3,800 results on '"Tyrosine kinase inhibitors"'
Search Results
2. Low-Dose Sorafenib Promotes Cancer Stem Cell Expansion and Accelerated Tumor Progression in Soft Tissue Sarcomas
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Cruz, Sylvia M, Iranpur, Khurshid R, Judge, Sean J, Ames, Erik, Sturgill, Ian R, Farley, Lauren E, Darrow, Morgan A, Crowley, Jiwon Sarah, Monjazeb, Arta M, Murphy, William J, and Canter, Robert J
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Biochemistry and Cell Biology ,Biological Sciences ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Microbiology ,Stem Cell Research ,Clinical Research ,Stem Cell Research - Nonembryonic - Human ,Rare Diseases ,Cancer ,Humans ,Sorafenib ,Tyrosine Kinase Inhibitors ,Aldehyde Dehydrogenase ,Protein Kinase Inhibitors ,Sarcoma ,Neoplastic Stem Cells ,Cell Line ,Tumor ,cancer stem cells ,sorafenib ,ALDH ,sarcoma ,survival ,Survival ,Other Chemical Sciences ,Genetics ,Other Biological Sciences ,Chemical Physics ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
The cancer stem cell (CSC) hypothesis postulates that heterogeneous human cancers harbor a population of stem-like cells which are resistant to cytotoxic therapies, thus providing a reservoir of relapse following conventional therapies like chemotherapy and radiation (RT). CSCs have been observed in multiple human cancers, and their presence has been correlated with worse clinical outcomes. Here, we sought to evaluate the impact of drug dosing of the multi-tyrosine kinase inhibitor, sorafenib, on CSC and non-CSCs in soft tissue sarcoma (STS) models, hypothesizing differential effects of sorafenib based on dose and target cell population. In vitro, human cancer cell lines and primary STS from surgical specimens were exposed to escalating doses of sorafenib to determine cell viability and expression of CSC marker aldehyde dehydrogenase (ALDH). In vivo, ALDHbright CSCs were isolated, exposed to sorafenib, and xenograft growth and survival analyses were performed. We observed that sarcoma CSCs appear to paradoxically respond to the tyrosine kinase inhibitor sorafenib at low doses with increased proliferation and stem-like function of CSCs, whereas anti-viability effects dominated at higher doses. Importantly, STS patients receiving neoadjuvant sorafenib and RT on a clinical trial (NCT00864032) showed increased CSCs post therapy, and higher ALDH scores post therapy were associated with worse metastasis-free survival. These data suggest that low-dose sorafenib may promote the CSC phenotype in STS with clinically significant effects, including increased tumor growth and higher rates of metastasis formation in sarcoma patients.
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- 2024
3. Atrial fibrillation in cancer, anticancer therapies, and underlying mechanisms.
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Shaaban, Adnan, Scott, Shane S., Greenlee, Ashley N., Binda, Nkongho, Noor, Ali, Webb, Averie, Guo, Shuliang, Purdy, Najhee, Pennza, Nicholas, Habib, Alma, Mohammad, Somayya J., and Smith, Sakima A.
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PROTEIN-tyrosine kinase inhibitors , *CANCER-related mortality , *CARDIOTOXICITY , *CANCER survivors , *CHEST pain , *ATRIAL fibrillation - Abstract
Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and cardiotoxic anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy-induced AF. • Atrial Fibrillation (AF) is prevalent among active cancer patients and survivors. • Several classes of anticancer drug therapies also increase AF risk. • Preexisting and cancer-related cardiac remodeling contributes to AF development. • Oxidative stress, inflammation, and ionic alterations have been documented. • Emerging data suggests a role for SGLT2i in management of anticancer-induced AF. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Underlying Mechanisms of Thrombosis Associated with Cancer and Anticancer Therapies.
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Pantazi, Despoina, Alivertis, Dimitrios, and Tselepis, Alexandros D.
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Opinion Statement: Cancer-associated thrombosis (CAT) has been identified as the second most prevalent cause of death after cancer itself. Moreover, the risk of thrombotic events in cancer patients increases due to anticancer drugs, such as tyrosine kinase inhibitors (TKIs). Venous thromboembolism (VTE) as well as arterial thromboembolic (ATE) events are present in CAT. Although VTE occurs more frequently, ATE events are very significant and in some cases are more dangerous than VTE. Guidelines for preventing thrombosis refer mainly VTE as well as the contribution of ATE events. Several factors are involved in thrombosis related to cancer, but the whole pathomechanism of thrombosis is not clear and may differ between patients. The activation of the coagulation system and the interaction of cancer cells with other cells including platelets, endothelial cells, monocytes, and neutrophils are promoted by a hypercoagulable state caused by cancer. We present an update on the pathomechanisms of CAT and the effect of anticancer drugs, mainly targeted therapies with a focus on TKIs. Considering the risk of bleeding associated with anticoagulation in each cancer patient, the anticoagulation strategy may involve the use of FXIa inhibitors, direct oral anticoagulants, and low-molecular-weight heparin. Further research would be valuable in developing strategies for reducing CAT. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Basic concepts of cancer genetics and receptor tyrosine kinase inhibition for pharmacists. A narrative review
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Orrico, Kathleen B
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Cancer ,Genetics ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Humans ,Receptor Protein-Tyrosine Kinases ,Pharmacists ,Signal Transduction ,Neoplasms ,Carcinogenesis ,Protein Kinase Inhibitors ,Receptor tyrosine kinase ,pharmacogenomics ,tyrosine kinase inhibitors ,molecular diagnostics ,cancer ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Pharmacology and pharmaceutical sciences - Abstract
The intent of this review is to present basic genetic concepts key to understanding oncogenesis and the role receptor tyrosine kinase (RTK) inhibition plays in the targeted treatment of many cancer types. Oncogenic signaling by RTKs can result from genetic events such as point mutations, chromosomal rearrangements, structural variation, and gene amplification in the cancer genome. The cancer pharmacogenes discussed encode RTKs that exemplify the link between gene variation, the oncogenic process, and the basis of targeted approaches to treatment. Biochemical pathways often involved in oncogenesis and affected by RTK variation are reviewed. Molecular diagnostic testing for the presence of specific gene variants, alterations, and amplifications direct therapy to indicated tyrosine kinase inhibitors and monoclonal antibody drugs. As pharmacists are integral to the selection, preparation, and monitoring of chemotherapy, it is important that they understand the genetic basis for targeted therapies as well as the underlying disease process.
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- 2023
6. Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy
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Rodriguez, Jonathan, Iniguez, Abdon, Jena, Nilamani, Tata, Prasanthi, Liu, Zhong-Ying, Lander, Arthur D, Lowengrub, John, and Van Etten, Richard A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Stem Cell Research ,Hematology ,Orphan Drug ,Clinical Research ,Cancer ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research - Nonembryonic - Human ,Mice ,Animals ,Tyrosine Kinase Inhibitors ,Protein Kinase Inhibitors ,Drug Resistance ,Neoplasm ,Myelopoiesis ,Fusion Proteins ,bcr-abl ,Mice ,Transgenic ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,cancer ,cancer biology ,chronic myeloid leukemia ,computational biology ,hematopoiesis ,mathematical model ,mouse ,nonlinear dynamics ,systems biology ,treatment dynamics ,Biochemistry and Cell Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Chronic myeloid leukemia (CML) is a blood cancer characterized by dysregulated production of maturing myeloid cells driven by the product of the Philadelphia chromosome, the BCR-ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKIs) have proved effective in treating CML, but there is still a cohort of patients who do not respond to TKI therapy even in the absence of mutations in the BCR-ABL1 kinase domain that mediate drug resistance. To discover novel strategies to improve TKI therapy in CML, we developed a nonlinear mathematical model of CML hematopoiesis that incorporates feedback control and lineage branching. Cell-cell interactions were constrained using an automated model selection method together with previous observations and new in vivo data from a chimeric BCR-ABL1 transgenic mouse model of CML. The resulting quantitative model captures the dynamics of normal and CML cells at various stages of the disease and exhibits variable responses to TKI treatment, consistent with those of CML patients. The model predicts that an increase in the proportion of CML stem cells in the bone marrow would decrease the tendency of the disease to respond to TKI therapy, in concordance with clinical data and confirmed experimentally in mice. The model further suggests that, under our assumed similarities between normal and leukemic cells, a key predictor of refractory response to TKI treatment is an increased maximum probability of self-renewal of normal hematopoietic stem cells. We use these insights to develop a clinical prognostic criterion to predict the efficacy of TKI treatment and design strategies to improve treatment response. The model predicts that stimulating the differentiation of leukemic stem cells while applying TKI therapy can significantly improve treatment outcomes.
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- 2023
7. Novel pharmacological and dietary approaches to target mTOR in B-cell acute lymphoblastic leukemia
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Buono, Roberta, Alhaddad, Muneera, and Fruman, David A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Orphan Drug ,Pediatric Cancer ,Cancer ,Pediatric ,Hematology ,Childhood Leukemia ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,leukemia ,B-ALL ,tyrosine kinase inhibitors ,mTOR ,metabolism ,nutrient restriction ,fasting mimicking diet ,targeted therapy ,Clinical sciences ,Oncology and carcinogenesis - Abstract
High-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) are frequently associated with aberrant activation of tyrosine kinases (TKs). These include Ph+ B-ALL driven by BCR-ABL, and Ph-like B-ALL that carries other chromosomal rearrangements and/or gene mutations that activate TK signaling. Currently, the tyrosine kinase inhibitor (TKI) dasatinib is added to chemotherapy as standard of care in Ph+ B-ALL, and TKIs are being tested in clinical trials for Ph-like B-ALL. However, growth factors and nutrients in the leukemia microenvironment can support cell cycle and survival even in cells treated with TKIs targeting the driving oncogene. These stimuli converge on the kinase mTOR, whose elevated activity is associated with poor prognosis. In preclinical models of Ph+ and Ph-like B-ALL, mTOR inhibitors strongly enhance the anti-leukemic efficacy of TKIs. Despite this strong conceptual basis for targeting mTOR in B-ALL, the first two generations of mTOR inhibitors tested clinically (rapalogs and mTOR kinase inhibitors) have not demonstrated a clear therapeutic window. The aim of this review is to introduce new therapeutic strategies to the management of Ph-like B-ALL. We discuss novel approaches to targeting mTOR in B-ALL with potential to overcome the limitations of previous mTOR inhibitor classes. One approach is to apply third-generation bi-steric inhibitors that are selective for mTOR complex-1 (mTORC1) and show preclinical efficacy with intermittent dosing. A distinct, non-pharmacological approach is to use nutrient restriction to target signaling and metabolic dependencies in malignant B-ALL cells. These two new approaches could potentiate TKI efficacy in Ph-like leukemia and improve survival.
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- 2023
8. Discovery of A Novel Series of Quinazoline–Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents.
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Șandor, Alexandru, Fizeșan, Ionel, Ionuț, Ioana, Marc, Gabriel, Moldovan, Cristina, Oniga, Ilioara, Pîrnău, Adrian, Vlase, Laurian, Petru, Andreea-Elena, Macasoi, Ioana, and Oniga, Ovidiu
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MOLECULAR dynamics , *MOLECULAR docking , *WOUND healing , *SORAFENIB , *THIAZOLES - Abstract
Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline–thiazole hybrids (SA01–SA07) as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC50 =1.83-4.24 µM) on HepG2 cells compared to sorafenib (IC50 = 6.28 µM). The affinity towards the VEGFR2 kinase domain was assessed through in silico prediction by molecular docking, molecular dynamics studies, and MM-PBSA. The series displayed a high degree of similarity to sorafenib regarding the binding pose within the active site of VEGFR2, with a different orientation of the 4-substituted-thiazole moieties in the allosteric pocket. Molecular dynamics and MM-PBSA evaluations identified SA05 as the hybrid forming the most stable complex with VEGFR2 compared to sorafenib. The impact of the compounds on vascular cell proliferation was assessed on EA.hy926 cells. Six compounds (SA01–SA05, SA07) displayed superior anti-proliferative activity (IC50 = 0.79–5.85 µM) compared to sorafenib (IC50 = 6.62 µM). The toxicity was evaluated on BJ cells. Further studies of the anti-angiogenic effect of the most promising compounds, SA04 and SA05, through the assessment of impact on EA.hy296 motility using a wound healing assay and in ovo potential in a CAM assay compared to sorafenib, led to the confirmation of the anti-angiogenic potential. [ABSTRACT FROM AUTHOR]
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- 2024
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9. HER2 and HER3 as Therapeutic Targets in Head and Neck Cancer
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Saddawi-Konefka, Robert, Schokrpur, Shiruyeh, Lui, Asona J, and Gutkind, J Silvio
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Dental/Oral and Craniofacial Disease ,Digestive Diseases ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Good Health and Well Being ,Antibodies ,Blocking ,Head and Neck Neoplasms ,Humans ,Receptor ,ErbB-2 ,Receptor ,ErbB-3 ,Signal Transduction ,Cancer immunotherapy ,ErbB ,EGFR ,head and neck cancer ,HER2 ,HER3 ,precision therapy ,signal transduction ,tyrosine kinase inhibitors ,Receptor ,erbB-2 ,Receptor ,erbB-3 ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
AbstractWork over the past several decades has identified that aberrations in the ErbB signaling pathways are key drivers of oncogenesis, and concurrent efforts to discover targetable vulnerabilities to counter this aberrant oncogenic signaling offer tremendous promise in treating a host of human cancers. These efforts have been centered primarily on EGFR (also known as HER1), leading to the discovery of the first targeted therapies approved for head and neck cancer. More recently, HER2 and HER3 signaling pathways have been identified as highly dysregulated in head and neck cancer. This review highlights the HER2 and HER3 signaling pathways and clinical efforts to target these receptors and their aberrant signaling to treat head and neck squamous cell carcinomas and other head and neck malignancies, including salivary gland carcinomas. This includes the use of small molecule inhibitors and blocking antibodies, both as single agents or as part of multimodal precision targeted and immunotherapies.
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- 2022
10. Losing a part of life: experiences of cancer survivors accessing treatment and sheltering in place during the COVID-19 pandemic.
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Wickersham, K. E., Morrill, K. E., Lopez-Pentecost, M., Heiney, S. P., King, J. J., Madhivanan, P., and Hirschey, R.
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COVID-19 pandemic ,CANCER survivors ,PSYCHO-oncology ,PROTEIN-tyrosine kinase inhibitors ,SOCIAL support ,OCCUPATIONAL roles - Abstract
Purpose: To explore experiences of sheltering in place and accessing treatment during the initial stages of the COVID-19 pandemic among survivors with cancer receiving tyrosine kinase inhibitor (TKI) therapy. Methods: Participants from two pilot studies evaluating TKI therapy use in the Southeastern United States during the start of the COVID-19 pandemic (March 2020) were interviewed. Identical interview guides were used across both studies to assess participants' experiences accessing cancer treatment, sheltering in place, and coping during the COVID-19 pandemic. Digitally recorded sessions were transcribed professionally and checked for accuracy. Descriptive statistics were used to summarize participant sociodemographics, and a six-step thematic approach was used to analyze interview data and identify salient themes. Dedoose qualitative research software was used to manage and organize qualitative codes, themes, and memos. Results: Participants (n = 15) ranged from 43 to 84 years of age, and were mostly female (53.3%), married (60%), and survivors with hematologic malignancies (86.7%). The research team identified five salient themes: Participants followed pandemic guidelines, Variable impact on well-being, Common feelings of fear, anxiety and anger, No barriers to accessing therapy and medical care, and Faith and God as powerful forces for coping. Conclusions: The conclusions of the study provide several implications for survivorship programs or clinics for supporting survivors who are taking chronic TKI therapy during COVID-19, including enhancement of current psychosocial support efforts for cancer survivors or development of new programs tailored to the unique needs of a survivor during a pandemic, such as focused coping strategies, modified physical activity programs, family/professional role changes, and access to safe public spaces. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Candidate biomarkers for treatment benefit from sunitinib in patients with advanced renal cell carcinoma using mass spectrometry-based (phospho)proteomics.
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van der Wijngaart, Hanneke, Beekhof, Robin, Knol, Jaco C., Henneman, Alex A., de Goeij-de Haas, Richard, Piersma, Sander R., Pham, Thang V., Jimenez, Connie R., Verheul, Henk M. W., and Labots, Mariette
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RENAL cell carcinoma , *SUNITINIB , *THROMBIN receptors , *MASS spectrometry , *PROTEOMICS , *PROTEIN-tyrosine kinase inhibitors , *POST-translational modification - Abstract
The tyrosine kinase inhibitor sunitinib is an effective first-line treatment for patients with advanced renal cell carcinoma (RCC). Hypothesizing that a functional read-out by mass spectrometry-based (phospho, p-)proteomics will identify predictive biomarkers for treatment outcome of sunitinib, tumor tissues of 26 RCC patients were analyzed. Eight patients had primary resistant (RES) and 18 sensitive (SENS) RCC. A 78 phosphosite signature (p < 0.05, fold-change > 2) was identified; 22 p-sites were upregulated in RES (unique in RES: BCAR3, NOP58, EIF4A2, GDI1) and 56 in SENS (35 unique). EIF4A1/EIF4A2 were differentially expressed in RES at the (p-)proteome and, in an independent cohort, transcriptome level. Inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) as determined by INKA was higher in SENS. Posttranslational modifications signature enrichment analysis showed that different p-site-centric signatures were enriched (p < 0.05), of which FGF1 and prolactin pathways in RES and, in SENS, vanadate and thrombin treatment pathways, were most significant. In conclusion, the RCC (phospho)proteome revealed differential p-sites and kinase activities associated with sunitinib resistance and sensitivity. Independent validation is warranted to develop an assay for upfront identification of patients who are intrinsically resistant to sunitinib. [ABSTRACT FROM AUTHOR]
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- 2023
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12. The History and Development of HER2 Inhibitors.
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Xia, Xiaohui, Gong, Chen, Zhang, Yinan, and Xiong, Huihua
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ANTIBODY-drug conjugates , *PROTEIN-tyrosine kinase inhibitors , *MONOCLONAL antibodies , *TRASTUZUMAB , *CANCER treatment - Abstract
HER2 is highly expressed in a variety of malignant tumors and affects the prognosis of patients, making it a highly sensitive target for cancer therapy. Since the approval of the first HER2 inhibitor, trastuzumab, in 1998, HER2-targeted drugs have rapidly evolved. Currently, targeting HER2 drugs mainly include monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). This article reviews the development of HER2 inhibitors for various tumors over the past 20 years. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Osimertinib as neoadjuvant therapy in a patient with stage IIIA non-small cell lung cancer: a case report
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Chen, Caroline Y, Fares, Charlene M, and Shin, Daniel Sanghoon
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,Lung Cancer ,Lung ,Development of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,5.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,Acrylamides ,Aniline Compounds ,Carcinoma ,Non-Small-Cell Lung ,Humans ,Lung Neoplasms ,Mutation ,Neoadjuvant Therapy ,Protein Kinase Inhibitors ,Non-small cell lung cancer ,Tyrosine kinase inhibitors ,Neoadjuvant ,Case report ,Other Medical and Health Sciences ,General & Internal Medicine ,Biomedical and clinical sciences - Abstract
IntroductionTyrosine kinase inhibitors (TKI) targeting epidermal growth factor receptor (EGFR) are approved for use in metastatic non-small cell lung cancer (NSCLC).Case presentationHere we present a case of a African American patient with stage IIIA NSCLC treated with osimertinib in the neoadjuvant setting with concurrent radiation, followed by resection. The patient remains disease-free 4 months after surgery.ConclusionThis case report suggests that osimertinib may be effective as neoadjuvant therapy in resectable stage III disease. Additionally, we provide a summary of previous case reports and ongoing clinical trials for neoadjuvant EGFR inhibition in stage III NSCLC patients.
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- 2021
14. EML4‐ALK biology and drug resistance in non‐small cell lung cancer: a new phase of discoveries
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Mariam Elshatlawy, Josephina Sampson, Katy Clarke, and Richard Bayliss
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cancer ,drug resistance ,NSCLC ,signalling ,tyrosine kinase inhibitors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Anaplastic lymphoma kinase (ALK) can be driven to oncogenic activity by different types of mutational events such as point‐mutations, for example F1174L in neuroblastoma, and gene fusions, for example with echinoderm microtubule‐associated protein‐like 4 (EML4) in non‐small cell lung cancer (NSCLC). EML4‐ALK variants result from different breakpoints, generating fusions of different sizes and properties. The most common variants (Variant 1 and Variant 3) form cellular compartments with distinct physical properties. The presence of a partial, probably misfolded beta‐propeller domain in variant 1 confers solid‐like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs). These differences translate to the clinic because variant 3, on average, worsens patient prognosis and increases metastatic risk. Latest generation ALK‐TKIs are beneficial for most patients with EML4‐ALK fusions. However, resistance to ALK inhibitors can occur via point‐mutations within the kinase domain of the EML4‐ALK fusion, for example G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4‐ALK variants, their impact on treatment response, ALK‐TKI drug resistance mechanisms and potential combination therapies.
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- 2023
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15. Tyrosine kinase inhibitors in osteosarcoma: Adapting treatment strategiesa
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Ahmad Assi, Mohamad Farhat, Maria Catherine Rita Hachem, Ziad Zalaquett, Marven Aoun, Mohammad Daher, Amer Sebaaly, and Hampig-Raphaël Kourie
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Tyrosine kinase inhibitors ,Osteosarcoma ,Management ,Cancer ,Sarcoma ,Diseases of the musculoskeletal system ,RC925-935 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Osteosarcoma (OS) is an aggressive primary bone malignancy that metastasizes rapidly. The standard of care has changed little over the previous four decades, and survival rates have plateaued. In this context, tyrosine kinase inhibitors (TKIs) emerge as potential treatments. A literature search was conducted to collect data related to receptor tyrosine kinase genetic alterations and expression in OS specimens. Gene amplification and protein expression of these receptors were linked to prognosis and tumor behavior. Relevant TKIs were evaluated as monotherapies and as parts of combination therapies. Certain TKIs, such as apatinib, regorafenib, and cabozantinib, present a potential therapeutic avenue for OS patients, especially when combined with chemotherapy. Producing long-lasting responses and enhancing quality of life remain key goals in OS treatment. To this effect, optimizing the use of TKIs by identifying biomarkers predictive of response and assessing promising TKIs in larger-scale trials to validate the efficacy and safety outcomes relative to these drugs reported in phase II clinical trials. To this effect, it is necessary to identify biomarkers predictive of response to TKIs in larger-scale trials and to validate the efficacy and safety of these drugs reported in phase II clinical trials.
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- 2023
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16. Small Molecules against Metastatic Tumors: Concrete Perspectives and Shattered Dreams.
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Serra, Massimo, Rubes, Davide, Schinelli, Sergio, and Paolillo, Mayra
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TUMOR treatment , *SMALL molecules , *DRUG efficacy , *GENETIC mutation , *LIFE expectancy , *CANCER chemotherapy , *PROTEIN kinase inhibitors , *METASTASIS , *PROTEIN-tyrosine kinase inhibitors , *CYCLIN-dependent kinases , *TUMORS , *CHEMICAL inhibitors - Abstract
Simple Summary: Recent advances in anticancer drug research led to the approval of new small molecules with different mechanisms of action, therapeutic indications, and adverse reactions. In this review, small molecules recently approved for metastatic cancer therapy or in trials belonging to different pharmacological classes are described. Particularly, we focus on receptor tyrosine kinase inhibitors, which are the largest category, and on other small molecules interfering with cell cycle mechanisms. Special attention is devoted to mutated KRAS inhibitors, which probably represent the first dream come true in anti-metastatic cancer therapy of pharmacology researchers and open the way to potentially very broad therapeutic indications. A second section deals with another family of small molecules, integrin antagonists, that has gone through light and shade moments, and the molecules of still relevant interest are critically discussed. Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Peptide G-Protein-Coupled Receptors and ErbB Receptor Tyrosine Kinases in Cancer.
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Moody, Terry W., Ramos-Alvarez, Irene, and Jensen, Robert T.
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PEPTIDE receptors , *EPIDERMAL growth factor receptors , *KINASES , *PEPTIDES , *TYROSINE , *EXTRACELLULAR signal-regulated kinases - Abstract
Simple Summary: Cancer growth is regulated by receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs). The epidermal growth factor receptor (EGFR) is an RTK that binds ligands and causes tyrosine phosphorylation of protein substrates. Alternatively, the EGFR can tyrosine itself, leading to the activation of the ERK pathway, increasing cellular proliferation. The EGFR is mutated in several lung cancer patients, and these patients can be treated with tyrosine kinase inhibitors. The neurotensin receptor (NTSR1) is a GPCR, which binds peptides and alters signal transduction. Adding neurotensin to lung cancer cells increases phosphatidylinositol turnover, resulting in elevating cytosolic Ca2+ and activating protein kinase C. SR48692 is an NTSR1 antagonist, which inhibits lung cancer proliferation. RTKs and GPCRs can act independently to alter cancer growth; however, NTSR1 regulates the tyrosine phosphorylation of RTKs such as the EGFR. RTKs and GPCRs interact to increase cancer proliferation. The ErbB RTKs (EGFR, HER2, HER3, and HER4) have been well-studied in cancer. EGFR, HER2, and HER3 stimulate cancer proliferation, principally by activating the phosphatidylinositol-3-kinase and extracellular signal-regulated kinase (ERK) pathways, resulting in increased cancer cell survival and proliferation. Cancer cells have high densities of the EGFR, HER2, and HER3 causing phosphorylation of tyrosine amino acids on protein substrates and tyrosine amino acids near the C-terminal of the RTKs. After transforming growth factor (TGF) α binds to the EGFR, homodimers or EGFR heterodimers form. HER2 forms heterodimers with the EGFR, HER3, and HER4. The EGFR, HER2, and HER3 are overexpressed in lung cancer patient tumors, and monoclonal antibodies (mAbs), such as Herceptin against HER2, are used to treat breast cancer patients. Patients with EGFR mutations are treated with tyrosine kinase inhibitors, such as gefitinib or osimertinib. Peptide GPCRs, such as NTSR1, are present in many cancers, and neurotensin (NTS) stimulates the growth of cancer cells. Lung cancer proliferation is impaired by SR48692, an NTSR1 antagonist. SR48692 is synergistic with gefitinib at inhibiting lung cancer growth. Adding NTS to lung cancer cells increases the shedding of TGFα, which activates the EGFR, or neuregulin-1, which activates HER3. The transactivation process is impaired by SRC, matrix metalloprotease, and reactive oxygen species inhibitors. While the transactivation process is complicated, it is fast and occurs within minutes after adding NTS to cancer cells. This review emphasizes the use of tyrosine kinase inhibitors and SR48692 to impair transactivation and cancer growth. [ABSTRACT FROM AUTHOR]
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- 2023
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18. Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma
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D’Costa, Ninadh M, Lowerison, Matthew R, Raven, Peter A, Tan, Zheng, Roberts, Morgan E, Shrestha, Raunak, Urban, Matthew W, Monjaras-Avila, Cesar U, Oo, Htoo Zarni, Hurtado-Coll, Antonio, Chavez-Munoz, Claudia, and So, Alan I
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Antimicrobial Resistance ,Cancer ,Rare Diseases ,Kidney Disease ,ATP Binding Cassette Transporter ,Subfamily B ,Animals ,Antineoplastic Agents ,Carcinoma ,Renal Cell ,Cell Line ,Tumor ,Disease Models ,Animal ,Drug Resistance ,Neoplasm ,Female ,Humans ,Immunohistochemistry ,Kidney Neoplasms ,Male ,Mice ,Models ,Biological ,Neoplasm Metastasis ,Neoplasm Staging ,Phenotype ,Sunitinib ,Treatment Outcome ,Xenograft Model Antitumor Assays ,Y-Box-Binding Protein 1 ,Angiogenesis ,Metastasis ,Renal cell carcinoma ,Resistance ,Tyrosine kinase inhibitors ,Oncology and carcinogenesis - Abstract
BACKGROUND:Renal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Unfortunately, TKI resistance eventually develops, and the underlying molecular mechanism is not well understood. METHODS:RCC cell-line with metastatic clear-cell histology (Caki-1), and patient samples were analysed to identify the role of Y-box binding protein 1 (YB-1) and ATP-binding cassette sub-family B member 1 (ABCB-1) in acquired sunitinib-resistance development. Caki-1 was conditioned with increasing sunitinib doses to recapitulate acquired resistance development in clinics. Sunitinib-conditioned and wild-type Caki-1 were subjected to cell viability assay, scratch assay, chicken embryo chorioallantoic membrane engraftment and proteomics analysis. Classical biochemical assays like flow cytometry, immunofluorescent staining, immunohistochemical staining, optical coherence tomography imaging, Western Blot and RT-PCR assays were applied to determine the possible mechanism of sunitinib-resistance development and the effect of drug treatments. Publicly available data was also used to determine the role of YB-1 upregulation in ccRCC and the patients' overall survival. RESULTS:We demonstrate that YB-1 and ABCB-1 are upregulated in sunitinib-resistant in vitro, ex vivo, in vivo and patient samples compared to the sensitive samples. This provides evidence to a mechanism of acquired sunitinib-resistance development in mccRCC. Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models. CONCLUSION:This work proposes a targeted therapy (elacridar and sunitinib) to re-sensitize sunitinib-resistant mccRCC and, possibly, slow disease progression.
- Published
- 2020
19. EML4‐ALK biology and drug resistance in non‐small cell lung cancer: a new phase of discoveries.
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Elshatlawy, Mariam, Sampson, Josephina, Clarke, Katy, and Bayliss, Richard
- Abstract
Anaplastic lymphoma kinase (ALK) can be driven to oncogenic activity by different types of mutational events such as point‐mutations, for example F1174L in neuroblastoma, and gene fusions, for example with echinoderm microtubule‐associated protein‐like 4 (EML4) in non‐small cell lung cancer (NSCLC). EML4‐ALK variants result from different breakpoints, generating fusions of different sizes and properties. The most common variants (Variant 1 and Variant 3) form cellular compartments with distinct physical properties. The presence of a partial, probably misfolded beta‐propeller domain in variant 1 confers solid‐like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs). These differences translate to the clinic because variant 3, on average, worsens patient prognosis and increases metastatic risk. Latest generation ALK‐TKIs are beneficial for most patients with EML4‐ALK fusions. However, resistance to ALK inhibitors can occur via point‐mutations within the kinase domain of the EML4‐ALK fusion, for example G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4‐ALK variants, their impact on treatment response, ALK‐TKI drug resistance mechanisms and potential combination therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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20. Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer.
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Viganò, Mauro, La Milia, Marta, Grassini, Maria Vittoria, Pugliese, Nicola, De Giorgio, Massimo, and Fagiuoli, Stefano
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HEPATOTOXICOLOGY , *SMALL molecules , *PROTEIN kinase inhibitors , *RISK assessment , *CANCER patients , *LIVER diseases , *PROTEIN-tyrosine kinase inhibitors , *TUMORS , *AMINOTRANSFERASES , *LIVER failure , *SUNITINIB ,RISK factors - Abstract
Simple Summary: This review reports the risk and management of the hepatotoxicity of all the approved protein kinase inhibitors (PKIs) for cancer. Hepatotoxicity is one of the major safety concerns of these drugs, as reflected by the discontinuation of the development of some of them due to liver injury, or by the significant number of warnings for hepatotoxicity reported in drug labeling. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing these drugs should be carefully pre-evaluated and monitored during treatment. Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs. [ABSTRACT FROM AUTHOR]
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- 2023
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21. REGULATION OF CELL PROLIFERATION BY TYROSINE PROTEINKINASES RECEPTORS AND THEIR ROLE IN TRIGGERING DIFFERENT TYPES OF CANCERS.
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T., Ceban and E., Simionică
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CELL proliferation ,CELLULAR control mechanisms ,EPHRIN receptors ,TYROSINE ,PHOSPHATES ,CANCER patients ,CHROMOSOMES ,GAIN-of-function mutations ,ADENOSINE triphosphate ,PROTEIN-tyrosine kinase inhibitors ,PROTEIN-tyrosine kinases ,GENE amplification - Abstract
Receptor tyrosine proteinkinases (RTKs) are transmembrane proteins that possess kinase activity catalyzing the transfer of phosphate groups from ATP to tyrosine residues in protein substrates. RTKs play an important role in the control of most fundamental cellular processes such as proliferation, differentiation, cell metabolism and survival, cell migration and cell cycle control. Tyrosine proteinkinase receptors comprise 58 different types in humans that are classified into 20 families according to structure and ligand. Mutations in RTKs and aberrant activation of their intracellular signalling pathways lead to the triggering of different types of cancers. In human cancers, four fundamental mechanisms have been found to lead to constitutive activation of RTKs: genomic amplification, gain-of-function mutations, chromosomal rearrangements and autocrine activation. Thus, aberrant activation of receptor tyrosine protein kinase is a potential therapeutic target. In recent decades, several drugs, such as tyrosine kinase inhibitors, have been developed and clinically evaluated to improve the survival of cancer patients. [ABSTRACT FROM AUTHOR]
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- 2023
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22. Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging.
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Rodríguez-Agustín, Andrea, Casanova, Víctor, Grau-Expósito, Judith, Sánchez-Palomino, Sonsoles, Alcamí, José, and Climent, Núria
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- *
PROTEIN-tyrosine kinase inhibitors , *HIV infections , *DASATINIB , *CHRONIC myeloid leukemia , *TERMINATION of treatment - Abstract
Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. Several studies reported that dasatinib expanded memory-like natural killer (NK) cells and γδ T cells that have been related with increased control of CML after treatment withdrawal. In the HIV infection setting, these innate cells are associated with virus control and protection, suggesting that dasatinib could have a potential role in improving both the CML and HIV outcomes. Moreover, dasatinib could also directly induce apoptosis of senescence cells, being a new potential senolytic drug. Here, we review in depth the current knowledge of virological and immunogenetic factors associated with the development of powerful cytotoxic responses associated with this drug. Besides, we will discuss the potential therapeutic role against CML, HIV infection and aging. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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23. What Is the Significance of Lysosomal-Mediated Resistance to Imatinib?
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Mlejnek, Petr
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NILOTINIB , *DRUG accessibility , *IMATINIB , *CHRONIC myeloid leukemia , *GASTROINTESTINAL stromal tumors , *DRUG bioavailability - Abstract
The lysosomal sequestration of hydrophobic weak-base anticancer drugs is one proposed mechanism for the reduced availability of these drugs at target sites, resulting in a marked decrease in cytotoxicity and consequent resistance. While this subject is receiving increasing emphasis, it is so far only in laboratory experiments. Imatinib is a targeted anticancer drug used to treat chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GISTs), and a number of other malignancies. Its physicochemical properties make it a typical hydrophobic weak-base drug that accumulates in the lysosomes of tumour cells. Further laboratory studies suggest that this might significantly reduce its antitumor efficacy. However, a detailed analysis of published laboratory studies shows that lysosomal accumulation cannot be considered a clearly proven mechanism of resistance to imatinib. Second, more than 20 years of clinical experience with imatinib has revealed a number of resistance mechanisms, none of which is related to its accumulation in lysosomes. This review focuses on the analysis of salient evidence and raises a fundamental question about the significance of lysosomal sequestration of weak-base drugs in general as a possible resistance mechanism both in clinical and laboratory settings. [ABSTRACT FROM AUTHOR]
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- 2023
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24. The History and Development of HER2 Inhibitors
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Xiaohui Xia, Chen Gong, Yinan Zhang, and Huihua Xiong
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HER2 inhibitors ,cancer ,antibodies ,tyrosine kinase inhibitors ,antibody-drug conjugates ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
HER2 is highly expressed in a variety of malignant tumors and affects the prognosis of patients, making it a highly sensitive target for cancer therapy. Since the approval of the first HER2 inhibitor, trastuzumab, in 1998, HER2-targeted drugs have rapidly evolved. Currently, targeting HER2 drugs mainly include monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). This article reviews the development of HER2 inhibitors for various tumors over the past 20 years.
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- 2023
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25. Principles of Resistance to Targeted Cancer Therapy: Lessons from Basic and Translational Cancer Biology
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Sabnis, Amit J and Bivona, Trever G
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Biotechnology ,Genetics ,Orphan Drug ,Cancer ,Development of treatments and therapeutic interventions ,Aetiology ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Antineoplastic Agents ,Biomarkers ,Tumor ,Drug Resistance ,Neoplasm ,Humans ,Molecular Targeted Therapy ,Neoplasms ,Precision Medicine ,Protein Kinase Inhibitors ,Research ,Signal Transduction ,Translational Research ,Biomedical ,cancer ,oncogene addiction ,resistance ,tyrosine kinase inhibitors ,Biological Sciences ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Identification of the genomic drivers of cancer has led to the clinical development of targeted therapies that strike at the heart of many malignancies. Nonetheless, many cancers outsmart such precision-medicine efforts, and thus therapeutic resistance contributes significantly to cancer mortality. Attempts to understand the basis for resistance in patient samples and laboratory models has yielded two major benefits: one, more effective chemical inhibitors and rational combination therapies are now employed to prevent or circumvent resistance pathways; and two, our understanding of how oncogenic mutations drive cancer cell survival and oncogene addiction is deeper and broader, highlighting downstream or parallel cellular programs that shape these phenotypes. This review discusses emerging principles of resistance to therapies targeted against key oncogenic drivers.
- Published
- 2019
26. A prospective analysis of symptom burden for patients with chronic myeloid leukemia in chronic phase treated with frontline second‐ and third‐generation tyrosine kinase inhibitors
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Zulbaran‐Rojas, Alejandro, Lin, Huei‐Kan, Shi, Qiuling, Williams, Loretta A, George, Binsah, Garcia‐Manero, Guillermo, Jabbour, Elias, O’Brien, Susan, Ravandi, Farhad, Wierda, William, Estrov, Zeev, Borthakur, Gautam, Kadia, Tapan, Cleeland, Charles, Cortes, Jorge E, and Kantarjian, Hagop
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Hematology ,Rare Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Dasatinib ,Female ,Humans ,Imidazoles ,Leukemia ,Myeloid ,Chronic-Phase ,Male ,Middle Aged ,Protein Kinase Inhibitors ,Pyridazines ,Pyrimidines ,Quality of Life ,Symptom Assessment ,Young Adult ,BCR-ABL ,chronic myeloid leukemia ,symptom burden ,tyrosine kinase inhibitors ,Biochemistry and Cell Biology ,Oncology and Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundTreatment with tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) is effective but needs to continue for several years, possibly indefinitely. Although generally safe, TKI may have hitherto poorly recognized effects in the quality of life (QoL) of such patients.MethodsWe prospectively measured the symptom burden of patients with chronic phase CML enrolled on frontline TKI trials with dasatinib, nilotinib, or ponatinib. A total of 219 patients were enrolled and filled out the MD Anderson Symptom Inventory (MDASI)-CML questionnaire before the start of therapy and during follow-up at defined time points of 3, 6, 9, 12, 18, and 24 months.ResultsThe median age was 50 years. Longitudinal analysis showed relatively stable symptom severity scores over time. Fatigue was the most common symptom in all three cohorts, both prior to the start of therapy and during therapy, including after achievement of deep molecular remission. Work was the most affected component of daily living. Overall patients tolerated therapy well with improvement of their symptoms from baseline, with few dose reductions related to toxicity or symptomatology. Although 31% of the patients who completed MDASI-CML achieved complete molecular remission by 24 months of treatment, nearly 90% experienced persistent mild symptoms.ConclusionSide effects related to TKIs may impact the quality of life in patients with CML-CP. Further studies should investigate factors (comorbidities, concomitant medications, dose and schedule, etc) associated with these symptoms and interventions that may improve the patients' QoL, including treatment discontinuation when safely feasible.
- Published
- 2018
27. Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7
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Qing Liu, Suyao Li, Yuran Qiu, Jiayu Zhang, Francisco J. Rios, Zhiguo Zou, and Rhian M. Touyz
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receptor tyrosine kinase ,TRPM7 ,cardiovascular toxicities ,cancer ,tyrosine kinase inhibitors ,magnesium ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Receptor tyrosine kinases (RTKs) are a class of membrane spanning cell-surface receptors that transmit extracellular signals through the membrane to trigger diverse intracellular signaling through tyrosine kinases (TKs), and play important role in cancer development. Therapeutic approaches targeting RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and TKs, such as c-Src, ABL, JAK, are widely used to treat human cancers. Despite favorable benefits in cancer treatment that prolong survival, these tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting RTKs are also accompanied by adverse effects, including cardiovascular toxicity. Mechanisms underlying TKI-induced cardiovascular toxicity remain unclear. The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme consisting of a membrane-based ion channel and intracellular α-kinase. TRPM7 is a cation channel that regulates transmembrane Mg2+ and Ca2+ and is involved in a variety of (patho)physiological processes in the cardiovascular system, contributing to hypertension, cardiac fibrosis, inflammation, and atrial arrhythmias. Of importance, we and others demonstrated significant cross-talk between TRPM7, RTKs, and TK signaling in different cell types including vascular smooth muscle cells (VSMCs), which might be a link between TKIs and their cardiovascular effects. In this review, we summarize the implications of RTK inhibitors (RTKIs) and TKIs in cardiovascular toxicities during anti-cancer treatment, with a focus on the potential role of TRPM7/Mg2+ as a mediator of RTKI/TKI-induced cardiovascular toxicity. We also describe the important role of TRPM7 in cancer development and cardiovascular diseases, and the interaction between TRPM7 and RTKs, providing insights for possible mechanisms underlying cardiovascular disease in cancer patients treated with RTKI/TKIs.
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- 2023
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28. Effect of Concomitant Proton Pump Inhibitors with Pazopanib on Cancer Patients: A Retrospective Analysis.
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Moreau-Bachelard, Camille, Letailleur, Valentin, Bompas, Emmanuelle, Soulié, Patrick, Paul, Julie, and Raoul, Jean-Luc
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- *
DRUG efficacy , *COMBINATION drug therapy , *CONFIDENCE intervals , *HEMOGLOBINS , *MULTIVARIATE analysis , *RETROSPECTIVE studies , *PROTON pump inhibitors , *CANCER patients , *PROTEIN-tyrosine kinase inhibitors , *TREATMENT effectiveness , *SURVIVAL analysis (Biometry) , *TUMORS , *DRUG side effects , *PATIENT safety , *LONGITUDINAL method - Abstract
Simple Summary: Accumulated evidence shows that co-prescribing proton pump inhibitors (PPIs) with major anticancer drugs is frequently harmful. We conducted a retrospective analysis of cancer patients treated with pazopanib in our health center. In this cohort of 147 patients, both the efficacy and the toxicity of pazopanib decreased in patients taking concomitant PPIs. The absorption of pazopanib depends on gastric pH. PPIs are frequently prescribed for cancer patients to modify gastric acidity, decreasing pazopanib absorption. The aim of our study was, retrospectively, to investigate the impact of PPIs on the clinical efficacy and safety of pazopanib in a cohort of patients treated in our health center. Of the 147 patients who were included retrospectively, 79 (54%) did not take PPIs concomitantly with pazopanib (cohort 1), while 68 (46%) patients did take PPIs concomitantly with pazopanib (cohort 2). The efficacy parameters were lower in patients taking pazopanib and PPIs: the i/tumor response was statistically different between the two cohorts (p = 0.008), in particular, with 19% vs. 3% of the objective response and 24% vs. 43% of progression in cohorts 1 and 2, respectively; ii/median overall survival was 17.6 (95% CI: 12.5–32.8) months in cohort 1 and 8.6 months (95% CI: 5.9–18.6) in cohort 2 (HR = 1.7 [95% CI: 1.2–2.5]; p < 0.006); on multivariable analysis, overall survival was associated with performance status, PPI intake, tumor location, hemoglobin, and PMN/lymphocyte ratio. In contrast, the dose reduction for toxicity and severe adverse events were (non-significantly) less frequent in cohort 1. To conclude, our study shows that combining PPIs with pazopanib has an adverse effect on overall survival. The clinical modifications that were observed are in line with a decrease in pazopanib absorption due to PPIs. This co-medication should be avoided. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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29. The Relationship between IGF Pathway and Acquired Resistance to Tyrosine Kinase Inhibitors in Cancer Therapy
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Yanjing Peng and Jinjing Tan
- Subjects
insulin-like growth factor ,tyrosine kinase inhibitors ,drug resistance ,cancer ,egfr ,her2 ,Biochemistry ,QD415-436 ,Biology (General) ,QH301-705.5 - Abstract
The tyrosine kinase signaling pathway is an important pathway for cell signal transduction, and is involved in regulating cell proliferation, cell cycle, apoptosis and other essential biological functions. Gene mutations involved in the tyrosine kinase signaling pathway often lead to the development of cancers. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) are well known receptor tyrosine kinases (RTKs), which belong to the ERBB family and have high mutation frequency in cancers. Tyrosine kinase inhibitors (TKI) targeting EGFR and HER2 have been widely used in the clinical treatment of lung and breast cancers. However, after a period of treatment, patients will inevitably develop resistance to TKI. The insulin-like growth factor (IGF) receptor family, like the ERBB receptor family, belongs to the receptor tyrosine kinase superfamily, which also conducts an important cell signal transduction function. There is an overlap between IGF signaling and EGFR signaling in biological functions and downstream signals. In this review, we summarize the current state of knowledge of how IGF signaling interacts with EGFR signaling can influence cell resistance to EGFR/HER2-TKI. We also summarize the current drugs designed for targeting IGF signaling pathways and their research progress, including clinical trials and preclinical studies. Altogether, we aimed to discuss the future therapeutic strategies and application prospects of IGF signaling pathway targeted therapy.
- Published
- 2023
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30. Small Molecules against Metastatic Tumors: Concrete Perspectives and Shattered Dreams
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Massimo Serra, Davide Rubes, Sergio Schinelli, and Mayra Paolillo
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metastasis ,cancer ,solid tumors ,small molecules ,tyrosine kinase inhibitors ,cyclin dependent kinase inhibitors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis.
- Published
- 2023
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31. Peptide G-Protein-Coupled Receptors and ErbB Receptor Tyrosine Kinases in Cancer
- Author
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Terry W. Moody, Irene Ramos-Alvarez, and Robert T. Jensen
- Subjects
G-protein-coupled receptor ,receptor tyrosine kinases ,transactivation ,tyrosine kinase inhibitors ,monoclonal antibodies ,cancer ,Biology (General) ,QH301-705.5 - Abstract
The ErbB RTKs (EGFR, HER2, HER3, and HER4) have been well-studied in cancer. EGFR, HER2, and HER3 stimulate cancer proliferation, principally by activating the phosphatidylinositol-3-kinase and extracellular signal-regulated kinase (ERK) pathways, resulting in increased cancer cell survival and proliferation. Cancer cells have high densities of the EGFR, HER2, and HER3 causing phosphorylation of tyrosine amino acids on protein substrates and tyrosine amino acids near the C-terminal of the RTKs. After transforming growth factor (TGF) α binds to the EGFR, homodimers or EGFR heterodimers form. HER2 forms heterodimers with the EGFR, HER3, and HER4. The EGFR, HER2, and HER3 are overexpressed in lung cancer patient tumors, and monoclonal antibodies (mAbs), such as Herceptin against HER2, are used to treat breast cancer patients. Patients with EGFR mutations are treated with tyrosine kinase inhibitors, such as gefitinib or osimertinib. Peptide GPCRs, such as NTSR1, are present in many cancers, and neurotensin (NTS) stimulates the growth of cancer cells. Lung cancer proliferation is impaired by SR48692, an NTSR1 antagonist. SR48692 is synergistic with gefitinib at inhibiting lung cancer growth. Adding NTS to lung cancer cells increases the shedding of TGFα, which activates the EGFR, or neuregulin-1, which activates HER3. The transactivation process is impaired by SRC, matrix metalloprotease, and reactive oxygen species inhibitors. While the transactivation process is complicated, it is fast and occurs within minutes after adding NTS to cancer cells. This review emphasizes the use of tyrosine kinase inhibitors and SR48692 to impair transactivation and cancer growth.
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- 2023
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32. Prognostic Value of the Systemic Immune-Inflammation Index in EGFR Mutation-Positive Lung Adenocarcinoma Patients Treated with Tyrosine Kinase Inhibitors.
- Author
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Marsheilla Riska, Haryati Haryati, Eko Suhartono, and Tenri Ashari Wanahari
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THERAPEUTIC use of antineoplastic agents ,ADENOCARCINOMA ,LUNG cancer ,PLATELET lymphocyte ratio ,GENETIC mutation ,SCIENTIFIC observation ,EPIDERMAL growth factor receptors ,RETROSPECTIVE studies ,ACQUISITION of data ,PROTEIN-tyrosine kinase inhibitors ,NEUTROPHIL lymphocyte ratio ,CANCER patients ,MEDICAL records ,KAPLAN-Meier estimator ,SURVIVAL analysis (Biometry) ,DESCRIPTIVE statistics ,TUMOR markers ,RECEIVER operating characteristic curves ,PROGRESSION-free survival ,BLOOD cell count ,DATA analysis software ,SMOKING ,OVERALL survival - Published
- 2022
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33. Intrinsically Fluorescent Anti-Cancer Drugs.
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Kabir, Md. Lutful, Wang, Feng, and Clayton, Andrew H. A.
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ANTINEOPLASTIC agents , *CRIZOTINIB , *REARRANGEMENTS (Chemistry) , *KINASE inhibitors , *DRUG development , *NATURAL immunity - Abstract
Simple Summary: Cancer is one of the biggest causes of death world-wide. The development of anti-cancer drugs is important in combatting this disease. As good as these drugs appear to be, they do suffer from problems such as side-effects and disease resistance. We surmise that an improved understanding of drug-target and drug non-target interactions is important in addressing these issues. Here we review the use of a spectroscopic method called fluorescence to provide this needed information on target and non-target interactions. Fortunately, some of the drugs used pre-clinically or in the clinic are intrinsically fluorescent and thus can be used as spectroscopic probes of their own environment. At present, about one-third of the total protein targets in the pharmaceutical research sector are kinase-based. While kinases have been attractive targets to combat many diseases, including cancer, selective kinase inhibition has been challenging, because of the high degree of structural homology in the active site where many kinase inhibitors bind. Despite efficacy as cancer drugs, kinase inhibitors can exhibit limited target specificity and rationalizing their target profiles in the context of precise molecular mechanisms or rearrangements is a major challenge for the field. Spectroscopic approaches such as infrared, Raman, NMR and fluorescence have the potential to provide significant insights into drug-target and drug-non-target interactions because of sensitivity to molecular environment. This review places a spotlight on the significance of fluorescence for extracting information related to structural properties, discovery of hidden conformers in solution and in target-bound state, binding properties (e.g., location of binding sites, hydrogen-bonding, hydrophobicity), kinetics as well as dynamics of kinase inhibitors. It is concluded that the information gleaned from an understanding of the intrinsic fluorescence from these classes of drugs may aid in the development of future drugs with improved side-effects and less disease resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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34. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients
- Author
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Jain, Preetesh, Kantarjian, Hagop M, Ghorab, Ahmad, Sasaki, Koji, Jabbour, Elias J, Nogueras Gonzalez, Graciela, Kanagal-Shamanna, Rashmi, Issa, Ghayas C, Garcia-Manero, Guillermo, Kc, Devendra, Dellasala, Sara, Pierce, Sherry, Konopleva, Marina, Wierda, William G, Verstovsek, Srdan, Daver, Naval G, Kadia, Tapan M, Borthakur, Gautam, O'Brien, Susan, Estrov, Zeev, Ravandi, Farhad, and Cortes, Jorge E
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Hematology ,Rare Diseases ,Cancer ,Clinical Research ,Stem Cell Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Blast Crisis ,Cohort Studies ,Female ,Humans ,Leukemia ,Myelogenous ,Chronic ,BCR-ABL Positive ,Male ,Middle Aged ,Prognosis ,Protein Kinase Inhibitors ,Protein-Tyrosine Kinases ,Risk Factors ,Survival Analysis ,Young Adult ,blast phase ,bosutinib ,chronic myeloid leukemia ,dasatinib ,imatinib ,nilotinib ,ponatinib ,tyrosine kinase inhibitors ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundOutcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era.MethodsA total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis.ResultsThe median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count
- Published
- 2017
35. Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study.
- Author
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Escudero-Ortiz, Vanesa, Domínguez-Leñero, Vanessa, Catalán-Latorre, Ana, Rebollo-Liceaga, Joseba, and Sureda, Manuel
- Subjects
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DRUG monitoring , *PROTEIN-tyrosine kinase inhibitors , *HIGH performance liquid chromatography , *SORAFENIB , *ANTINEOPLASTIC agents , *HYPOGLYCEMIC agents , *NILOTINIB - Abstract
Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. Objective: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. Materials and methods: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. Results: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure–efficacy analysis. Conclusions: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice. [ABSTRACT FROM AUTHOR]
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- 2022
- Full Text
- View/download PDF
36. Impact of imatinib treatment on renal function in chronic myeloid leukaemia patients.
- Author
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Singh, Avinash Kumar, Hussain, Salman, Ahmed, Rayaz, Agrawal, Narendra, Bhurani, Dinesh, Klugar, Miloslav, and Sharma, Manju
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CHRONIC myeloid leukemia , *IMATINIB , *KIDNEY physiology , *PROTEIN-tyrosine kinase inhibitors , *CHRONIC kidney failure - Abstract
Background: Recently, multiple epidemiological studies have linked imatinib with the alteration of renal function in chronic myeloid leukaemia (CML) patients. This meta‐analysis aimed to summarize the impact of imatinib use on renal function in CML patients. Methods: A systematic search was conducted on MEDLINE and Embase to identify articles assessing the impact of imatinib exposure on renal function in CML patients. The risk of bias was assessed using the Newcastle‐Ottawa scale (NOS). Two authors independently performed literature‐screening, risk of bias and data extraction. The risk of renal dysfunction (chronic kidney disease or acute kidney injury) among imatinib users was computed as the primary outcome of interest. The certainty of findings was assessed using the grading of recommendations assessment, development and evaluation (GRADE) criteria. Results: A total of nine articles qualified for inclusion in the systematic review, of which four articles were eligible for meta‐analysis. Based on the scoring on NOS, majority of the included studies were found to be of moderate risk of bias. Majority of the studies (n = 6) reported significantly (p <.05) decrease in estimated glomerular filtration rate (eGFR) after imatinib treatment. The risk of developing renal dysfunction (chronic kidney disease or acute kidney injury) was found to be significantly higher in imatinib users as compared to other tyrosine kinase inhibitor (TKI) users with a pooled relative risk of 2.70 (95% CI: 1.49–4.91). Sensitivity analysis also revealed a consistently high risk of renal dysfunction with imatinib use. GRADE criteria revealed low certainty of evidence. Conclusion: This meta‐analysis found an increased risk of renal dysfunction in imatinib users compared to other TKI users. SUMMARY AT A GLANCE: This meta‐analysis demonstrated that imatinib increased the risk of renal dysfunction more than other tyrosine kinase inhibitors in patients with chronic myeloid leukaemia. [ABSTRACT FROM AUTHOR]
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- 2022
- Full Text
- View/download PDF
37. Kanserde Hedefe Yönelik Tedavi: Tirozin Kinaz İnhibitörleri.
- Author
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Küpeli, Serhan
- Subjects
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PROTEIN-tyrosine kinase inhibitors , *TUMOR growth , *TREATMENT effectiveness , *TYROSINE , *EPIGENETICS , *EPIDERMAL growth factor receptors - Abstract
Cancers generally contain multiple genetic and epigenetic abnormalities, but several key genes maintain the malignant phenotype and cellular survival. Tyrosine kinases are often involved in the cellular response with growth factors, cytokines, and hormones. These molecules are responsible for tumor growth by various mechanisms. It is thought that tyrosine kinase inhibitors may have a wide range of therapeutic efficacy. Significant response rates could not be obtained in phase 1 studies with any of the agents in monotherapy, and other options are being investigated by administering high doses in short periods and combining drugs that may affect different pathways. [ABSTRACT FROM AUTHOR]
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- 2022
- Full Text
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38. Recent and Ongoing Research into Metastatic Osteosarcoma Treatments.
- Author
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Harris, Michael A. and Hawkins, Christine J.
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OSTEOSARCOMA , *METASTASIS , *SURVIVAL rate , *PROGRESSION-free survival , *DRUG efficacy - Abstract
The survival rate for metastatic osteosarcoma has not improved for several decades, since the introduction and refinement of chemotherapy as a treatment in addition to surgery. Over two thirds of metastatic osteosarcoma patients, many of whom are children or adolescents, fail to exhibit durable responses and succumb to their disease. Concerted efforts have been made to increase survival rates through identification of candidate therapies via animal studies and early phase trials of novel treatments, but unfortunately, this work has produced negligible improvements to the survival rate for metastatic osteosarcoma patients. This review summarizes data from clinical trials of metastatic osteosarcoma therapies as well as pre-clinical studies that report efficacy of novel drugs against metastatic osteosarcoma in vivo. Considerations regarding the design of animal studies and clinical trials to improve survival outcomes for metastatic osteosarcoma patients are also discussed. [ABSTRACT FROM AUTHOR]
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- 2022
- Full Text
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39. A Phase III Trial of One vs. Two Years of Maintenance Olaparib, With or Without Bevacizumab, in Patients With BRCA1/2 Mutated or Homologous Recombination Deficient (HRD+) Ovarian Cancer Following Response to First Line Platinum Based Chemotherapy.
- Published
- 2024
40. Research from Chiang Mai University in Breast Cancer Provides New Insights (Changes in Mitochondrial Function and Cell Death Patterns in Peripheral Blood Mononuclear Cells during Trastuzumab Treatment Following Doxorubicin Chemotherapy).
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- 2024
41. Reports from Memorial Sloan-Kettering Cancer Center Highlight Recent Findings in Ovarian Cancer (Secondary Cytoreductive Surgery and Oncologic Outcomes In the Era of Targeted Maintenance Therapy for Recurrent, Platinum-sensitive Ovarian Cancer).
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- 2024
42. Studies from Aichi Cancer Center Hospital Yield New Data on Colon Cancer (PRABITAS study design: a pragmatic, randomized phase III trial of bi-weekly versus conventional trifluridine/tipiracil plus bevacizumab for metastatic colorectal cancer).
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- 2024
43. Findings from Nehru Hospital in the Area of Chronic Myeloid Leukemia Described (Prognostic Significance of Regulatory T-cells and Pd-1+cd8 T-cells In Chronic Myeloid Leukemia Patients Treated With Generic Imatinib).
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- 2024
44. Research from Shaoxing People's Hospital Has Provided New Data on Glioblastomas (The efficacy of stereotactic radiotherapy followed by bevacizumab and temozolomide in the treatment of recurrent glioblastoma: a case report).
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- 2024
45. Researcher from Soonchunhyang University Bucheon Hospital Publishes Findings in Ulcerative Colitis (Atezolizumab-Induced Ulcerative Colitis in Patient with Hepatocellular Carcinoma: Case Report and Literature Review).
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- 2024
46. "Inhalable Rapamycin Formulation For Treating Age-Related Conditions" in Patent Application Approval Process (USPTO 20240285524).
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- 2024
47. Findings in Liver Cancer Reported from Zhejiang University School of Medicine (CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis).
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- 2024
48. Research from Houston Methodist Hospital Provides New Data on Liver Cancer (The Impact of Infections in Patients Treated with Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma).
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- 2024
49. Phase I/II Clinical Study of the Combination of Disitamab Vedotin and Trastuzumab in the Treatment of HER2 Positive Gastric/Gastroesophageal Junction Tumors With Previous Systemic Therapy Failure.
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- 2024
50. Recep Tayyip Erdogan University Researcher Publishes New Study Findings on Breast Cancer (PAI1 Regulates Cell Morphology and Migration Markers in Trastuzumab-Resistant HER2-Positive Breast Cancer Cells).
- Published
- 2024
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