Sunitinib inhibits papillary thyroid carcinoma with RET/PTC rearrangement but not BRAF mutation

Jeong, Woo Jin; Mo, Ji‐Hun; Park, Min Woo; Choi, Ik Joon; An, Soo Youn; Jeon, Eun Hee; Ahn, Sang‐Hyeon

doi:10.4161/cbt.12.5.16303

Cited by 34 publications

(21 citation statements)

References 24 publications

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“…Others, however, do report some success with TPC-1 cells in an orthotopic model. Ahn and colleagues reported a 10% take rate of TPC-1 in an orthotopic model [1], and this group has followed this report with other studies utilizing TPC-1 and subclones of TPC-1 (BHP2-7, TPC-1m) with success in the orthotopic model [16, 15, 18, 19, 21]…”

Section: Discussionmentioning

confidence: 80%

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

et al. 2015

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Thyroid cancer incidence has been increasing over time, and it is estimated that ~1950 advanced thyroid cancer patients will die of their disease in 2015. To combat this disease, an enhanced understanding of thyroid cancer development and progression as well as the development of efficacious, targeted therapies are needed. In vitro and in vivo studies utilizing thyroid cancer cell lines and animal models are critically important to these research efforts. In this report, we detail our studies with a panel of authenticated human anaplastic and papillary thyroid cancer (ATC and PTC) cell lines engineered to express firefly luciferase in two in vivo murine cancer models- an orthotopic thyroid cancer model as well as an intracardiac injection metastasis model. In these models, primary tumor growth in the orthotopic model and the establishment and growth of metastases in the intracardiac injection model are followed in vivo using an IVIS imaging system. In the orthotopic model, the ATC cell lines 8505C and T238 and the PTC cell lines K1/GLAG-66 and BCPAP had take rates >90% with final tumor volumes ranging 84–214 mm3 over 4–5 weeks. In the intracardiac model, metastasis establishment was successful in the ATC cell lines HTh74, HTh7, 8505C, THJ-16T, and Cal62 with take rates ≥70%. Only one of the PTC cell lines tested (BCPAP) was successful in the intracardiac model with a take rate of 30%. These data will be beneficial to inform the choice of cell line and model system for the design of future thyroid cancer studies.

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Section: Discussionmentioning

confidence: 80%

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

et al. 2015

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“…Addition of axitinib resulted in numerically higher ORR, but did not improve PFS or OS compared with chemotherapy alone. However, it remains to be seen if certain subsets of patients may derive some benefits from the use of TKIs, including axitinib, as reported for other TKIs in patients with genomic abnormalities such as EGFR mutations [25-27], crizotinib in ALK-positive NSCLC [28], or in preclinical studies involving RET proto-oncogene rearrangements [29,30]. …”

Section: Discussionmentioning

confidence: 99%

Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer

et al. 2014

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BackgroundThe efficacy and safety of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non–small-cell lung cancer (NSCLC).MethodsOverall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS).ResultsMedian PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%).ConclusionAxitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC.Trial registrationClinicalTrials.gov: NCT00768755 (October 7, 2008).

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“…Sunitinib was part of a large indolinone compound collection at SUGEN Inc (later acquired by Pfizer), which was initially developed to block angiogenic kinases belonging to the split tyrosine kinase domain family (VEGFR, FGFR, PDGFR) (Sun et al 1998(Sun et al , 1999(Sun et al , 2000. Later, a few closely related compounds from this series were shown to inhibit RET at submicromolar concentrations in vitro and in vivo (Kim et al 2006, Mologni et al 2006, Chow & Eckhardt 2007, Jeong et al 2011. Among these, SU11248 showed the best pharmacologic properties and progressed into clinical trials.…”

Section: Investigational Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

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Sunitinib inhibits papillary thyroid carcinoma with RET/PTC rearrangement but not BRAF mutation

Cited by 34 publications

References 24 publications

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer

Novel targeted therapeutics for MEN2

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