Book Volume 5
Second-Generation Protein Kinase Inhibitor – A Focus on Quizartinib, A Promising Targeted Therapy for High-Risk FLT3+ Patients with Acute Myeloid Leukemia
Page: 1-21 (21)
Author: Xavier Thomas and Etienne Paubelle
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Fms-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in acute myeloid leukemia (AML). While first-generation FLT3 tyrosine kinase inhibitors are relatively non-specific for FLT3 with other potential targets, the nextgeneration inhibitors appear more potent and selective. Among them quizartinib is the most clinically advanced. The greater potency and selectivity of this drug promises greater efficacy and less toxicity in FLT3-mutated AML. It is currently studied across virtually all disease settings, and its use in combination with chemotherapy appears promising in FLT3+ patients. In this review, we summarize the current data on quizartinib and the encouraging clinical data that have also emerged with other secondor further-generation FLT3 inhibitors, after recalling results observed with firstgeneration inhibitors.
Page: 22-49 (28)
Author: Shinichiro Morishita, Atsuhiro Tsubaki and Jack B. Fu
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The use of chemotherapy in the treatment of cancer, although increasingly efficacious for improving survival, produces short- and long-term negative physiological side effects. Sleep disturbance, fatigue, and depressed mood are common and distressing problems that occur during and after chemotherapy. Furthermore, after chemotherapy, cancer patients tend to experience decreased cardiorespiratory fitness and muscle strength. These changes lead to a decrease in physical function and quality of life (QoL). Physical exercise has been shown to improve physical function and QoL in cancer patients during and after chemotherapy. Physical exercise may also alleviate symptoms that interfere with physical fatigue, mental fatigue, treatment-related fatigue, muscle pain, arthralgia, and other pain, depression, anxiety, and insomnia. Furthermore, physical exercise prolongs survival and reduces the mortality of these patients. Based on previous scientific reports, this chapter introduces the role of physical exercise in the care of cancer patients treated with chemotherapy.
Cancer Immune Evasion in Gastrointestinal Cancer: Can this be Overcome by Combination of Histone Deacetylase and Immune Checkpoint Inhibitors?
Page: 50-84 (35)
Author: Yuequan Shi, Onyinyechi Duru, Zifang Zou and David Kerr
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Although immune checkpoint inhibitors have been used for the treatment of gastrointestinal malignancies, clinical benefit has been modest compared to other tumour sites. Microsatellites high cancers have shown a better response to immunotherapy but they make up a small percentage of this group of tumours. Efforts to improve results have been made, particularly through the use of combination therapy and such an example would be the combination with anti-VEGF agents which have shown some promise in gastric cancers. Histone deacetylase inhibitors (HDACi) have been shown to be effective anti-cancer agents particularly for haematological malignancies with multiple anti-tumour mechanisms of action including the induction of apoptosis, cell cycle arrest and the upregulation of major histocompatibility complex (MHC) in tumour cells. Although there has not been much clinical success in the context of gastrointestinal cancers, there is preclinical evidence to suggest that combination therapy with traditional chemotherapy agents may have some therapeutic benefit. However, the combination of HDACi with immune checkpoint inhibitors has not been studied. Both HDACi and immune checkpoint inhibitors have already demonstrated satisfactory safety profiles and furthermore, clinical activity of HDACi can be monitored by the use of biomarkers. Therefore, it has been hypothesised that by combining the two treatment agents together, synergism may be observed in the form of improved host immune anti- tumour response as a result of enhanced immunogenicity conferred by HDACi, which will ultimately result in effective tumour killing.
Page: 85-112 (28)
Author: Chang Gong, Zihao Liu, Andrew J. Sanders and Wen G. Jiang
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long non-coding RNAs (lncRNAs) are a diverse group of functional RNAs which were once regarded as “transcription noise”. However, the latest evidence has revealed that lncRNAs are often cancer-specific and the expression of lncRNAs is frequently aberrant in a variety of cancers. Several studies have highlighted the fundamental roles of lncRNAs in cancer proliferation, self-renewal, chemotherapy resistance and metastasis. Thus, lncRNAs lie at the crossroad of tumorigenesis. Recently, several articles have explored the molecular mechanisms notably governing lncRNAs in multiple biological processes of the tumor. LncRNAs in the nucleus act in trans or in cis to promote the transcription of tumorigentic genes. LncRNAs in the nucleus play an important role in alternative splicing or genetic imprinting. In addition, lncRNAs residing in the cytoplasm can exert their peculiar regulation on mRNA, microRNA or protein via post-transcriptional modification. Targeting lncRNAs can reverse cancer progression and might be promising for anti-cancer treatment. Several different approaches to target lncRNAs including: small interfering RNAs, antisense oligonucleotide, aptamer, small molecular inhibitors and CRISPR systems have been considered for therapeutic purposes. This review will focus on the involvement of lncRNAs in cancer progression and provide valuable therapeutic information to target lncRNAs for anti-cancer treatment.
Page: 113-121 (9)
Author: Işıl Yıldırım
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Due to an excessive production of ROS production by the cell's loss of its ability to metabolize, an oxidative stress is expressed. An excessive accumulation of ROS alters not only the biochemical but also genetic and epigenetic mechanisms. These changes could lead to cancer development. In previous studies, it was determined that ROS plays a critical role and the therapy target has also been discussed. So, throughout this manuscript, I aimed to review the role of ROS and its associated signaling pathways in the initiation and progression and apoptosis of breast cancer. This fine distinction of the ROS action depends not only on pro-apoptotic agents and anti-apoptotic agents; ROS leads to the activation of several signaling pathways but also on the duration, type, dosage (concentration) and site of ROS generation and change gene expressions. This study will keep current on the relevant mechanisms of ROS-mediated apoptosis and will guide future studies.
Generations of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Battle against Drug Resistant Lung Cancer
Page: 122-165 (44)
Author: Kenneth K.W. To and Wing-Sum Tong
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The discovery of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), such as gefitinib and erlotinib, has produced remarkable clinical response in a sub-population of lung cancer patients harboring the sensitizing EGFR mutations (L858R or exon 19 deletion). However, their successful clinical application is significantly hindered by the development of acquired resistance predominantly caused by the secondary EGFR T790M mutation, usually occurring within a year after the initial TKI therapy. Second generation irreversible EGFR TKIs have been developed to bind covalently to Cys-797 of the EGFR kinase binding domain in order to bypass these EGFR T790M mutations. However, these irreversible EGFR TKIs are not sufficiently effective against the resistant cells in vivo at clinically achievable drug concentrations. In order to overcome resistant mutations and also to reduce toxic effects, highly potent third generation EGFR TKIs have been designed against EGFR T790M-bearing cancer while sparing the wild-type receptor. However, acquired resistance to the third generation TKIs has already been reported, which is mediated by the induction of another secondary EGFR C797S mutation and in some instances MET amplification. This chapter summarizes the current research in the development of EGFR TKIs, mainly focusing on pharmacological properties, safety and clinical status.
Frontiers in Clinical Drug Research - Anti-Cancer Agents is a book series intended for pharmaceutical scientists, postgraduate students and researchers seeking updated and critical information for developing clinical trials and devising research plans in anti-cancer research. Reviews in each volume are written by experts in medical oncology and clinical trials research and compile the latest information available on special topics of interest to oncology researchers. The fifth volume of the book features reviews on biochemical inhibitors (second-generation protein kinase Inhibitors, histone deacetylase inhibitors, immune checkpoint inhibitors, EGFR Tyrosine Kinase inhibitors, non-coding RNAs), apoptosis, and physical exercise therapy for cancer patients undergoing chemotherapy. The treatment strategies in this volume cover cancers such as acute myeloid leukemia, gastrointestinal cancer, breast cancer and lung cancer.