Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Feb. 15, 2021

Abstract Cancer stem cells (CSCs) show a self-renewal capacity and differentiation potential that contribute to tumor progression therapy resistance. However, the underlying processes are still unclear. Elucidation of key hallmarks resistance mechanisms CSCs may help improve patient outcomes reduce relapse by altering therapeutic regimens. Here, we reviewed identification CSCs, intrinsic extrinsic in signaling pathways mediate treatment failure, CSC-targeting agents various tumors from clinical perspective. Targeting described here might further drug discovery therapy.

Language: Английский

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A Phase I Dose–Escalation Study of Regorafenib (BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors

Clinical Cancer Research, Journal Year: 2012, Volume and Issue: 18(9), P. 2658 - 2667

Published: March 16, 2012

Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, efficacy profiles regorafenib in patients with advanced solid tumors.Patients aged 18 years or older tumors refractory to standard treatment were recruited. was administered orally for 21 days on/seven off repeating cycles, until discontinuation due toxicity tumor progression. Adverse events (AE) using National Cancer Institute Common Terminology Criteria Events v3.0. Pharmacokinetic measured after single dose on day 21. Pharmacodynamic evaluations included perfusion assessment dynamic contrast-enhanced MRI, plasma cytokines, response RECIST (v1.0).Fifty-three enrolled into eight cohorts at levels from 10 220 mg daily. The recommended future studies determined be 160 daily, schedule 28-day cycles. most common drug-related grade 3 4 AEs dermatologic (hand-foot skin reaction, rash), hypertension, diarrhea. analysis revealed similar exposure steady state parent compound two pharmacologically active metabolites. Tumor cytokine showed biologic activity regorafenib. Three 47 evaluable achieved partial (renal cell carcinoma, colorectal osteosarcoma).Regorafenib an acceptable safety profile preliminary evidence antitumor tumors.

Language: Английский

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Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial

Journal of Hepatology, Journal Year: 2018, Volume and Issue: 69(2), P. 353 - 358

Published: April 26, 2018

Language: Английский

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Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry

Journal of Clinical Oncology, Journal Year: 2017, Volume and Issue: 35(13), P. 1403 - 1410

Published: April 5, 2017

Purpose In addition to prospective trials for non–small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response targeted therapies. Here, we present the results of an international registry patients with RET-rearranged NSCLCs, providing largest data set, our knowledge, outcomes RET-directed therapy thus far. Methods A global, multicenter network thoracic oncologists identified pathologically confirmed NSCLC harbored a RET rearrangement. Molecular profiling was performed locally reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data—clinical, pathologic, and molecular features—were collected centrally analyzed independent statistician. Best tyrosine kinase inhibition administered outside clinical trial determined RECIST v1.1. Results By April 2016, 165 from 29 centers across Europe, Asia, United States were accrued. Median age 61 years (range, 89 years). The majority never smokers (63%) adenocarcinomas (98%) advanced disease (91%). most frequent rearrangement KIF5B-RET (72%). Of those patients, 53 received one more inhibitors sequence: cabozantinib (21 patients), vandetanib (11 sunitinib (10 sorafenib (two alectinib lenvatinib nintedanib ponatinib regorafenib (one patient). rate any complete partial cabozantinib, vandetanib, 37%, 18%, 22%, respectively. Further responses observed lenvantinib nintedanib. progression-free survival 2.3 months (95% CI, 1.6 5.0 months), median overall 6.8 3.9 14.3 months). Conclusion Available multikinase had limited activity this retrospective study. investigation biology identification new therapeutics will be required improve these patients.

Language: Английский

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Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial

The Lancet Oncology, Journal Year: 2018, Volume and Issue: 20(1), P. 110 - 119

Published: Dec. 3, 2018

Language: Английский

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