RET mutation and increased angiogenesis in medullary thyroid carcinomas

Verrienti, Antonella; Tallini, Giovanni; Colato, Chiara; Boichard, Amélie; Checquolo, Saula; Pecce, Valeria; Sponziello, Marialuisa; Rosignolo, Francesca; Biase, Dario de; Rhoden, Kerry J.; Casadei, Gian Piero; Russo, Diego; Visani, Michela; Acquaviva, Giorgia; Ferdeghini, M; Durante, Cosimo

doi:10.1530/erc-16-0132

Cited by 28 publications

(22 citation statements)

References 39 publications

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“…Following treatment, the AD80 treated tumors appeared smaller and displayed less vascularization (Figure 3D and Supplemental Figure 4C), suggesting that AD80 treatment restricted tumor progression possibly via reduction of angiogenesis which has been reported in other neuroendocrine tumor types treated with RET inhibitors (18). To interrogate the molecular characteristics of the different treatments, the tumors were fixed and sectioned for staining.…”

Section: Resultssupporting

confidence: 59%

Targeting RET Kinase in Neuroendocrine Prostate Cancer

VanDeusen

Morel

Sheahan

et al. 2019

Preprint

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24Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation 25 anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate 26 cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express 27 neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests 28 kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed 29 global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified 30 multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell 31 lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET 32 pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor 33 growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC 34 tumors with high RET expression and may be a novel treatment option. 35 36 Statement of Significance: 37 There are limited treatment options for patients with metastatic aggressive variant prostate cancer and 38 none are curative. Here we identified aberrantly activated RET kinase signaling in multiple models of 39 NEPC. Inhibiting RET restricted tumor growth, providing a novel approach for treating NEPC. 40 41 42

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Section: Resultssupporting

confidence: 59%

Targeting RET Kinase in Neuroendocrine Prostate Cancer

VanDeusen

Morel

Sheahan

et al. 2019

Preprint

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“…Angiogenesis is critical for tumor growth, and the MKI anti-angiogenic effect is likely to play a role in response to therapy. Of interest, angiogenesis appears to be more intense in RET positive tumors, a feature that might increase their susceptibility to antiangiogenic treatment (Verrienti et al 2016).…”

Section: Mutational Profile and Response To Multikinase Inhibitor Thementioning

confidence: 99%

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

Ceolin

Duval

Benini

et al. 2019

Endocrine-Related Cancer

109

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Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

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“…RET is a member of the cadherin superfamily, which is encoded for receptor tyrosine kinases, a cell-surface molecule that transduces signal for cell growth and differentiation [34]. RET mutation was previously reported to increase angiogenesis in thyroid carcinoma [35, 36]. APS placenta was reported to have poor blood circulation due to infarction [37].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA and Gene Expression Analysis on Placenta Tissue: An Approach to Understanding Obstetric Antiphospholipid Syndrome at the Molecular Level

Asnawi

Mohamad

Manzor

et al. 2019

Preprint

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Obstetric antiphospholipid syndrome is initiated by the action of antiphospholipid antibodies on placenta. The characteristics of APS in pregnancy include vascular thrombosis, inflammation and impairment of trophoblast implantation. MicroRNA (miRNA) expression has been suggested as one of the genetic factors that contribute to the development of this syndrome. miRNAs regulate gene expressions in a vast assortment of cellular biological mechanisms include the development of placental tissue. Hence, further investigation on the regulation of placental miRNA in APS is required. In this study, we aimed to profile miRNA expressions from placenta tissue of patients with APS. Differentially expressed miRNAs were determined for its targeted genes and pathways. Agilent microarray platform was used to measure placental microRNA expressions between normal placental tissue and those obtained from patients with APS. Differentially expressed miRNAs were detected using GeneSpring GX software 14.2 and sequences were mapped using TargetScan software to generate the predicted target genes. Pathway analysis for the genes was then performed on PANTHER and REACTOME software. Selected miRNAs and their associated genes of interest were validated using qPCR. Microarray findings revealed, 9 downregulated and 21 upregulated miRNAs expressed in placenta of patients with APS. Quantitative expressions of 3 selected miRNAs were in agreement with the microarray findings, however only miR-525-5p expression was statistically significant. Pathway analysis revealed that the targeted genes of differentially expressed miRNAs were involved in several hypothesized signalling pathways such as the vascular endothelial (VE) growth factor (VEGF) and inflammatory pathways. VE-cadherin, ras homolog member A (RHOA) and tyrosine kinase receptor (KIT) showed significant downregulation from the qPCR data while retinoblastoma gene (RET), dual specificity protein phosphatase 10 (DUSP10) and B-lymphocyte kinase (BLK) were significantly upregulated. These preliminary findings suggest the involvement of miRNAs and identified novel associated genes involvement in the mechanism of obstetric APS, particularly through the alteration of vascular-associated regulators and the inflammatory signalling cascade.

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RET mutation and increased angiogenesis in medullary thyroid carcinomas

Cited by 28 publications

References 39 publications

Targeting RET Kinase in Neuroendocrine Prostate Cancer

Targeting RET Kinase in Neuroendocrine Prostate Cancer

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

MicroRNA and Gene Expression Analysis on Placenta Tissue: An Approach to Understanding Obstetric Antiphospholipid Syndrome at the Molecular Level

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