Efficacy and Safety of Third-generation EGFR-TKI Combined With Anlotinib as Maintenance Therapy Following 4-6 Cycles of Chemotherapy and Immunotherapy in NSCLC With Small Cell Transformation After EGFR-TKI Resistance: a Single-arm Prospective Phase II Study

This study aimed to evaluate the efficacy and safety of third-generation EGFR-TKI plus anlotinib as maintenance after chemotherapy plus immunotherapy in advanced NSCLC with small cell transformation after EGFR-TKI resistance.

Start Date30 Nov 2024

Sponsor / Collaborator

Hunan Cancer Hospital

NCT06662877 / Not yet recruitingPhase 2/3IIT

Anlotinib Plus Nab-Paclitaxels and S-1 Versus FOLFOX for Patients with Advanced Biliary Tract Cancer As Second-Line Treatment: a Phase 2/3, Multi-centric Double-stage Randomized Controlled Trial

Biliary tract cancer (BTC) presents with a 5-year survival rate less than 5%. The goal of this clinical trial is to evaluate if Anlotinib plus Nab-Paclitaxels and S-1 as second-line regimen can improve the treatment efficacy in advanced biliary tract cancer (BTC) after progression upon first-line standard treatment, in comparison with standard second-line FOLFOX regimen.

Start Date25 Nov 2024

Sponsor / Collaborator

Sun Yat-Sen University

100 Clinical Results associated with FGFRs x PDGFR x VEGFR2

100 Translational Medicine associated with FGFRs x PDGFR x VEGFR2

0 Patents (Medical) associated with FGFRs x PDGFR x VEGFR2

Literatures (Medical) associated with FGFRs x PDGFR x VEGFR2

01 Jan 2023·European Journal of Medicinal Chemistry

Antiproliferative, antiangiogenic and apoptotic effect of new hybrids of quinazoline-4(3H)-ones and sulfachloropyridazine

Article

Author: Mahmoud, Walaa R ; Ragab, Fatma A ; Zahran, Sally S ; Ghorab, Mostafa M ; Soliman, Aiten M ; El-Gazzar, Marwa G

Three new sets of quinazolinones bearing sulfachloropyridazine 4a-f, 6a-i and 8a-i were designed and synthesized. All the synthesized compounds were screened for their in vitro cytotoxicity against a panel of 60 cancer cell lines. The most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were evaluated as VEGFR-2 inhibitors. Compounds 8f, 8c and 6f were the most active with IC₅₀ = 66 ± 0.002, 108 ± 0.004 and 146 ± 0.006 nM, respectively. Compound 8f showed also moderate inhibition against PDGFR (IC₅₀ = 180 ± 0.009 nM), EGFR (IC₅₀ = 98 ± 0.004 nM), FGFR-1 (IC₅₀ = 82 ± 0.004 nM) and ability to reduce migration of cells in wound healing assay. Compound 8f showed cell cycle arrest at S-phase and induced early and late apoptosis in Annexien V-FITC assay. In addition, compound 8f increased the level of caspase-3 and up regulate Bax expression and down regulate Bcl-2 in UO-31 cells. The cytotoxicity of compounds 6f, 6g and 8f against UO-31 and melanoma cells was slightly affected by combination with γ-radiation. Also, compound 8f showed low toxicity against human normal renal (RPTEC) cell line. Docking studies of the most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were performed to have more insights on their binging mode within VEGFR-2 active site.

01 Nov 2022·Translational Oncology

Anlotinib exerts potent antileukemic activities in Ph chromosome negative and positive B-cell acute lymphoblastic leukemia via perturbation of PI3K/AKT/mTOR pathway

Article

Author: Zhang, Li ; Xu, Bing ; Deng, Manman ; Zhou, Yong ; Yao, Jingwei ; Chen, Qinwei ; Wang, Caiyan ; Jiang, Yuelong ; Chen, Qiuling ; Lai, Qian

OBJECTIVESDespite advances in the development of novel targeted therapies, the need for B-ALL alternative treatments has not been met. Anlotinib could blunt the proangiogenic activity of VEGFR, PDGFR, and FGFR, and has shown strong antitumor activities across multiple tumors. However, anlotinib cytotoxicity against B-ALL has not ever been evaluated, thus prompting us to initiate this study.METHODSExpression2Kinases program was used to identify potential treatment targets. Cell viability and apoptosis were determined by CCK-8 and Annexin V/PI staining kit, respectively. qRT-PCR and Western blotting were utilized to investigate the molecular mechanisms. In vivo antileukemia activity of Anlotinib was evaluated in a Ph⁺ B-ALL patient-Derived Xenograft (PDX) model.RESULTSCompared with treatment-naive B-ALL cases, RR B-ALL patients had higher activities in the VEGF/VEGFR signaling and the PI3K/AKT/mTOR pathway. Exposure of Ph^- and Ph⁺ B-ALL cells to anlotinib resulted in significant cell viability reduction, apoptosis enhancement, and cell cycle arrest at G2/M phase. Importantly, anlotinib treatment led to remarkably decreased leukemia burdens and extended the survival period in a Ph⁺ B-ALL PDX model. Blockade of the role of the proangiogenic mediators, comprising VEGFR2, PDGFR-beta, and FGFR3, played a critical role in the cytotoxicity of anlotinib against Ph^- and Ph⁺ B-ALL. Moreover, anlotinib dampened the activity of PI3K/AKT/mTOR pathway that resides in the convergence of the three mentioned proangiogenic signals.CONCLUSIONThis work provides impressive preclinical evidence of anlotinib against Ph^- and Ph⁺ B-ALL and raises a rationale for future clinical evaluation of this drug in the management of Ph^- and Ph⁺ B-ALL.

01 Mar 2021·Cellular and Molecular Life SciencesQ2 · BIOLOGY

FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK

Q2 · BIOLOGY

Article

Author: Chiang, Po-Min ; Tsai, Kuen-Jer ; Tsai, Hung-Wen ; Hsueh, Ya-Wen ; Lee, Yi-Hsuan ; Chen, Peng-Chieh

It is critical to specify a signal that directly drives the transition that occurs between cell states. However, such inferences are often confounded by indirect intercellular communications or secondary transcriptomic changes due to primary transcription factors. Although FGF is known for its importance during mesoderm-to-endothelium differentiation, its specific role and signaling mechanisms are still unclear due to the confounding factors referenced above. Here, we attempted to minimize the secondary artifacts by manipulating FGF and its downstream mediators with a short incubation time before sampling and protein-synthesis blockage in a low-density angioblastic/endothelial differentiation system. In less than 8 h, FGF started the conversion of KDR^low/PDGFRA^low nascent mesoderm into KDR^high/PDGFRA^low angioblasts, and the priming by FGF was necessary to endow endothelial formation 72 h later. Further, the angioblastic conversion was mediated by the FGFR1/BRAF/MEK/ERK pathway in mesodermal cells. Finally, two transcription factors, ETV2 and LMO2, were the early direct functional responders downstream of the FGF pathway, and ETV2 alone was enough to complement the absence of FGF. FGF's selective role in mediating the first-step, angioblastic conversion from mesoderm-to-endothelium thus allows for refined control over acquiring and manipulating angioblasts. The noise-minimized differentiation/analysis platform presented here is well-suited for studies on the signaling switches of other mesodermal-lineage fates as well.

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