Oncogenic conversion of the RET (REarranged during Transfection) transmembrane receptor tyrosine kinase (RTK) is associated with several human malignancies ( 1 ). The treatment landscape for patients with thyroid cancers has expanded rapidly in the era of precision medicine. More than 10 rearranged forms of RET, referred to as RET/PTC 1–9, ELKS/RET and RFP/RET, have been … Germline point mutations were identified in multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. Pralsetinib is an investigational, highly potent, selective inhibitor of oncogenic RET alterations. It was just approved in the last year. Retevmo demonstrated highly selective and potent RET inhibition 1,14,15 Retevmo inhibited wild-type RET and multiple mutated RET isoforms, and was 250 times more selective for RET than 98% of ~300 kinases tested in preclinical studies 1,16. The RET fusion group (N = 49) included 38 patients with NSCLC, 9 with papillary thyroid cancer, and 2 with pancreatic cancer. The RET proto‐oncogene is responsible for the development of several human inherited and non‐inherited diseases. Activating point mutations in RET can give rise to the hereditary cancer syndrome, multiple endocrine neoplasia 2 (MEN2; PMID: 11061555).Activating somatic point mutations in RET are associated with sporadic medullary thyroid cancer … Clinical trials are research studies that involve people. In RET-mutant medullary thyroid cancer, 76% and 61% of pretreated patients and treatment-naïve patients [respectively] had a response that endured for more than 6 months. Multikinase inhibitors (MKIs) that target the RET pathway have been tested for their antitumor activity in patients with thyroid cancer. With the recent approval of the selective RET kinase inhibitor selpercatinib, as well as the anticipated approval of a second RET inhibitor, pralsetinib, a new standard of care has arrived for patients with RET-altered thyroid cancers. The RET gene (ret proto-oncogene), encodes the proto-oncogene tyrosine-protein kinase receptor Ret, a receptor tyrosine kinase (RTK). The pharma giant picked up the oral RET inhibitor after acquiring Loxo Oncology for $8bn in January 2019. Updated data from the ARROW study with BLU-667 in patients with advanced RET-fusion-positive non-small cell lung cancer (NSCLC) and with RET-altered medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC), demonstrate potent, durable and broad antitumour activity with treatment being well tolerated.Enrolment of the expansion is ongoing … Unfortunately, RET gene mutations and fusions can cause health conditions and cancers. The RET inhibitor selpercatinib (Retevmo) exhibited clinical activity in almost half of patients with non-lung/non-thyroid cancers associated with RET gene fusions, according to a subgroup analysis of a randomized trial.. In 19 patients with previously treated RET fusion–positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, … Basically, it was approved [to treat] both [patients with] differentiated thyroid cancer [who] have RET fusions or RET point mutations, as well as patients who have medullary thyroid cancer with RET mutations. LOXO-292, medullary, neoadjuvant, selective RET inhibitor, selpercatinib 1 | INTRODUCTION Medullary thyroid cancer (MTC) is a neuroendocrine malignancy that arises from the parafollicular C-cells of Yelda Jozaghi and Mark Zafereo are co-first authors. The RET receptor tyrosine kinase proto-oncogene is activated by somatic or germline mutations in a majority of medullary thyroid cancers (MTC). Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Retevmo also inhibited certain isoforms of VEGFR and FGFR at higher concentrations that were still clinically achievable. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. Background. This study was conducted through a single patient Investigational Drug All trials on the list are supported by NCI.. NCI’s basic information about clinical trials explains the types and phases of trials and how they are carried out. Objective responses occurred in 15 of 32 (47%) patients with RET fusion-positive tumors representing nine different types of cancer. On December 1, 2020, the FDA accelerated the approval of a new indication for pralsetinib (Gavreto; Blueprint Medicines), a RET kinase inhibitor, for the treatment of patients aged ≥12 years with advanced or metastatic medullary thyroid cancer and RET mutation who require systemic therapy or for patients with thyroid cancer and RET fusion who require … The growth of TT thyroid carcinoma cells harboring an RET a new ret inhibitor for nsclc and thyroid cancer Point mutations or gene rearrangements in the receptor tyrosine kinase proto-oncogene RET have been seen in several tumors, including medullary thyroid carcinoma (MTC) and non–small cell lung cancer (NSCLC). At 20 and 60 mg/kg daily oral doses, alectinib strongly inhibited growth of xenografts of the CCDC6-RET positive LC-2/ad lung adenocarcinoma cell line, while it had weak effects in a medullary thyroid carcinoma RET/C634W positive TT cell xenograft model, in which instead compounds like vandetanib, cabozantinib and sorafenib are active. Multikinase inhibitors Multikinase inhibitors for thyroid cancer. The clinical trials on this list are studying RET Inhibitor LOXO-292. Oncology/Hematology > Lung Cancer FDA OKs RET Inhibitor for Lung, Thyroid Cancers — High response rates with selpercatinib in treated, untreated disease. Clinical activity of BLU-667, a highly selective RET inhibitor, in advanced RET-altered thyroid cancers: updated results from the phase 1 ARROW study Mimi I. Hu, Matthew Taylor, Lori Wirth, Viola Zhu, Robert Doebele, Dae Ho Lee, Ignacio Matos, Christina Baik, Marcia Brose, Giuseppe Curigliano, Gilberto de Lima Lopes, In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. It is a selective RET kinase inhibitor. However, treatment of MTC has been challenging due to the lack of effective and tolerable RET-specific therapy, thus testing tumors for the presence of somatic RET mutation has not been warranted. 19 Between them, cabozantinib and vandetanib have been … Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. In the phase I component of the LIBRETTO-001 trial investigating LOXO-292, an ATP-competitive highly selective small molecule RET inhibitor , LOXO-292 showed robust antitumor activity in patients with RET fusion-positive PTC and NSCLC, and RET mutation-positive medullary thyroid cancer. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET.LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET … In the registration-enabling Phase 1/2 ARROW study (NCT03037385), pralsetinib demonstrated an overall … The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. Cancer Res. Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma. 67 , 6956–6964 (2007). Background: RET gene fusions are targetable oncogenic drivers in multiple tumor types, including up to 20% of papillary thyroid cancers (PTC). Thyroid cancer is relatively rare, but it is thought in many cases to be driven by the Ret mutation. Clinical trials look at new ways to prevent, detect, or treat disease. Although RET activating fusions and mutations are only observed in a small number of cancer patients – around 1-2% in NSCLC and 10-20% in papillary thyroid cancer – they are thought to be key disease drivers. Oncogenic alteration of RET results in constitutive activation of RET activity. Phase 1 / 2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors - … Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. Some drugs have shown clinical efficacy, such as vandetanib, cabozantinib, lenvatinib, alectinib, and sorafenib. RET-targeted therapy with the highly selective RET inhibitor selpercatinib (formerly known as LOXO-292; Retevmo) has been an FDA approved treatment strategy for patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, and those with advanced or metastatic RET fusion-positive thyroid cancer who … In fact, as many as 60% of medullary thyroid cancer cases might have this as their basis, hence the relevance to both groups; Blueprint and Loxo’s respective projects BLU-667 and LOXO-292 are both Ret signalling inhibitors. Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86 John P Alao1*, Sona Michlikova1, Peter Dinér1,2, Morten Grøtli1 and Per Sunnerhagen1 Abstract Background: The RET tyrosine kinase receptor has emerged as a target in thyroid and endocrine resistant breast cancer. Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. 109. Retevmo is being hailed as an innovation in gene-specific therapies for those cancers – an important advance for patients who didn’t previously have a targeted treatment option for RET cancers. It’s a selective RET inhibitor, so this is not for all-comers.
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