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Gastric Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Mark A. Baxter, Russell D. Petty
The development of a precision medicine approach to systemic therapy by identifying predictive biomarkers for chemotherapy, targeted therapies, and immunotherapies is a key aim of future research. The proof of principle that this is effective in gastric cancer has been demonstrated with HER2 and trastuzumab in the ToGA trial. The more recent negative trials of other receptor tyrosine kinase inhibitors and targeted agents, even in biomarker selected patients, have revealed a more complex molecular pathogenesis characterized by high levels of genomic heterogeneity.
Fetal Growth Factors*
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Philip A. Gruppuso, Thomas R. Curran, Roderick I. Bahner
More recently, mechanisms involved in tyrosine kinase-mediated signal transmission have been elucidated to a sufficient degree to confirm direct involvement of receptor tyrosine kinases.59 The best characterized pathway involves direct activation of phospholipase C-γ-1 (PLC-γ-1) (Figure 5). Phos-pholipase C catalyzes the conversion of phospharidylinositol-4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol trisphosphate (IP3). Nishibe and co-workers60 were able to show that the addition of EGF to cells is followed rapidly by phosphorylation of PLC-γ-1 on tyrosine. More recently, Gold-schmidt-Clermont et al.61 showed that tyrosine phosphorylation of PLC-γ-1 increases activity with a complex of PIP2 and profilin. Profilin is a cytoplasmic actin binding protein which binds PIP2 with high affinity. Thus, the current working hypothesis states that PLC-γ-1 activation by the EGF receptor leads to IP3 production and release of profilin, which can interact with the cyto-skeleton (Figure 5). This may account, at least in part, for rapid effects of EGF on cell shape and motility.
mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
The past decade has witnessed a revolution in our understanding of the biochemical mechanisms that contribute to the survival and proliferation of neoplastic cells. Several of these mechanisms depend on signaling by the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. This pathway integrates signals from multiple receptor tyrosine kinases and regulates many cellular processes, including proliferation, growth, and survival. Because these processes are critical for oncogenic transformation, the PI3K/mTOR pathway is being extensively studied in the hope that it will lead to promising new treatments for hematological malignancies. In the sections that follow, we summarize current understanding of this pathway and the results of recent studies of mTOR inhibitors in lymphoma and leukemia.
A bispecific decoy receptor VEGFR-EGFR/Fc binding EGF-like ligands and VEGF shows potent antitumor efficacy
Published in Journal of Drug Targeting, 2022
Xiao-Fang Guo, Yue-Yue Zhang, Jia Kang, Qiao-Hua Dou, Xiao-Fei Zhu
Most of the reported decoy receptors are mono-specific, including Ziv-aflibercept and FP-1039. VEGFR-EGFR/Fc protein we constructed in this study is a novel bispecific decoy receptor. It not only binds to EGF and TGF-α, but also bind to VEGF with high affinity, and then block the transduction of both EGFR and VEGFR signalling pathways, so it will play a superior anti-tumour activity to monospecific decoy receptor or expand the coverage of benefitted patients. VEGFR-EGFR/Fc showed potent inhibitory effect on cell proliferation, invasion and migration against human NSCLC A549 and HUVEC. In vivo, VEGFR-EGFR/Fc displayed significant growth inhibition on the A549 xenografts. It was also able to effectively induce cell apoptosis and inhibit the neovascularisation in the tumour tissues. However, future studies should be directed to the activity of VEGFR-EGFR/Fc protein on more tumour cell lines and more tumour types, especially on cells with different expression levels of EGF and VEGF. Whether the anti-tumour activity of VEGFR-EGFR/Fc is superior to its corresponding mono-specific molecules also needs to be further clarified. Additionally, VEGFR-EGFR/Fc competitively bound with the ligands and prevented ligand-dependent receptor activation. It may have synergistic effect with the receptor tyrosine kinase inhibitors. Therefore, the antitumor efficacy of VEGFR-EGFR/Fc protein in combination with the tyrosine kinase inhibitors, such as gefitinib, erlotinib and lapatinib should be investigated in next to achieve more effective inhibition of EGFR and VEGFR signalling pathway.
A phase II study on the neo-adjuvant combination of pazopanib and radiotherapy in patients with high-risk, localized soft tissue sarcoma
Published in Acta Oncologica, 2021
Milan van Meekeren, Judith V. M. G. Bovee, Frits van Coevorden, Winan van Houdt, Yvonne Schrage, Anne Miek Koenen, Aisha B. Miah, Shane Zaidi, Andrew J. Hayes, Khin Thway, Stijn Krol, Marta Fiocco, Hans Gelderblom, Neeltje Steeghs, Rick L. Haas
Pazopanib is an oral multitarget tyrosine kinase inhibitor (TKI), and its mode of action is suggested to be an interference with angiogenesis by blocking the VEGF-axis. Additionally, it provides a direct anti-growth effect through the blockade of various other receptor tyrosine kinases. Pazopanib has demonstrated activity in metastatic soft tissue sarcoma, after the phase III PALETTE trial [9], randomizing pazopanib to placebo, showed a significant improvement in progression-free survival. Furthermore, pazopanib has demonstrated promising results when combined with radiotherapy for several tumor types, with a potential synergistic, radiosensitizing effect [10,11]. This has led to the investigation of the neo-adjuvant combination of pazopanib and radiotherapy for localized, high-risk soft tissue sarcoma in our phase I trial in 2015 [12] (NCT01985295, acronym PASART-1). A 27% rate of grade 3+ hepatotoxicity (3 out of 11 patients) was observed, which was transient in all 3 patients after a maximum of 3 weeks. Apart from hepatotoxicity, the combination of 50 Gy radiotherapy and 800 mg daily pazopanib appeared tolerable and showed promising efficacy, with 4 out of 10 evaluable patients showing a complete pathological response.
L-GILZ binds and inhibits nuclear factor κB nuclear translocation in undifferentiated thyroid cancer cells
Published in Journal of Chemotherapy, 2020
Maria Cristina Marchetti, Lorenza Cannarile, Simona Ronchetti, Domenico V. Delfino, Carlo Riccardi, Emira Ayroldi
The MAPK signalling pathway regulates the proliferation, differentiation and apoptosis of normal cells, but when abnormally activated, it contributes to cancer cell survival, spreading and resistance to therapy. Indeed, pharmacological treatment of cancer includes kinase inhibitors targeting either the receptor tyrosine kinase or MAPK signalling pathways.4 Another critical element that can support thyroid cancer cell proliferation is nuclear factor κB (NF-κB), a transcription factor that regulates the expression of genes involved in the immune and inflammatory responses.5 In cancer cells, NF-κB induces the expression of growth factors, anti-apoptotic and mitogenic genes, cytokines and molecules that directly affect tumour growth and the tumour microenvironment.6 NF-κB activation has been observed in PTC and FTC as well as in aggressive ATC.7,8 Therefore, targeting and inhibiting NF-κB may help control neoplastic cell proliferation and spread.