Cellular Effects and Antitumor Activity of RET Inhibitor RPI-1 on MEN2A-Associated Medullary Thyroid Carcinoma

Cuccuru, Giuditta; Lanzi, Cinzia; Cassinelli, Giuliana; Pratesi, Graziella; Tortoreto, Monica; Petrangolini, Giovanna; Seregni, Ettore; Martinetti, Antonia; Laccabue, Diletta; Zanchi, Chiara; Zunino, Franco

doi:10.1093/jnci/djh184

Cited by 105 publications

(85 citation statements)

References 29 publications

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“…2]. Activating RET mutations lead to enhanced downstream signaling with multiple effectors, including those in the MAPK and PI3K pathways, resulting in increased cell proliferation and anchorage-independent cell growth (33)(34)(35). Clinically, RET mutations are associated with poor clinical outcomes, including larger tumor size, metastasis, and poorer survival, when compared with RET wild-type cases among patients with medullary thyroid carcinoma (7).…”

Section: Discussionmentioning

confidence: 99%

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

Kato

Subbiah

Marchlik³

et al. 2017

Clinical Cancer Research

223

157

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Purpose: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RET.Experimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.Results

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Section: Discussionmentioning

confidence: 99%

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

Kato

Subbiah

Marchlik³

et al. 2017

Clinical Cancer Research

223

157

View full text Add to dashboard Cite

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“…BAY 43-9006 is a novel investigational cancer therapeutic that potently inhibits the serine/threonine kinases RAF-1 and wildtype and V600E mutant BRAF, as well as several receptor tyrosine kinases (Lyons et al, 2001;Lowinger et al, 2002;Karasarides et al, 2004;Wilhelm et al, 2004). Similarly, studies of several small molecule RET inhibitors such as RPI-1 (Cuccuru et al, 2004), PP2 (Carlomagno et al, 2003) and ZD6474 (Carlomagno et al, 2002) suggest that RET oncoproteins are valid therapeutic targets. One of the most important aspects of the work presented here is the implication that RAF and RET inhibitors will be effective in PCs with BRAF and RET/PTC mutations, respectively.…”

Section: Discussionmentioning

confidence: 99%

Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

et al. 2005

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Thyroid cancer poses a significant clinical challenge, and our understanding of its pathogenesis is incomplete. To gain insight into the pathogenesis of papillary thyroid carcinoma, transcriptional profiles of four normal thyroids and 51 papillary carcinomas (PCs) were generated using DNA microarrays. The tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS. Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status. By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups. Using small numbers of genes, a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations. One tumor without a detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis. Among the mutation-specific expression signatures were genes whose differential expression was a direct consequence of the mutation, as well as genes involved in a variety of biological processes including immune response and signal transduction. Expression of one mutationspecific differentially expressed gene, TPO, was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors. The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors, a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations.

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“…Subchronic administration of cabozantinib was well tolerated, as determined by stable body weights collected throughout the dosing period (data not shown). Given that TT xenograft tumors are known to secrete high amounts of human calcitonin, which correlates with tumor size (45), serum concentrations of circulating calcitonin were determined at the end of the dosing period. Serum from vehicle-treated control animals exhibited high levels of circulating calcitonin that was markedly reduced (75%; p < 0.005) at both the 30 and 60 mg/kg doses when compared to vehicle control animals (Fig.…”

Section: Cabozantinib Inhibits Tt Tumor Growthmentioning

confidence: 99%

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

Bentzien

Zuzow

Heald

et al. 2013

Thyroid

113

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Background: A limited number of approved therapeutic options are available to metastatic medullary thyroid cancer (MTC) patients, and the response to conventional chemotherapy and/or radiotherapy strategies is inadequate. Sporadic and inherited mutations in the tyrosine kinase RET result in oncogenic activation that is associated with the pathogenesis of MTC. Cabozantinib is a potent inhibitor of MET, RET, and vascular endothelial factor receptor 2 (VEGFR2), as well as other tyrosine kinases that have been implicated in tumor development and progression. The object of this study was to determine the in vitro biochemical and cellular inhibitory profile of cabozantinib against RET, and in vivo antitumor efficacy using a xenograft model of MTC. Methods: Cabozantinib was evaluated in biochemical and cell-based assays that determined the potency of the compound against wild type and activating mutant forms of RET. Additionally, the pharmacodynamic modulation of RET and MET and in vivo antitumor activity of cabozantinib was examined in a MTC tumor model following subchronic oral administration. Results: In biochemical assays, cabozantinib inhibited multiple forms of oncogenic RET kinase activity, including M918T and Y791F mutants. Additionally, it inhibited proliferation of TT tumor cells that harbor a C634W activating mutation of RET that is most often associated with MEN2A and familial MTC. In these same cells grown as xenograft tumors in nude mice, oral administration of cabozantinib resulted in dose-dependent tumor growth inhibition that correlated with a reduction in circulating plasma calcitonin levels. Moreover, immunohistochemical analyses of tumors revealed that cabozantinib reduced levels of phosphorylated MET and RET, and decreased tumor cellularity, proliferation, and vascularization. Conclusions: Cabozantinib is a potent inhibitor of RET and prevalent mutationally activated forms of RET known to be associated with MTC, and effectively inhibits the growth of a MTC tumor cell model in vitro and in vivo.

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Cellular Effects and Antitumor Activity of RET Inhibitor RPI-1 on MEN2A-Associated Medullary Thyroid Carcinoma

Abstract: Ret oncoproteins represent exploitable targets for therapeutic intervention in MEN2A-associated medullary thyroid carcinoma. The antitumor efficacy and oral bioavailability of RPI-1 support its therapeutic potential.

Cited by 105 publications

References 29 publications

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

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