Nanoformulations of anticancer FGFR inhibitors with improved therapeutic index.
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ABSTRACT:
SUBMITTER: Kallus S
PROVIDER: S-EPMC7611408 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns. IMPLICATIONS FOR PRACTICE: Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Most recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns.
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Project description:The fibroblast growth factor receptor tyrosine kinases (FGFR1, 2, 3, and 4) represent promising therapeutic targets in a number of cancers. We have developed the first potent and selective irreversible inhibitor of FGFR1, 2, 3, and 4, which we named FIIN-1 that forms a covalent bond with cysteine 486 located in the P loop of the FGFR1 ATP binding site. We demonstrated that the inhibitor potently inhibits Tel-FGFR1-transformed Ba/F3 cells (EC(50) = 14 nM) as well as numerous FGFR-dependent cancer cell lines. A biotin-derivatized version of the inhibitor, FIIN-1-biotin, was shown to covalently label FGFR1 at Cys486. FIIN-1 is a useful probe of FGFR-dependent cellular phenomena and may provide a starting point of the development of therapeutically relevant irreversible inhibitors of wild-type and drug-resistant forms of FGFR kinases.
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Project description:ObjectiveIntrahepatic cholangiocarcinoma (iCCA), the second most common type of primary liver tumor, has an increasing incidence in the past few decades. iCCA is highly malignant, with a 5-year survival rate of approximately 5-10%. Surgical resection is usually the prescribed treatment for patients with early stage iCCA; however, patients are usually in an advanced stage iCCA upon diagnosis. Currently, targeted therapy combined with chemotherapy and other comprehensive treatment measures have been mainly adopted as palliative treatment measures. As a common candidate of targeted therapy, FGFR inhibitors have demonstrated their unique advantages in clinical trials. At present, the prospect of FGFR targeted therapy is encouraging. The landscape of FGFR inhibitors in iCCA is needed to be showed urgently.MethodsWe searched relative reports of clinical trials on FGFR inhibitors in PubMed as well as Web of Science. We also concluded other available clinical trials of FGFR inhibitors (Data were collected from clinicaltrials.gov).ResultsSeveral relatively effective targeted drugs are being used in clinical trials. Some preliminary results indicate the outlook of targeted therapy such as BGJ398, TAS120, and HSP90 inhibitors.ConclusionsIn summary, FGFR targeted therapy has broad prospects for the treatment of iCCA.
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Project description:Patients with intrahepatic cholangiocarcinoma (iCCA) face a highly dismal prognosis, due to late stage diagnosis, the relative chemoresistance of the disease, and an overall limited portfolio of established therapeutic concepts. In recent years, a number of next generation sequencing studies have provided detailed information on the molecular landscape of biliary malignancies, and have laid the groundwork for the evaluation of novel, targeted therapeutic opportunities. Although nearly 40% of patients harbor genetic alterations for which targeted options exist, rapid translation into clinical trials is hampered by the overall low patient numbers. One of the most frequent genetic events in patients with iCCAs are fusions that involve the fibroblast growth factor receptor 2 (FGFR2). Impressive results from pivotal phase II studies in pre-treated patients have confirmed that FGFR-inhibitors are a promising therapeutic option for this genetic subgroup, and the rapid pace with which these inhibitors are being clinically developed is clearly justified by the imminent benefit for the patients. However, the success of these agents should not blind us to key challenges that need to be addressed to optimize FGFR-directed therapies in the future. A better understanding of mechanisms that convey primary and secondary resistance will be crucial to improve up-front patient stratification, to prolong the duration of response, and to implement reasonable co-treatment approaches. In this review, we provide background information on the pathobiology of oncogenic FGFR fusions and selected genetic testing strategies, summarize the latest clinical data, and discuss future directions of FGFR-directed therapies in patients with iCCA.
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