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Kinase targeting and ovarian clear cell carcinoma

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https://www.readbyqxmd.com/read/27364904/synthetic-lethal-targeting-of-arid1a-mutant-ovarian-clear-cell-tumors-with-dasatinib
#1
Rowan E Miller, Rachel Brough, Ilirjana Bajrami, Chris T Williamson, Simon McDade, James Campbell, Asha Kigozi, Rumana Rafiq, Helen Pemberton, Rachel Natrajan, Josephine Joel, Holly Astley, Claire Mahoney, Jonathan D Moore, Chris Torrance, John D Gordan, James T Webber, Rebecca S Levin, Kevan M Shokat, Sourav Bandyopadhyay, Christopher J Lord, Alan Ashworth
New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction...
July 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26622535/checkpoint-kinase-1-inhibitors-as-targeted-molecular-agents-for-clear-cell-carcinoma-of-the-ovary
#2
Hiroshi Kobayashi, Hiroshi Shigetomi, Chiharu Yoshimoto
In clear cell carcinoma of the ovary, chemoresistance frequently results in treatment failure. The present study aimed to review the potential association of transcription factor hepatocyte nuclear factor (HNF)-1β with cell cycle checkpoint machinery, as a mechanism for chemoresistance. The English-language literature on the subject was reviewed to identify genomic alterations and aberrant molecular pathways interacting with chemoresistance in clear cell carcinoma. Oxidative stress induced by repeated hemorrhage induces greater susceptibility of endometriotic cells to DNA damage, and subsequent malignant transformation results in endometriosis-associated ovarian cancer...
August 2015: Oncology Letters
https://www.readbyqxmd.com/read/26170971/sgk3-cisk-may-induce-tumor-angiogenesis-hypothesis
#3
Minzhi Hou, Yingrong Lai, Shanyang He, Weiling He, Hongwei Shen, Zunfu Ke
Serum- and glucocorticoid-inducible protein kinase 3 (SGK3), also known as cytokine-independent survival kinase (CISK), encoded by chromosome 8q12.2, is a downstream mediator of phosphatidylinositol 3-kinase (PI3K) oncogenic signaling. As a downstream target of PI3K, SGK3 has been reported to mediate pivotal roles in oncogenic progress in various cancers, including breast cancer, ovarian cancer and hepatocellular carcinoma. Functionally parallel to v-akt murine thymoma viral oncogene homolog (AKT)/protein kinase B, SGK3 serves as a hallmark mediating glycogen synthase kinase-β (GSK3-β), B-cell lymphoma (Bcl)-2-associated death promoter, forkead family of transcription factors, Bcl-extra large, Bcl-2, mammalian target of rapamycin, C-X-C chemokine receptor type 4 (CXCR4) and numerous other molecules in cell proliferation, growth, survival, migration and even tumor angiogenesis...
July 2015: Oncology Letters
https://www.readbyqxmd.com/read/25962016/functional-specificity-of-akt-isoforms-in-cancer-progression
#4
Anne-Marie Fortier, Eric Asselin, Monique Cadrin
Akt/PKB kinases are central mediators of cell homeostasis. There are three highly homologous Akt isoforms, Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ. Hyperactivation of Akt signaling is a key node in the progression of a variety of human cancer, by modulating tumor growth, chemoresistance and cancer cell migration, invasion and metastasis. It is now clear that, to understand the mechanisms on how Akt affects specific cancer cells, it is necessary to consider the relative importance of each of the three Akt isoforms in the altered cells...
April 1, 2011: Biomolecular Concepts
https://www.readbyqxmd.com/read/25893298/elevated-cdcp1-predicts-poor-patient-outcome-and-mediates-ovarian-clear-cell-carcinoma-by-promoting-tumor-spheroid-formation-cell-migration-and-chemoresistance
#5
Y He, A C Wu, B S Harrington, C M Davies, S J Wallace, M N Adams, J S Palmer, D K Roche, B G Hollier, T F Westbrook, H Hamidi, G E Konecny, B Winterhoff, N P Chetty, A J Crandon, N B Oliveira, C M Shannon, A V Tinker, C B Gilks, J I Coward, J W Lumley, L C Perrin, J E Armes, J D Hooper
Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined...
January 28, 2016: Oncogene
https://www.readbyqxmd.com/read/25692284/multifocal-endometriotic-lesions-associated-with-cancer-are-clonal-and-carry-a-high-mutation-burden
#6
Michael S Anglesio, Ali Bashashati, Yi Kan Wang, Janine Senz, Gavin Ha, Winnie Yang, Mohamed R Aniba, Leah M Prentice, Hossein Farahani, Hector Li Chang, Anthony N Karnezis, Marco A Marra, Paul J Yong, Martin Hirst, Blake Gilks, Sohrab P Shah, David G Huntsman
Endometriosis is a significant risk factor for clear cell and endometrioid ovarian cancers and is often found contiguous with these cancers. Using whole-genome shotgun sequencing of seven clear cell ovarian carcinomas (CCC) and targeted sequencing in synchronous endometriosis, we have investigated how this carcinoma may evolve from endometriosis. In every case we observed multiple tumour-associated somatic mutations in at least one concurrent endometriotic lesion. ARID1A and PIK3CA mutations appeared consistently in concurrent endometriosis when present in the primary CCC...
June 2015: Journal of Pathology
https://www.readbyqxmd.com/read/25677064/the-pi3k-akt-mtor-pathway-as-a-therapeutic-target-in-ovarian-cancer
#7
REVIEW
Seiji Mabuchi, Hiromasa Kuroda, Ryoko Takahashi, Tomoyuki Sasano
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the malignant transformation of human tumors and their subsequent growth, proliferation, and metastasis. Preclinical investigations have suggested that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma. Thus, this pathway is regarded as an attractive candidate for therapeutic interventions, and inhibitors targeting different components of this pathway are in various stages of clinical development...
April 2015: Gynecologic Oncology
https://www.readbyqxmd.com/read/25429856/sphingosine-kinase-1-as-a-potential-therapeutic-target-in-epithelial-ovarian-cancer
#8
Jeong-Won Lee, Ji-Yoon Ryu, Gun Yoon, Hye-Kyung Jeon, Young-Jae Cho, Jung-Joo Choi, Sang Yong Song, In-Gu Do, Yoo-Young Lee, Tae-Joong Kim, Chel Hun Choi, Byoung-Gie Kim, Duk-Soo Bae
Sphingosine kinase 1 (SK1) is over-expressed in multiple types of human cancer. SK1 has growth-promoting effects and has been proposed as a potential therapeutic target. We investigated the therapeutic effects of SK1 inhibition in epithelial ovarian carcinoma (EOC). SK1 siRNA or inhibitors were tested in EOC cell lines, including A2780, SKOV3ip1, A2780-CP20, SKOV3-TR, ES2 and RMG2. Cells were treated with SK inhibitor or FTY720, and cell proliferation, apoptosis, angiogenesis and invasion were examined by MTT, FACS, ELISA and wound-healing assays, respectively...
July 1, 2015: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/25281027/chromosome-20q13-2-znf217-locus-amplification-correlates-with-decreased-e-cadherin-expression-in-ovarian-clear-cell-carcinoma-with-pi3k-akt-pathway-alterations
#9
Hsien-Neng Huang, Wen-Chih Huang, Ching-Hung Lin, Ying-Cheng Chiang, Hsin-Ying Huang, Kuan-Ting Kuo
This study aims to evaluate the relationships between chromosome 20q13.2 zinc finger protein 217 (ZNF217) locus amplification, ZNF217 expression, E-cadherin expression, and PI3K-Akt pathway alterations (activating PIK3CA mutations or loss of phosphatase and tensin homolog [PTEN] expression), and whether these molecular alterations can predict the clinical survival data in ovarian clear cell carcinoma (OCCC) patients. Samples and clinical data of 72 OCCC patients were collected. Chromosome 20q13.2 ZNF217 locus amplification was detected by fluorescence in situ hybridization...
November 2014: Human Pathology
https://www.readbyqxmd.com/read/24767251/involvement-of-mir-29b-signaling-in-the-sensitivity-to-chemotherapy-in-patients-with-ovarian-carcinoma
#10
Furong Dai, Yi Zhang, Yuxiang Chen
Although the molecular mechanisms driving chemoresistance and relapse of ovarian cancer have been widely studied, the key molecules have not been identified. In this study, the expression of miR-29b messenger RNA (mRNA) and its targeted genes, myeloid cell leukemia sequence 1, mitogen-activated protein kinase 10 (MAPK10), and autophagy-related protein 9A (ATG9A), were investigated in ovarian carcinomas, and their associations with clinicopathological characteristics and survival of patients with ovarian cancer were analyzed...
June 2014: Human Pathology
https://www.readbyqxmd.com/read/24692678/targeted-treatment-of-ovarian-cancer-the-multiple-kinase-inhibitor-sorafenib-as-a-potential-option
#11
REVIEW
Elisabeth Smolle, Valentin Taucher, Edgar Petru, Johannes Haybaeck
Ovarian cancer (OC) is ranked as the eighth most common gynecological malignancy and is the leading cause of gynecological cancer-related deaths in women worldwide. The response to platinum- and taxane-based chemotherapy is very often poor, and targeted-therapeutics are currently being tested in patients with OC. Sorafenib is a non-selective multiple kinase inhibitor with proven antiproliferative effects in thyroid, renal and hepatocellular carcinoma. Sorafenib acts on vascular endothelial growth factor (VEGF) and on platelet-derived growth factor (PDGF) related pathways...
April 2014: Anticancer Research
https://www.readbyqxmd.com/read/24523919/targeted-inhibition-of-fak-pyk2-and-bcl-xl-synergistically-enhances-apoptosis-in-ovarian-clear-cell-carcinoma-cell-lines
#12
Heejei Yoon, Yoon-La Choi, Ji-Young Song, Ingu Do, So Young Kang, Young-Hyeh Ko, Sangyong Song, Byoung-Gie Kim
Ovarian clear cell carcinoma (OCCC) displays a higher resistance to first line chemotherapy, requiring the development of new therapeutics. We previously identified a frequent chromosomal gain at 8q24 that harbors the focal-adhesion kinase (FAK) gene; the potential of this gene as a therapeutic target remains to be evaluated in OCCCs. We first examined the dependence of OCCCs on FAK and the PI3K/AKT signaling pathway. FAK was overexpressed in 20% of 67 OCCC samples, and this overexpression was correlated with its copy number gain...
2014: PloS One
https://www.readbyqxmd.com/read/24309512/multi-kinase-inhibition-in-ovarian-cancer
#13
EDITORIAL
Paul Dent
Sorafenib (Nexavar) is a multi-kinase inhibitor that was developed as an inhibitor of RAF-1, in the ERK1/2 pathway, but which was subsequently shown to inhibit class III tyrosine kinase receptors. (1) More recently regorafenib (Stivarga) has been developed, which is a further fluorinated version of sorafenib with greater bioavailability and similar inhibitory properties against RAF-1/class III RTKs. (2) Some of the anti-tumor effects of sorafenib have been ascribed to anti-angiogenic actions of this agent on endothelial associated kinases such as VEGFR2...
January 2014: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/24096267/two-cases-of-recurrent-ovarian-clear-cell-carcinoma-treated-with-sorafenib
#14
Masafumi Koshiyama, Noriomi Matsumura, Tsukasa Baba, Ken Yamaguchi, Yumiko Yoshioka, Ikuo Konishi
Sorafenib is an oral multikinase inhibitor targeting Raf and other kinases. The anti-tumor effect of sorafenib is thought to be mediated through its inhibition of the RAS-Raf-Erk pathway, as well as its inhibition of VEGFR and PDGFR. Sorafenib has been effective at treating patients with renal cell carcinoma (RCC). Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer. OCCC is represented by cells with clear cytoplasm that resemble those observed in RCC. Using a microarray database, the gene expression profile of OCCC was similar to that of RCC...
January 2014: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/23819061/stathmin-regulates-hypoxia-inducible-factor-1%C3%AE-expression-through-the-mammalian-target-of-rapamycin-pathway-in-ovarian-clear-cell-adenocarcinoma
#15
Kazuhiro Tamura, Mikihiro Yoshie, Eri Miyajima, Mika Kano, Eiichi Tachikawa
Stathmin, a microtubule-destabilizing phosphoprotein, is highly expressed in ovarian cancer, but the pathophysiological significance of this protein in ovarian carcinoma cells remains poorly understood. This study reports the involvement of stathmin in the mTOR/HIF-1 α /VEGF pathway in ovarian clear cell adenocarcinoma (CCA) during hypoxia. HIF-1 α protein and VEGF mRNA levels were markedly elevated in RMG-1 cells, a CCA cell line, cultured under hypoxic conditions. Rapamycin, an inhibitor of mTOR complex 1, reduced the level of HIF-1 α and blocked phosphorylation of ribosomal protein S6 kinase 1 (S6K), a transcriptional regulator of mTOR, demonstrating that hypoxia activates mTOR/S6K/HIF-1 α signaling in CCA...
2013: ISRN Pharmacology
https://www.readbyqxmd.com/read/23726144/integrative-analysis-of-copy-number-alteration-and-gene-expression-profiling-in-ovarian-clear-cell-adenocarcinoma
#16
Chang Ohk Sung, Chel Hun Choi, Young-Hyeh Ko, Hyunjeong Ju, Yoon-La Choi, Nyunsu Kim, So Young Kang, Sang Yun Ha, Kyusam Choi, Duk-Soo Bae, Jeong-Won Lee, Tae-Joong Kim, Sang Yong Song, Byoung-Gie Kim
Ovarian clear cell adenocarcinoma (Ov-CCA) is a distinctive subtype of ovarian epithelial carcinoma. In this study, we performed array comparative genomic hybridization (aCGH) and paired gene expression microarray of 19 fresh-frozen samples and conducted integrative analysis. For the copy number alterations, significantly amplified regions (false discovery rate [FDR] q <0.05) were 1q21.3 and 8q24.3, and significantly deleted regions were 3p21.31, 4q12, 5q13.2, 5q23.2, 5q31.1, 7p22.1, 7q11.23, 8p12, 9p22...
May 2013: Cancer Genetics
https://www.readbyqxmd.com/read/23615631/potential-role-of-mtorc2-as-a-therapeutic-target-in-clear-cell-carcinoma-of-the-ovary
#17
Takeshi Hisamatsu, Seiji Mabuchi, Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Ryoko Takahashi, Kenjiro Sawada, Kimihiko Ito, Hirohisa Kurachi, Russell J Schilder, Joseph R Testa, Tadashi Kimura
The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR)...
July 2013: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/23558892/new-perspectives-on-molecular-targeted-therapy-in-ovarian-clear-cell-carcinoma
#18
REVIEW
D S P Tan, R E Miller, S B Kaye
Ovarian clear cell carcinomas (OCCCs) account for about 5-13% of all epithelial ovarian carcinomas in Western populations. It is characterised by resistance to conventional platinum-based chemotherapy, and new therapeutic strategies are urgently required. This article will focus on how recent discoveries have enhanced our understanding of the molecular pathogenesis of OCCCs, leading to new therapeutic opportunities. These include mutations in ARID1A, which provides a link to endometriosis, upregulation of the phosphatidylinositol 3-kinase/AKT pathway, particularly through mutations of PIK3CA and inactivation of PTEN, and increased activity of pathways involved in angiogenesis...
April 30, 2013: British Journal of Cancer
https://www.readbyqxmd.com/read/23464458/prevalence-and-clinical-significance-of-mammalian-target-of-rapamycin-phosphorylation-p-mtor-and-vascular-endothelial-growth-factor-vegf-in-clear-cell-carcinoma-of-the-ovary
#19
Nipon Khemapech, Sunaree Pitchaiprasert, Surang Triratanachat
BACKGROUND: To determine the prevalence of mammalian target of rapamycin phosphorylation (p-mTOR) and vascular endothelial growth factor (VEGF) and any correlation with clinical characteristics and prognosis in ovarian clear cell carcinoma patients. MATERIALS AND METHOD: Seventy four paraffin-embedded specimens of such carcinomas frompatients who underwent surgery, received adjuvant chemotherapy and were followed up at King Chulalongkorn Memorial Hospital during January 2002 to December 2008 were stained with rabbit monoclonal IgG p-mTOR and rabbit polyclonal IgG VEGF using immunohistochemical methods...
2012: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/23163984/gpr30-regulates-the-egfr-akt-cascade-and-predicts-lower-survival-in-patients-with-ovarian-cancer
#20
Satoe Fujiwara, Yoshito Terai, Hiroshi Kawaguchi, Masaaki Takai, Saha Yoo, Yoshimichi Tanaka, Tomohito Tanaka, Satoshi Tsunetoh, Hiroshi Sasaki, Masanori Kanemura, Akiko Tanabe, Yoshiki Yamashita, Masahide Ohmichi
UNLABELLED: HASH(0x4bca9c0) OBJECTIVES: G protein-coupled receptor 30 (GPR30) is a 7-transmembrane estrogen receptor that functions alongside traditional estrogen receptors to regulate the cellular responses to estrogen. Recent studies suggest that GPR30 expression is associated with a poor prognosis, and that this is due to the GPR30-mediated transactivation of the EGFR in breast cancer. However, the biological contribution of GPR30 in ovarian cancer remains unclear...
2012: Journal of Ovarian Research
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