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5. SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers

Author

Lu, Zhen, Mao, Weiqun, Yang, Hailing, Santiago-OFarrill, Janice M., Rask, Philip J., Mondal, Jayanta, Chen, Hu, Ivan, Cristina, Liu, Xiuping, Liu, Chang-Gong, Xi, Yuanxin, Masuda, Kenta, Carrami, Eli M., Chen, Meng, Tang, Yitao, Pang, Lan, Lakomy, David S., Calin, George A., Liang, Han, Ahmed, Ahmed A., Vankayalapati, Hariprasad, and Bast, Robert C., Jr.

Subjects
Drug therapy, Physiological aspects, Models, Dosage and administration, Polymerization inhibitors -- Dosage and administration -- Physiological aspects, Triple negative breast cancer -- Drug therapy -- Models, Drug synergism, Kinase inhibitors -- Dosage and administration -- Physiological aspects, Ovarian cancer -- Drug therapy -- Models
Abstract

Introduction Recent studies indicate that DNA damage, aberrations in the DNA damage response, and defects in DNA repair machinery play a major role in ovarian cancer and triple-negative breast cancer [...], Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.

Published
2022
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7. Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche

Author

Miranda, Fabrizio, Mannion, David, Liu, Shujuan, Zheng, Yiyan, Mangala, Lingegowda S., Redondo, Clara, Herrero-Gonzalez, Sandra, Xu, Ruoyan, Taylor, Charlotte, Chedom, Donatien Fotso, Carrami, Eli M., Albukhari, Ashwag, Jiang, Dahai, Pradeep, Sunila, Rodriguez-Aguayo, Cristian, Lopez-Berestein, Gabriel, Salah, Eidarus, Abdul Azeez, Kamal R., Elkins, Jonathan M., Campo, Leticia, Myers, Kevin A., Klotz, Daniel, Bivona, Serena, Dhar, Sunanda, Bast, Robert C., Jr., Saya, Hideyuki, Choi, Hwan Geun, Gray, Nathanael S., Fischer, Roman, Kessler, Benedikt M., Yau, Christopher, Sood, Anil K., Motohara, Takeshi, Knapp, Stefan, and Ahmed, Ahmed Ashour

Published
2016
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8. Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

Author

Hellner, Karin, Miranda, Fabrizio, Fotso Chedom, Donatien, Herrero-Gonzalez, Sandra, Hayden, Daniel M., Tearle, Rick, Artibani, Mara, Carrami, Eli M., Williams, Ruth, Gaitskell, Kezia, Elorbany, Samar, Xu, Ruoyan, Laios, Alex, Buiga, Petronela, Ahmed, Karim, Dhar, Sunanda, Zhang, Rebecca Yu, Campo, Leticia, Myers, Kevin A., Lozano, María, Ruiz-Miró, María, Gatius, Sónia, Mota, Alba, Moreno-Bueno, Gema, Matias-Guiu, Xavier, Benítez, Javier, Witty, Lorna, McVean, Gil, Leedham, Simon, Tomlinson, Ian, Drmanac, Radoje, Cazier, Jean-Baptiste, Klein, Robert, Dunne, Kevin, Bast, Robert C., Jr, Kennedy, Stephen H., Hassan, Bassim, Lise, Stefano, Garcia, María José, Peters, Brock A., Yau, Christopher, Sauka-Spengler, Tatjana, and Ahmed, Ahmed Ashour

Published
2016
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10. In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Author

Tefferi, Ayalew, Kantarjian, Hagop, Rajkumar, S. Vincent, Baker, Lawrence H., Abkowitz, Jan L., Adamson, John W., Advani, Ranjana Hira, Allison, James, Antman, Karen H., Bast, Robert C., Jr., Bennett, John M., Benz, Edward J., Jr., Berliner, Nancy, Bertino, Joseph, Bhatia, Ravi, Bhatia, Smita, Bhojwani, Deepa, Blanke, Charles D., Bloomfield, Clara D., Bosserman, Linda, Broxmeyer, Hal E., Byrd, John C., Cabanillas, Fernando, Canellos, George Peter, Chabner, Bruce A., Chanan-Khan, Asher, Cheson, Bruce, Clarkson, Bayard, Cohn, Susan L., Colon-Otero, Gerardo, Cortes, Jorge, Coutre, Steven, Cristofanilli, Massimo, Curran, Walter J., Jr., Daley, George Q., DeAngelo, Daniel J., Deeg, H. Joachim, Einhorn, Lawrence H., Erba, Harry P., Esteva, Francisco J., Estey, Elihu, Fidler, Isaiah J., Foran, James, Forman, Stephen, Freireich, Emil, Fuchs, Charles, George, James N., Gertz, Morie A., Giralt, Sergio, Golomb, Harvey, Greenberg, Peter, Gutterman, Jordan, Handin, Robert I., Hellman, Samuel, Hoff, Paulo Marcelo, Hoffman, Ronald, Hong, Waun Ki, Horowitz, Mary, Hortobagyi, Gabriel N., Hudis, Clifford, Issa, Jean Pierre, Johnson, Bruce Evan, Kantoff, Philip W., Kaushansky, Kenneth, Khayat, David, Khuri, Fadlo R., Kipps, Thomas J., Kripke, Margaret, Kyle, Robert A., Larson, Richard A., Lawrence, Theodore S., Levine, Ross, Link, Michael P., Lippman, Scott M., Lonial, Sagar, Lyman, Gary H., Markman, Maurie, Mendelsohn, John, Meropol, Neal J., Messinger, Yoav, Mulvey, Therese M., O’Brien, Susan, Perez-Soler, Roman, Pollock, Raphael, Prchal, Josef, Press, Oliver, Radich, Jerald, Rai, Kanti, Rosenberg, Saul A., Rowe, Jacob M., Rugo, Hope, Runowicz, Carolyn D., Sandmaier, Brenda M., Saven, Alan, Schafer, Andrew I., Schiffer, Charles, Sekeres, Mikkael A., Silver, Richard T., Siu, Lillian L., Steensma, David P., Stewart, F. Marc, Stock, Wendy, Stone, Richard, Storb, Rainer, Strong, Louise C., Tallman, Martin S., Thompson, Michael, Ueno, Naoto T., Van Etten, Richard A., Vose, Julie M., Wiernik, Peter H., Winer, Eric P., Younes, Anas, Zelenetz, Andrew D., and LeMaistre, Charles A.

Published
2015
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15. Prevention and Early Detection of Ovarian Cancer: Mission Impossible?

Author

Bast, Robert C., Jr., Brewer, Molly, Zou, Changping, Hernandez, Mary A., Daley, Mary, Ozols, Robert, Lu, Karen, Lu, Zhen, Badgwell, Donna, Mills, Gordon B., Skates, Steven, Zhang, Zhen, Chan, Dan, Lokshin, Anna, Yu, Yinhua, Schlag, P. M., editor, Senn, H. -J., editor, Kleihues, P., editor, Stiefel, F., editor, Groner, B., editor, Wallgren, A., editor, Rentchnik, P., editor, Senn, Hans-Jörg, editor, and Kapp, Ursula, editor

Published
2007
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19. Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer

Author

Fu, Siqing, Hennessy, Bryan T., Ng, Chaan S., Ju, Zhenlin, Coombes, Kevin R., Wolf, Judith K., Sood, Anil K., Levenback, Charles F., Coleman, Robert L., Kavanagh, John J., Gershenson, David M., Markman, Maurie, Dice, Kristine, Howard, Adrienne, Li, Jane, Li, Yang, Stemke-Hale, Katherine, Dyer, Mary, Atkinson, Edward, Jackson, Ed, Kundra, Vikas, Kurzrock, Razelle, Bast, Robert C., Jr., and Mills, Gordon B.

Published
2012
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21. Current Challenges and Future Directions in the Management of Ovarian Cancer: Proceedings of the First Global Workshop on Ovarian Cancer

Author

Thigpen, J. Tate, Alberts, David, Birrer, Michael, Copeland, Larry, Coleman, Robert L., Markman, Maurie, Bast, Robert C., Jr, Eisenhauer, Eric L., Fleming, Gini, Fracasso, Paula M., Gershenson, David M., Herzog, Thomas, Monk, Bradley J., Ozols, Robert F., Rustin, Gordon, Brady, Mark F., Shrader, Marissa, and Ranganathan, Aarati

Published
2010
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22. SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer

Author

Ahmed, Ahmed Ashour, Lu, Zhen, Jennings, Nicholas B., Etemadmoghadam, Dariush, Capalbo, Luisa, Jacamo, Rodrigo O., Barbosa-Morais, Nuno, Le, Xiao-Feng, Vivas-Mejia, Pablo, Lopez-Berestein, Gabriel, Grandjean, Geoffrey, Bartholomeusz, Geoffrey, Liao, Warren, Andreeff, Michael, Bowtell, David, Glover, David M., Sood, Anil K., and Bast, Robert C., Jr.

Published
2010
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31. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis

Author

Yang, Gong, Rosen, Daniel G., Zhang, Zhihong, Bast, Robert C., Jr., Mills, Gordon B., Colacino, Justin A., Mercado-Uribe, Imelda, and Liu, Jinsong

Subjects
Ovarian cancer -- Care and treatment, Ovarian cancer -- Prevention, Ovarian cancer -- Research, Chemokines -- Research, Chemokines -- Growth, Ras genes -- Research, Genetic markers -- Research, Company growth, Science and technology
Abstract

Epithelial-stromal interactions play a critical role in tumor initiation and progression; cancer-associated stroma, but not normal stroma, is known to be tumor-promoting. However, the molecular signal used by epithelial cancer cells to reprogram normal stroma to a tumorigenic stroma is not known. Here, we present evidence to suggest that the chemokine growth-regulated oncogene 1 (Gro-1) may be one such signaling molecule. We showed that the expression of Gro-1 is activated by RAS and is vital for cell survival and the malignant transformation of ovarian epithelial cells. Surprisingly, we found that Gro-1 is a potent inducer of senescence in stromal fibroblasts and that this effect depends on functional p53. Senescent fibroblasts induced by Gro-1 can promote tumor growth whereas abrogation of senescence through immortalization results in loss of such tumor promoting activity. We also demonstrated that stromal fibroblasts adjacent to epithelial cancer cells are senescent in human ovarian cancer specimens and in heterografts from RAS-transformed human ovarian epithelial cells and ovarian cancer cells. Moreover, Gro-1 was expressed at significantly higher amounts in ovarian cancer than in normal tissues and was higher in serum samples from women with ovarian cancer than in serum from women without ovarian cancer. These findings provide strong evidence that RAS-induced Gro-1 can reprogram the stromal microenvironment through the induction of senescence of fibroblasts and thus can promote tumorigenesis. Therefore, Gro-1 may be a therapeutic target as well as a diagnostic marker in ovarian cancer. ovarian cancer | Ras | transformation | tumor microenvironment

Published
2006

36. Dasatinib induces autophagic cell death in human ovarian cancer

Author

Le, Xiao-Feng, Mao, Weiqun, Lu, Zhen, Carter, Bing Z., and Bast, Robert C., Jr.

Subjects
Dasatinib -- Dosage and administration, Dasatinib -- Research, Autophagy (Cytology) -- Reports, Apoptosis -- Research, Ovarian cancer -- Care and treatment, Ovarian cancer -- Research, Health
Published
2010

40. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas

Author

Yu, Yinhua, Xu, Fengji, Peng, Hongqi, Fang, Xianjun, Zhao, Shulei, Li, Yang, Cuevas, Bruce, Kuo, Wen-Lin, Gray, Joe W., Siciliano, Michael, Mills, Gordon B., and Bast, Robert C., Jr.

Subjects
Tumor suppressor genes -- Research, Rats -- Genetic aspects, Epithelial cells -- Research, Gene expression -- Research, Ovarian cancer -- Genetic aspects, Breast cancer -- Genetic aspects, Science and technology
Abstract

Using differential display PCR, we have identified a gene [NOEY2, ARHI (designation by the Human Gene Nomenclature Committee)] with high homology to ras and rap that is expressed consistently in normal ovarian and breast epithelial cells but not in ovarian and breast cancers. Reexpression of NOEY2 through transfection suppresses clonogenic growth of breast and ovarian cancer cells. Growth suppression was associated with down-regulation of the cyclin D1 promoter activity and induction of [p21.sup.WAF1/CIP1]. In an effort to identify mechanisms leading to NOEY2 silencing in cancer, we found that the gene is expressed monoallelically and is imprinted maternally. Loss of heterozygosity of the gene was detected in 41% of ovarian and breast cancers. In most of cancer samples with loss of heterozygosity, the non-imprinted functional allele was deleted. Thus, NOEY2 appears to be a putative imprinted tumor suppressor gene whose function is abrogated in ovarian and breast cancers.

Published
1999

41. Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation

Author

Feng, Weiwei, Marquez, Rebecca T., Lu, Zhen, Liu, Jinsong, Lu, Karen H., Issa, Jean-Pierre J., Fishman, David M., Yu, Yinhua, and Bast, Robert C., Jr.

Subjects
Ovarian cancer -- Genetic aspects, Ovarian cancer -- Development and progression, Tumor suppressor genes -- Physiological aspects, Tumor suppressor genes -- Research, Genomic imprinting -- Research, Health
Published
2008

45. Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor

Author

McGeehan, Gerard M., Becherer, J. David, Boyer, Cinda M., Champion, Brian, Connolly, Kevin M., Conway, James G., Furdon, Paul, Karp, Stephen, Kidao, Sudha, McElroy, Andrew B., Nichols, James D., Pryzwansky, Katherine M., Schoenen, Frank, Sekut, Les, Truesdale, Anne, Verghese, Margrith, Warner, Janet, Ways, Judy P., and Bast, Robert C., Jr.

Subjects
Enzyme inhibitors -- Research, Tumor necrosis factor -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A metalloproteinase inhibitor, GI 129471, selectively inhibits a distinct Zn(2+) endopeptidase that regulates the processing of tumor necrosis factor-alpha (TNF-alpha). This inhibitory process takes place at a post-translational step during TNF-alpha generation. The anti-inflammatory activity of GI 129471 is due to suppression of TNF-alpha secretion.

Published
1994

50. Specific Keynote: Molecular Therapeutics in Ovarian Cancer

Author

Mills, Gordon B., Fang, Xianjun, Lu, Yiling, Hasegawa, Yutaka, Eder, Astrid, Tanyi, Janos, Tabassam, Fazad Haq, Mao, Muling, Wang, Hongwei, Cheng, Kwai Wa, Nakayama, Yasuhisa, Kuo, Wenlin, Erickson, Jim, Gershenson, David, Kohn, Elise C., Jaffe, Robert, Bast, Robert C., Jr., and Gray, Joe

Published
2003
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