Kinase Inhibitors
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2021 ◽  
Vol 11 ◽  
Author(s):  
Siran Yang ◽  
Jianping Xiao ◽  
Qingfeng Liu ◽  
Ye Zhang ◽  
Nan Bi ◽  
...  

PurposeThe high intracranial efficacy of targeted therapeutic agents poses a challenge in determining the optimal sequence of local radiation therapy (RT) and systemic treatment with tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). Therefore, we conducted a cohort study to elucidate the appropriate treatment strategy, either upfront RT or deferred RT including a toxicity assessment, in these patients.Patients and MethodsWe retrospectively evaluated patients with gene-driven BMs from a single institution and divided them into deferred and upfront RT groups. Survival was estimated using a log-rank test. Intracranial progression was estimated using Fine-Gray competing risks model. Cox proportional hazards regression was performed for multivariable analysis in the entire group and subgroups.ResultsAmong the 198 eligible patients, 94 and 104 patients received deferred and upfront RT, respectively. The upfront RT group showed a lower intracranial progression risk with an adjusted sub-distribution hazard ratios of 0.41 (95% CI, 0.30–0.57) than did the deferred RT group (median intracranial progression-free survival [iPFS], 19.9 months vs. 11.1 months; p < 0.001). The median overall survival (OS; 43.2 months vs. 49.1 months, p = 0.377) and BM-specific survival (92.1 months vs. 82.9 months, p = 0.810) after salvage therapy were not significantly different between the upfront and deferred groups. Among patients with progressed extracranial disease, the deferred RT group showed significantly better OS than did the upfront RT group (44.0 vs. 28.1 months, p = 0.022). Grade 3–4 treatment-related adverse events were rare, and similar toxicities were observed between the two groups.ConclusionCompared to the deferred RT group, the upfront RT group achieved longer iPFS and similar survival outcomes in most patients with gene-driven NSCLC BM, although patients with progression of extracranial disease might benefit from deferred RT. Both groups showed well-tolerated toxicities.Trial registration IDNCT04832672.


Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5116
Author(s):  
Takaaki Ono

With the use of tyrosine kinase inhibitors (TKIs), chronic myelogenous leukemia in chronic phase (CML-CP) has been transformed into a non-fatal chronic disease. Hence, "treatment-free remission (TFR)" has become a possible treatment goal of patients with CML-CP. Currently, four types of TKIs (imatinib, nilotinib, dasatinib, and bosutinib) are used as the first-line treatment for newly diagnosed CML-CP. However, the second-generation TKI (2GTKI), the treatment response of which is faster and deeper than that of imatinib, is not always recommended as the first-line treatment for CML-CP. Factors involved in TKI selection in the first-line treatment of CML-CP include not only patients’ medical background, but also patients’ choice regarding the desired treatment goal (survival or TFR?). Therefore, it is important that clinicians select an appropriate TKI to successfully achieve the desired treatment goal for each patient, while minimizing the development of adverse events. This review compares the pros and cons of using imatinib and 2GTKI for TKI selection as the first-line treatment for CML-CP, mainly considering treatment outcomes, medical history (i.e., desire for pregnancy, aging factor, and comorbidity), and cost. The optimal use of 2GTKIs is also discussed.


2021 ◽  
Vol 11 ◽  
Author(s):  
Lisha Mou ◽  
Xiaohe Tian ◽  
Bo Zhou ◽  
Yongqiang Zhan ◽  
Jiao Chen ◽  
...  

Targeted therapies such as oral tyrosine kinase inhibitors (TKIs) are the main therapeutic strategy effective for advanced hepatocellular carcinoma (HCC). Currently six tyrosine kinase inhibitors for HCC therapy have been approved. The newly approved first-line drug donafenib represent the major milestones in HCC therapeutics in recent years. However, drug resistance in HCC remains challenging due to random mutations in target receptors as well as downstream pathways. TKIs-based combinatorial therapies with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies afford a promising strategy to further clinical application. Recent developments of nanoparticle-based TKI delivery techniques improve drug absorption and bioavailability, enhance efficient targeting delivery, prolonged circulation time, and reduce harmful side effects on normal tissues, which may improve the therapeutic efficacy of the TKIs. In this review, we summarize the milestones and recent progress in clinical trials of TKIs for HCC therapy. We also provide an overview of the novel nanoparticle-based TKI delivery techniques that enable efficient therapy.


2021 ◽  
Vol 2 (2) ◽  
pp. 191-199
Author(s):  
Otília Menyhárt ◽  
Virag Vas ◽  
Balázs Győrffy ◽  
László Buday

Összefoglaló. A molekuláris onkológia térnyerésével számos új lehetőség érhető el a daganatos betegek hatékonyabb kezelésére. Ilyen a klinikai vizsgálatokban alkalmazott, a valóban személyre szabott kezelést elősegítő génpanelelemzés, illetve a célzott kezelés szövettípustól független alkalmazása. A személyre szabott terápiák jelentős hányada valamelyik kinázt gátolja. Az összefoglalónkban bemutatjuk a RAS jelátviteli út sejten belüli komplex szabályozását, valamint ismertetjük az útvonal további farmakológiai szempontból kiaknázható célpontjait nemzetközi és saját eredményeink alapján. A kinázokat érintő gyakori mutációk ellenére számos daganattípusban nem áll rendelkezésre személyre szabott terápia. A hagyományos terápiával nem kezelhető agydaganatok példáján keresztül bemutatjuk a tirozin-kinázok várható jövőbeli terápiás jelentőségét. Summary. With the advent of molecular oncology, the identification of mutations in solid tumours is now clinically routine. The growing repertoire of targeted therapeutic agents has supported the rise of a new type of clinical trial in which the selection of the therapeutic agent is no longer restricted to a single option. Instead, a panel of genes is screened to identify the most suitable drug for each patient. Such trials have delivered objective response rates in 5–30% of patients. Most of the signal transduction pathways targeted by these agents involves RAS signaling. Somatic mutations in RAS genes are common in human tumours. Such mutations generally decrease the ability of RAS to hydrolyze GTP, maintaining the protein in a constitutively active GTP-bound form that drives uncontrolled cell proliferation. Recent emerging data suggest that RAS regulation is more complex than the scientific community has appreciated for decades. We discuss a novel type of RAS regulation that involves direct phosphorylation and dephosphorylation of RAS tyrosine residues. The discovery that pharmacological inhibition of the tyrosine phosphoprotein phosphatase SHP2 maintains mutant Ras in an inactive state suggests that SHP2 could be a novel drug target for the treatment of Ras-driven human cancers. In addition to RAS gene mutations, other common oncogenic events have also been identified, including mutation of EGFR (epidermal growth factor receptor) or BRAF (isoform B of rapidly accelerated fibrosarcoma). EGFR has tyrosine kinase activity while BRAF acts as a serine/threonine kinase. In some tumours, mutant forms of these kinases over-activate cell proliferation, leading to uncontrolled tumour cell growth; therefore, it seems rational to develop inhibitor molecules that target these hyper-active oncogenic kinases to reduce tumour cell burden in cancer patients. Fusion protein kinases activated via the RAS pathway represent target proteins with high clinical success rates. Recently approved TRK fusion protein kinase inhibitors have reached response rates in almost 80% of patients regardless of tumour type. Although these drugs can only be administered to patients whose tumours harbour a TRK fusion protein, such success stories pave the way for future development of agents that target similar genetic mutations. Glioblastoma multiforme, a relatively frequent, almost uniformly fatal brain tumour, has ubiquitous alterations in tyrosine-kinase signalling. Nevertheless, to this day, no tyrosine-kinase inhibitors have been approved for its treatment. We have ongoing research projects to uncover associations between initial gene expression levels in untreated glioblastoma samples and treatment-related survival, and we have identified overexpression of druggable tyrosine-kinase receptors in chemotherapy-resistant patients. Our approach will help to identify patients who might benefit from concurrent use of tyrosine kinase inhibitors and conventional cytotoxic therapies.


Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1431
Author(s):  
Hyunwook Cho ◽  
Jung-Mi Hah

c-Jun N-terminal kinase (JNK) plays an important role in cell death caused by various stimuli. Because the isoform JNK3 is mainly expressed in the brain, it is believed to play a pivotal role in various neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), which still lack plausible therapeutics. To develop a novel and selective JNK3 inhibitor, we conducted a decadal review (2011 to 2021) of published articles on JNK inhibitors, particularly those focusing on a structural perspective and docking insights. We observed the structures of three isoforms of JNK, namely holo-proteins and co-crystal structures, with JNK3 inhibitors and summarized the significant structural aspects of selective JNK3 inhibitors as AD therapeutics.


Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1416
Author(s):  
I-Hsien Lee ◽  
Ching-Yao Yang ◽  
Jin-Yuan Shih ◽  
Chong-Jen Yu

Background: Respiratory failure requiring mechanical ventilation is the major reason for lung cancer patients being admitted to the intensive care unit (ICU). Though molecular targeted therapies, especially epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), have largely improved the survival of oncogene-driven lung cancer patients, few studies have focused on the performance of TKI in such settings. Materials and Methods: This was a retrospective cohort study enrolling non-small cell lung cancer (NSCLC) patients who harbored sensitizing EGFR mutation and had received EGFR-TKIs as first-line cancer therapy in the ICU with mechanical ventilator use. The primary outcome was the 28-day ICU survival rate, and secondary outcomes were the rate of successful weaning from the ventilator and overall survival. Results: A total of 35 patients were included. The 28-day ICU survival rate was 77%, and the median overall survival was 67 days. Multivariate logistic regression revealed that shock status was associated with a lower 28-day ICU survival rate independently (odds ratio (OR) 0.017, 95% confidence interval (CI), 0.000–0.629, p = 0.027), and that L858R mutation (L858R compared with exon 19 deletion, OR, 0.014, 95% CI 0.000–0.450, p = 0.016) and comorbidities of diabetes mellitus (DM) (OR, 0.032, 95% CI, 0.000–0.416, p = 0.014)) were independently predictive of weaning failure. The successful weaning rate was 43%, and the median of ventilator-dependent duration was 22 days (IQR, 12–29). Conclusion: For EGFR mutant lung cancer patients suffering from respiratory failure and undergoing mechanical ventilation, TKI may still be useful, especially in those with EGFR del19 mutation or without shock and DM comorbidity.


2021 ◽  
pp. annrheumdis-2021-221366
Author(s):  
Alessia Alunno ◽  
Aurélie Najm ◽  
Pedro M Machado ◽  
Heidi Bertheussen ◽  
Gerd-Rüdiger R Burmester ◽  
...  

ObjectivesTo update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19.MethodsAccording to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting.ResultsWe updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapyConclusionsGrowing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.


Author(s):  
Sara Malik ◽  
Shahzeb Hassan ◽  
Ahmet Emre Eşkazan

Author(s):  
He Zhu ◽  
Scott B. Ficarro ◽  
William M. Alexander ◽  
Laura E. Fleming ◽  
Guillaume Adelmant ◽  
...  

2021 ◽  
Author(s):  
Khyati Gohil ◽  
M. Zain Kazmi ◽  
Florence Williams

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.


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