Goldman AR, Kannan T, Kossenkov AV, Drapkin R, Montaner LJ, Claiborne DT, Zhang N, Wu S, Zhang R. Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis. Cancer Cell In press. PMID: 36963401.