LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Zhang, Qing; Hou, Xiaonan; Evans, Bradley J.; VanBlaricom, Jamison; Weroha, S. John; Cliby, William A.

doi:10.3390/cancers10080260

Cited by 46 publications

(52 citation statements)

References 54 publications

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“…3) implicating activation of TGF-β signaling in OC metastasis. Supporting the proposed importance of TGF-β in metastases, we have demonstrated that inhibition of TGF-β signaling delays tumor growth and suppresses ascites development in OC xenograft models [18]. Collectively these observations demonstrate the potential of TGF-β signaling targeting as a therapeutic strategy in HGSOC.…”

Section: Discussionsupporting

confidence: 58%

“…The stimulatory contribution of stroma in tumor progression, coupled with the fact that stroma is more genetically stable compared with cancer cells, has led to stroma increasingly being recognized as a therapeutic target [16,17]. In support of this, we recently published that inhibition of TGF-β signaling, which suppresses the cancer-stroma interplay, can delay tumor growth and ascites development in MES subtype HGSOC patient-derived xenografts [18]. In comparison with the advances in our understanding of cancer cell biology, our knowledge of the nature and roles of stromal contribution has lagged.…”

Section: Discussionmentioning

confidence: 96%

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Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer

Zhang

Wang

Cliby

2019

Gynecologic Oncology

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Objective.-Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from 'tumor', consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC. Methods.-Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites. Results.-COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma. Conclusions.-The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 96%

Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer

Zhang

Wang

Cliby

2019

Gynecologic Oncology

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“…In addition to this study showing benefit of TGFBR2 blockade, another recent study using the TGFBR1 small molecule inhibitor LY2157299/ Galunisertib showed promise in several EOC xenograft models. 34 They showed that LY215729 treatments prior to EOC cell injection, and throughout tumor outgrowth, led to reduced ascites development and tumor growth. 34 Given these recent findings, it will be important to test whether pretreatment of mice with our inhibitory TGFBR2 antibodies leads to improved efficacy as a monotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…34 They showed that LY215729 treatments prior to EOC cell injection, and throughout tumor outgrowth, led to reduced ascites development and tumor growth. 34 Given these recent findings, it will be important to test whether pretreatment of mice with our inhibitory TGFBR2 antibodies leads to improved efficacy as a monotherapy. It will also be important to extend further testing of LY215729 to immune competent models of EOC in combination with chemotherapy and immunotherapy regimes.…”

Section: Discussionmentioning

confidence: 99%

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

et al. 2018

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Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models, OncoImmunology, 8:2, e1539613, ABSTRACT Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. EOC is often diagnosed at late stages, with peritoneal metastases and ascites production. Current surgery and platinum-based chemotherapy regimes fail to prevent recurrence in most patients. High levels of Transforming growth factor-β (TGF-β) within ascites has been linked to poor prognosis. TGF-β signaling promotes epithelial-mesenchymal transition (EMT) in EOC tumor cells, and immune suppression within the tumor microenvironment, with both contributing to chemotherapy resistance and metastasis. The goal of this study was to develop specific synthetic inhibitory antibodies to the Type II TGF-β receptor (TGFBR2), and test these antibodies in EOC cell and tumor models. Following screening of a phage-displayed synthetic antigen-binding fragment (Fab) library with the extracellular domain of TGFBR2, we identified a lead inhibitory Fab that suppressed TGF-β signaling in mouse and human EOC cell lines. Affinity maturation of the lead inhibitory Fab resulted in several derivative Fabs with increased affinity for TGFBR2 and efficacy as suppressors of TGF-β signaling, EMT and EOC cell invasion. In EOC xenograft and syngeneic tumor models, blockade of TGFBR2 with our lead antibodies led to improved chemotherapy response. This correlated with reversal of EMT and immune exclusion in these tumor models with TGFBR2 blockade. Together, these results describe new inhibitors of the TGF-β pathway that improve antitumor immunity, and response to chemotherapy in preclinical EOC models. ARTICLE HISTORY

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“…Interfering collagen biosynthesis enzymes Collagen genes MiR-129-5p, MiR-29b, MiR-384 [275][276][277] Prolyl 4-hydroxylase Budesonide, catechol, N-oxalylglycine, coumalic acid, ethyl dihydroxybenzoic acid [278][279][280] Heat shock protein 90 1G6-D7, dipalmitoyl-radicicol, 17-DMAG, ganetespib [281][282][283][284] Heat shock protein 47 MiR-29, 1,3-dimethylol-5-FU, AK778, pirfenidone, terutroban [285,286] Matrix metalloproteinases Gallium complex GS2, isoflavonoids, bisphosphonates [287,288] Lysyl oxidases Beta-aminopropionitrile [289] Disturbing cancer cell signaling pathways Snail transcription factors Toosendanin, ponicidin, ferulic acid [290] Hypoxia-inducible factor Tamoxifen, 28-O-propynoylbetulin [291,292] STAT3 signaling pathway VS-4718, stattic, ruxolitinib, S3I-201 [293,294] TGF-β signaling pathway LY2157299 monohydrate, trabedersen, fresolimumab, galunisertib [295,296] NF-κB signaling pathway Honokiol, aspirin, ormeloxifene [297][298][299] AKT signaling pathway Quetiapine, pirfenidone [300] Notch signaling pathway Rovalpituzumab tesirine, taladegib, crenigacestat, MiR-148a [301] Hedgehog signaling pathway Itraconazole, sonidegib, vismodegib [302] RAS signaling pathway Perindopril, losartan [100,303] Tyrosine kinase receptor Bevacizumab, imatinib, ponatinib, dasatinib [304,305] Discoidin domain receptor WRG-28, 7rh, AZD0156 [306][307][308] G protein family receptor AT13148, KD025, Azaindole 1, chelerythrine…”

Section: Effects Of Inhibitors Targeted Sites Of Inhibitors Typical Imentioning

confidence: 99%

The role of collagen in cancer: from bench to bedside

et al. 2019

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Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.

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LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Cited by 46 publications

References 54 publications

Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer

Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

The role of collagen in cancer: from bench to bedside

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