Rugang Zhang, Ph.D.

1. Developing novel therapeutic strategies for unmet clinical needs in clear cell and endometrioid histosubtypes of epithelial ovarian cancer, the most lethal gynecological malignancy is the developed world. For example, clear cell ovarian cancer carries worst prognosis when diagnosed at advanced stages because there is currently no effective therapeutic treatment.  Our published works explored new therapeutic strategies based on unique genetic makeup such as ARID1A mutation in clear cell and endometrioid epithelial ovarian cancer.

• Biter BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, Schultz DC, Liu Q, Shih IM, Conejo-Garcia JR, Speicher DW, Zhang R. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nature Medicine, 21:231-238, 2015. PMCID: PMC4352133.
• Bitler BG, Park PH, Hai Y, Aird KM, Wu S, Wang Y, Kossenkov AV, Rauscher FJ, Conejo-Garcia JR, Zou W, Speicher DW, Huntsman DG, Cho KR, Christianson DW, Zhang R. ARID1A-mutated ovarian cancers depend on HDAC6 acitvity.  Nature Cell Biology, 19: 962-973, 2017. PMCID: PMC5541905.
• 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. Nature Communications, 9: 4116, 2018. PMCID: PMC6175882.
• Wu S, Fukumoto T, Lin J, Nacarelli T, Wang Y, Ong D, Fatkhutdinov N, Zundell JA, Karakashev S, Zhou W, Schwartz LE, Tang HY, Drapkin R, Liu Q, Huntsman DG, Kossenkov AV, Speicher DW, Schug ZT, Dang CV, Zhang R. Therapeuitc targeting glutamine dependence in SWI/SNF-inactivated cancers. Nature Cancer, in press.

2. Understanding the epigenetic basis of high-grade serous epithelial ovarian cancer. Our published works explored new therapeutic strategies in high-grade serous ovarian cancer through targeting epigenetic regulators such as EZH2 and BRD4.

• Karakashev S, Zhu H, Yokoyama Y, Zhao B, Fathutdinov N, Kossenkov AV, Wilson AJ, Simpkins F, Speicher D, Khabele D, Bitler B, Zhang R. BET bromodomian inhibition synergizes with PARP inhibitor in epithelial ovarian cancers. Cell Reports, 21: 3398-3405, 2017. PMCID: PMC5745042.
• Karakashev S, Zhu H, Wu S, Zhao B, Yokoyama Y, Bitler BG, Park PH, Lee JH, Kossenkov AV, Gaonkar KS, Yan H, Drapkin R, Conejo-Garica JR, Speicher DW, Ordog T, Zhang R. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nature Communications, 9 (1): 631, 2017. PMCID: PMC5809368.
• Fukumoto T, Zhu H, Nacarelli T, Karakashev S, Fatkhutdinov N, Wu S, Liu P, Kossenkov AV, Showe L, Jean S, Zhang L, Zhang R. N⁶-methylation of adenosine (m⁶A) of FZD10 mRNA contributes to PARP inhibitor resistance. Cancer Research, 79 (11): 2812-2820, 2019. PMCID: PMC6825538.
• Karakashev S, Fukumoto T, Zhao B, Lin J, Wu S, Fatkhutdinov N, Park PW, Semenova G, Jean S, Gadungog 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: 157-167, 2020. PMCID: PMC7155421.

3. Understanding the molecular basis of tumor immunity in ovarian cancer. Our published works explored new roles of epigenetic regulators such as BRD4 and SATB1 in regulating anti-tumor immunity and immune environment of ovarian cancer.

• Rutkowski MR, Stephen TL, Svoronos N, Allegrezza MJ, Tesone AJ, Perales-Puchalt A, Brencicova E, Escovar-Fadul X, Nguyen JM, Cadungog MG, Zhang R, Salatino M, Tchou J, Rabinovich GA, Conejo-Garcia JR. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell, 27:27-40, 2015. PMCID: PMC4293269.
• Zhu H, Bengsch F, Svoronons N, Rutkowski MR, Bitler BG, Allegrezza MJ, Yokoyama Y, Bradner JE, Conejo-Garcia JR, Zhang R. BET bromodomain inhibition promotes anti-tumor immunity by inhibiting PD-L1 expression.  Cell Reports, 16:2829-2837, 2016. PMCID: PMC5177024.
• 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 Supressor Cells. Cancer Discovery, 7: 72-85, PMCID: PMC5222699.
• Stephen TL, Payne KK, Chaurio RA, Allegrezza MJ, Zhu H, Perez-Sanz J, Perales-Puchalt A, Nguyen JM, Vava-Ailor AE, Eruslanov EB, Borowsky ME, Zhang R, Laufer TM, Conejo-Garcia JR. SATB1 expression governs epigentic repression of PD-1 in tumor-activated T cells. Immunity, 46: 51-64, 2017. PMCID: PMC5336605.

4. Identification of novel pathways regulating cellular senescence through epigenetic mechanisms and their implications in ovarian cancer. We defined key epigenetic regulators such as HIRA/ASF1a complex, HMGB2 and RNA m⁶A methyltransferase complex that drive changes in the chromatin landscape during senescence.

• Bitler BG, Nicodemus JP, Li H, Cai Q, Wu H, Hua X, Li T, Birrer MJ, Godwin AK, Cairns P, Zhang R. Wnt5a suppresses epithelial ovarian cancer by promoting cellular senescence. Cancer Research, 71: 6184-6194, 2011. PMCID: PMC3185156.
• Zhu H, Ren S, Bitler BG, Aird KM, Tu Z, Skordalakes E, Zhu Y, Yan J, Sun Y, Zhang R. SPOP E3 ubiquitin ligase adaptor promotes cellular senescence by degrading the SENP7 deSUMOylase. Cell Reports, 13: 1183-1193, 2015.  PMCID: PMC4644471.
• Aird KM, Iwasaki O, Kossenkov A, Tanizawa H, Fatkhutdinov N, Bitler BG, Le L, Yang T, Johnson FB, Noma K, Zhang R. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. Journal of Cell Biology, 215: 325-334, 2016. PMCID: PMC5100296.
• 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 senescence-associated secretory phenotype. Nature Cell Biology, in press.

5. Understanding the role of DNA damage and metabolic pathways in mediating senescence-associated cell growth arrest. Our study helps explain a major paradox in the senescence field: How activated oncogenes induce senescence but at the same time predispose cells to transformation through BRCA1 pathway. In addition, we explored the role of metabolic pathways in regulating replication stress and DNA damage during senescence.

• Tu Z, Nicodemus J, Beehary N, Xia B, Yen T, Zhang R. Oncogenic Ras regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence. Developmental Cell, 21: 1077-1091, 2011. PMCID: PMC3241855.
• Aird KM, Zhang G, Li H, Tu Z, Bitler BG, Garipov A, Wu H, Wei Z, Wagner SN, Herlyn M, Zhang R. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Reports, 3: 1252-1265, 2013. PMCID: PMC3840499.
• Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, Aird KM, Iwasaki O, Kossenkov AV, Schultz D, Noma K, Baur JA, Schug Z, Tang HY, Speicher DW, David G, Zhang R. NAD⁺ metabolism governs the proinflammatory senescence-associated secretome. Nature Cell Biology, 21: 397-407, 2019. PMCID: PMC6448588.
• Zhao B, Liu P, Fukumoto T, Nacarelli T, Fatkhutdinov N, Wu S, Lin J, Aird KM, Tang SY, Liu Q, Speicher DW,Zhang R. Topoisomerase 1 cleavage complex enables pattern recongnition and inflammation during senescence. Nature Communications, 11: 908, 2020. PMCID: PMC7031389.