Molecular targeted agents for enhancing tumour response
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
A promising approach therefore is to combine radiotherapy with drugs which target the EGFR. Such drugs can either be monoclonal antibodies against the EGFR or small molecules which specifically inhibit phosphorylation of the EGFR (tyrosine kinase inhibitors [TKIs]). Figure 20.3 shows the downstream molecular pathways that may be altered by these two approaches. For a large number of tumour cell lines in vitro it has been demonstrated that EGFR inhibition with or without irradiation results in reduced cell proliferation. For some but not all of these cell lines, a radiosensitizing effect could also be shown which at least in part seems to be related to inhibition of repair of DNA damage (reviewed in [7]). Also, for many tumour models in vivo, prolonged growth delay was demonstrated for different EGFR inhibitors combined with radiotherapy ([32], and reviewed in [6]). Experiments demonstrated improved local tumour control when the monoclonal anti-EGFR antibody C225 was given with single-dose or fractionated irradiation (32,43,50,53), however, this effect is heterogeneous between different tumours of the same histology (32).
Capitalizing on being “othered”
Shirley Sun in Socio-economics of Personalized Medicine in Asia, 2016
While the case of BiDil is now relatively well known (Roberts 2011a, 2011b; Kahn 2013), how IRESSA (for treatment of non-small-cell lung cancer) became an Asian-focused drug has attracted less critical examination. We suggest that the case of IRESSA deserves a closer look, not least because it has been hailed as an exemplary case of personalized medicine. As noted in the European Science Foundation publication Forward Look, health care professionals must “raise awareness of examples in which stratified approaches have already begun to be used effectively in the clinic as precursors of a wider vision of personalized medicine” (European Science Foundation, 2012:15). “Drugs such as gefitinib and erlotinib, for instance, are being used to treat patients with non-small-cell lung cancer who have mutations in the epidermal growth factor receptor (EGFR)” (European Science Foundation, 2012:13).
Phase II Trials for Targeted Agents
John Crowley, Antje Hoering in Handbook of Statisticsin Clinical Oncology, 2012
The story for EGFR inhibitors is complicated because there may be benefits in the subgroup of patients who are nonsmokers due to genetic differences in the tumors. It is not clear if the survival benefit may be due to mutations, gene copy number, or protein expression [5]. The results for these EGFR inhibitors motivate several more general targeted therapy questions: Is there a genetic subgroup where such treatments are effective (or more effective) and how should study designs be modified where feasible? Should all patients of a particular tumor type be treated with a targeted agent or should only those patients who are positive for the target (or marker) be so treated? As mentioned earlier, traditional cytotoxic agents “target” dividing cells, thus killing tumor cells but at the cost of collateral damage (toxicity), especially for other organs with a high proliferative fraction. Also, targeted agents can have collateral benefit, in that they can be effective in patients classified as negative for the target, either because there is a weak signal for the target in such patients, or because the agent hits a different target. For example, there is now evidence that trastuzumab has some effect on Her-2 neu negative breast cancer patients [9]. Another example is imatinib, which was developed to target the CML defining bcr-abl translocation but also destroys tumor cells that are c-kit positive (which virtually defines GI stromal tumors) [4].
Pharmacologic agents directed at the treatment of pain associated with maladaptive neuronal plasticity
Published in Expert Opinion on Pharmacotherapy, 2022
Joseph V. Pergolizzi, Giustino Varrassi, Peter Magnusson, Frank Breve, Robert B. Raffa, Paul J. Christo, Maninder Chopra, Antonella Paladini, Jo Ann LeQuang, Kailyn Mitchell, Flaminia Coluzzi
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor inhibitor and is used in oncology. EGFR drugs can interrupt the mitogen-activated protein kinase (MAPK) signaling involved in neuropathic pain signaling. A case study reported that a 68-year-old male cancer patient found remarkable pain relief for long-standing unrelated neuropathic pain when taking cetuximab, an EGFR drug prescribed for cancer [52]. This has prompted interest in cetuximab in chronic neuropathic pain and an open-label study (n = 20) of EGFR inhibition for neuropathic pain. Ninety percent of patients experienced pain reduction of a median of 8.5 (interquartile range 5 to 9.5) on a 0 to 10 pain scale. Neuropathic pain was relieved within 24 hours in most patients. This study evaluated four different EGFR-I drugs and effectiveness was similar among these drugs [53].
Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Yi Le, Yiyuan Gan, Yihong Fu, Jiamin Liu, Wen Li, Xue Zou, Zhixu Zhou, Zhenchao Wang, Guiping Ouyang, Longjia Yan
Epidermal growth factor receptor (EGFR) tyrosine kinase (TK) plays an indispensable role in cancer cell proliferation, survival, adhesion, migration and differentiation. Overexpression and mutation of EGFR have been associated with a variety of cancers1,2. Development of EGFR inhibitors has become a main focus in antitumor drug campaigns. At present, several drugs such as Gefitinib, Erlotinib, Afatinib, and Lapatinib, have been approved by the Food and Drug Administration (FDA) for clinical use as EGFR inhibitors (Figure 1)3,4. However, the emergence of acquired point mutations has weakened their therapeutic efficacy, leading to drug resistance and toxicity burden5. Consequently, it is an urgent goal to discover new structural EGFR inhibitors for cancer therapy6.
Targeting the EGFR signaling pathway in cancer therapy: What’s new in 2023?
Published in Expert Opinion on Therapeutic Targets, 2023
Sushanta Halder, Soumi Basu, Shobhit P. Lall, Apar K. Ganti, Surinder K. Batra, Parthasarathy Seshacharyulu
Numerous studies have shown that EGF stimulation led to the activation of EGFR downstream signaling driving the cellular phenotype of epithelial cells. Treatment of non-epithelial and cancerous epithelial cells using EGFR inhibitors demonstrated an inhibited network of EGFR signaling events. EGFR family members’ overexpression was associated with poor clinical outcomes in all cancers. EGFR gene expression and protein expression in various cancers are summarized in Figure 4 and Table 2. Over several years of research, our research community has identified several targeted therapies against activated and mutated EGFR, HER2, HER3, and HER4 (panEGFR inhibitors). These agents were approved by the US FDA, the European Medicines Agency (EMA), and the National Medical Products Administration (NMPA) in China for early, late, and advanced-stage cancer patients. More importantly, EGFR-targeted inhibitors are the first molecular agents to be approved and applied for several advanced cancers. They are the first targeted agents to be used as monotherapy with superior efficacy over conventional chemotherapy in cancer patients.