scholarly journals Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet?

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3077
Author(s):  
Shayan Khalafi ◽  
Albert Craig Lockhart ◽  
Alan S. Livingstone ◽  
Wael El-Rifai
Keyword(s):  
Growth Factor ◽  
Esophageal Adenocarcinoma ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Western World ◽  
Term Survival ◽  
Recent Advances

Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.

scholarly journals High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 624
Author(s):  
Miriam Sartages ◽  
Ebel Floridia ◽  
Mar García-Colomer ◽  
Cristina Iglesias ◽  
Manuel Macía ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Vascular Malformations ◽  
Mrna Level ◽  
Growth Factor Receptor ◽  
Surgical Removal ◽  
Cavernous Malformations ◽  
Cellular Effects

Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically.

scholarly journals Receptor Tyrosine Kinases as Druggable Targets in Glioblastoma: Do Signaling Pathways Matter?

2021 ◽  
Author(s):  
Anna Qin ◽  
Anna Musket ◽  
Phillip R Musich ◽  
John B Schweitzer ◽  
Qian Xie
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Neutralizing Antibodies ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Clinical Phase

Abstract Glioblastoma (GBM) is the most malignant primary brain tumor without effective therapies. Since bevacizumab was FDA approved for targeting vascular endothelial growth factor receptor 2 (VEGFR2) in adult patients with recurrent GBM, targeted therapy against receptor tyrosine kinases (RTKs) has become a new avenue for GBM therapeutics. In addition to VEGFR, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) are major RTK targets. However, results from clinical Phase II/III trials indicate that most RTK-targeting therapeutics including tyrosine kinase inhibitors (TKIs) and neutralizing antibodies lack clinical efficacy, either alone or in combination. The major challenge is to uncover the genetic RTK alterations driving GBM initiation and progression, as well as to elucidate the mechanisms toward therapeutic resistance. In this review, we will discuss the genetic alterations in these five commonly targeted RTKs, the clinical trial outcomes of the associated RTK-targeting therapeutics, and the potential mechanisms toward the resistance. We anticipate that future design of new clinical trials with combination strategies, based on the genetic alterations within an individual patient’s tumor and mechanisms contributing to therapeutic resistance after treatment, will achieve durable remissions and improve outcomes in GBM patients

scholarly journals Evolving Management Strategies for Metastatic Esophageal and Gastroesophageal Junction Adenocarcinoma

2018 ◽  
Vol 14 (2) ◽  
pp. 82
Author(s):  
Satya Das ◽  
Michael K Gibson ◽  
◽  
Keyword(s):  
Growth Factor ◽  
Esophageal Adenocarcinoma ◽  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Management Strategies ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Biologic Agents ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Area Of Interest

Metastatic or unresectable esophageal and gastroesophageal junction adenocarcinoma represent a devastating disease with 5-year survival rate of <5%. Although cytotoxic chemotherapy with platinum doublet based regimens is initially effective, patients inevitably progress. Patients often decline rapidly after this initial progression, making later lines of therapy a challenge to successfully administer. There have been multiple efforts to incorporate biologic agents, targeting pathways known to be dysregulated in esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, into existing chemotherapy backbones. Other than therapeutics targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor receptor (VEGFR), other strategies have failed. Given the mixed success of biologic agents, along with the promise of immunotherapy to generate durable and sometimes complete responses, immune-agent based trials are a major area of interest for patients with this disease. Checkpoint inhibitors blocking programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated modest single-agent efficacy in patients with progressive esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma. However, other approaches such as novel checkpoint combinations, vaccine-based approaches and autologous T cells hold more promise to change the trajectory of disease.

Pharmacologic Evidence of Green Tea in Targeting Tyrosine Kinases

2020 ◽  
Vol 15 ◽  
Author(s):  
Joyce T.S. Li ◽  
Kam L. Hon ◽  
Alexander K.C. Leung ◽  
Vivian W.Y. Lee
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Green Tea ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Growth Factor Receptor ◽  
Green Tea Extract ◽  
Potential Health ◽  
Tea Extract

Background: Green tea has been extensively studied for its potential health benefits against diseases, such as cancers, cognitive degenerative diseases, and cardiovascular diseases. Methods: The authors undertook a structured search of peer-reviewed research articles from three databases including PubMed, Embase, and Ovid MEDLINE. Recent and up-to-date studies relevant to the topic were included. Results: Green tea extract exerts its functions through interacting with multiple signalling pathways in human cells. Protein tyrosine kinase is one of the examples. Abnormal activation of tyrosine kinase is observed in some tumour cells. Green tea extract inhibits phosphorylation, reduces expression, or attenuates downstream signalling of epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor, and non-receptor tyrosine kinase. Combination of green tea extract with tyrosine kinase inhibitors may provide synergistic effects by overcoming acquired resistance. Conclusion: Green tea extract can affect multiple receptor targets. In the current review, we discuss the pharmacological mechanisms of green tea on tyrosine kinases and their implications on common diseases.

scholarly journals Angiogenesis and Immunity in Renal Carcinoma: Can We Turn an Unhappy Relationship into a Happy Marriage?

2020 ◽  
Vol 9 (4) ◽  
pp. 930 ◽  
Author(s):  
Alessia Mennitto ◽  
Veronica Huber ◽  
Raffaele Ratta ◽  
Pierangela Sepe ◽  
Filippo de Braud ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Suppressor Cells ◽  
European Medicines Agency ◽  
Frontline Treatment ◽  
Happy Marriage ◽  
And Function

The frontline treatment options for patients with metastatic renal cell carcinoma (mRCC) are evolving rapidly since the approval of combination immunotherapies by the U.S. Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). In particular, in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) have significantly improved the outcome of patients with mRCC compared to TKI monotherapy. Here, we review the preclinical data supporting the combination of ICIs with VEGFR TKIs. The VEGF-signaling inhibition could ideally sustain immunotherapy through a positive modulation of the tumor microenvironment (TME). Antiangiogenetics, in fact, with their inhibitory activity on myelopoiesis that indirectly reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells’ (Tregs) frequency and function, could have a role in determining an effective anti-tumor immune response. These findings are relevant for the challenges posed to clinicians concerning the clinical impact on treatment strategies for mRCC.

scholarly journals Subcellular localization of several structurally different tyrosine kinase inhibitors

ADMET & DMPK ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 258-266 ◽  
Author(s):  
Richard Honeywell ◽  
Sarina Hitzerd ◽  
Ietje Kathmann ◽  
Godefridus Peters
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Similar Distribution ◽  
Lysosomal Accumulation ◽  
Vegfr Inhibitor ◽  
General Localization

Protein tyrosine kinases form an important target for a new class of anticancer drugs, the tyrosine kinase inhibitors (TKIs). Recently we demonstrated that sunitinib, an inhibitor of the membrane-associated vascular endothelial growth factor receptor (VEGFR), is trapped in lysosomes which isolates the drug from its intended target. Therefore we investigated whether this also holds for other TKIs, targeted against different protein kinases. For this purpose we used the ProteoExtractR kit, which enables a subcellular extraction separating cellular proteins into four distinct fractions covering the cytosol, membranes and membrane organelles (including lysosomes), nuclear proteins and the cytoskeleton. Since TKIs are 98-100 % protein bound we used this property to study their subcellular distribution and used Caco-2 cells as a model. As expected after 2 hours exposure sunitinib was trapped in cytosol (58 %) and organelles (42 % including lysosomes). Crizotinib, an inhibitor of ALK-EML4, showed a similar distribution. However, erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) showed a very low cellular accumulation and was limited to the organelle fraction. In contrast, the other EGFR inhibitor, gefitinib was predominantly located in the cytosolic (39 %) and membrane fraction (44 %). Sorafenib, another VEGFR inhibitor was predominantly located in the organelle fraction (85 %) and cytosol (15 %) after 2 hours, while after 24 hours distribution decreased (9.9 fold) with a slight shift. Dasatinib, an inhibitor of BCR-Abl was located only in the cytosol (100 %). In general localization after 24 hours was comparable, albeit several small changes were seen. In conclusion protein fractionation with the ProteoExtractR Subcellular Proteome Extraction kit demonstrated large differences in TKI levels in various cellular organelles, with a pattern in agreement with lysosomal accumulation of sunitinib.

scholarly journals Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5799
Author(s):  
Paula Aldaz ◽  
Imanol Arozarena
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Medical Community ◽  
Molecular Events

Glioblastoma (GBM) is the most common and lethal form of malignant brain tumor. GBM patients normally undergo surgery plus adjuvant radiotherapy followed by chemotherapy. Numerous studies into the molecular events driving GBM highlight the central role played by the Epidermal Growth Factor Receptor (EGFR), as well as the Platelet-derived Growth Factor Receptors PDGFRA and PDGFRB in tumor initiation and progression. Despite strong preclinical evidence for the therapeutic potential of tyrosine kinase inhibitors (TKIs) that target EGFR, PDGFRs, and other tyrosine kinases, clinical trials performed during the last 20 years have not led to the desired therapeutic breakthrough for GBM patients. While clinical trials are still ongoing, in the medical community there is the perception of TKIs as a lost opportunity in the fight against GBM. In this article, we review the scientific rationale for the use of TKIs targeting glioma drivers. We critically analyze the potential causes for the failure of TKIs in the treatment of GBM, and we propose alternative approaches to the clinical evaluation of TKIs in GBM patients.

scholarly journals P033 Scleroderma-like fibrotic disorder associated with a gastro-intestinal stromal tumour which responded only to imatinib

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Zaran A Butt ◽  
Wan Lin NG ◽  
Donough Howard ◽  
Kamal Osman
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Negative Symptoms ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Gastric Fundus ◽  
Stromal Tumour ◽  
Platelet Derived Growth Factor ◽  
Rapid Improvement ◽  
Metastatic Recurrence

Abstract Background/Aims  Gastro-intestinal stromal tumour (GIST) is recognised as the most prevalent mesenchymal tumour of the gastro-intestinal (GI) tract. The vast majority of GIST display activating mutations in receptor tyrosine kinases, such as platelet-derived growth factor receptor alpha (PDGFRA) and c-kit. This characteristic has lead to the development and approval of targeted therapies such as Imatinib for metastatic GIST. Scleroderma is an idiopathic fibrotic syndrome which involves excess collagen deposition in multiple tissues and organs. There is emerging evidence that dysfunctional fibroblasts are central to the underlying pathogenesis of this disease. An increasing awareness of the complex interplay of these fibroblasts with other cells and inflammatory mediators, such as platelet-derived growth factor (PDGF), is being recognised. This novel case serves to further develop our understanding of these pathological interactions, and to highlight a prospective role for Imatinib in disrupting them. Methods  We present a case report below. Results  A 54-year-old Caucasian male was referred to our rheumatology clinic due to worsening Raynaud's syndrome, arthralgia, and dry cough. He subsequently developed weight loss, pyrosis and skin thickening. This clinical picture was suggestive of a new diagnosis of systemic sclerosis. However, fibrotic skin changes did not extend to the distal finger, and anti-nuclear antibody (ANA) was negative. Symptoms were also refractory to various vasodilator and immunosuppressive therapies, including nifedipine, repeated iloprost infusions, azathioprine, mycophenolic acid, prednisolone, and sildenafil. Computed tomography (CT) imaging revealed interstitial pulmonary fibrosis and a mass within the gastric fundus. Histopathologic features and immunological staining of this mass were consistent with a GIST. Resection of the tumour did not improve fibrotic symptoms. Surveillance imaging one-year later was highly concerning for metastatic recurrence, which was later confirmed with tissue biopsy. He was subsequently initiated on Imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. Conclusion  While there have been previous descriptions of para-neoplastic fibrotic syndromes, this is the first reported case of a scleroderma-mimicking disorder associated with GIST. It hints at an important potential overlap in the pathogenesis of these disease processes, and a potential role for tyrosine-kinase inhibitors in the treatment of scleroderma-like fibrotic disorders. Disclosure  Z.A. Butt: None. W. Ng: None. D. Howard: None. K. Osman: None.

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