scholarly journals Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors

2021 ◽  
Vol 22 (2) ◽  
pp. 635
Author(s):  
Mathias Elsocht ◽  
Philippe Giron ◽  
Laila Maes ◽  
Wim Versées ◽  
Gustavo J. Gutierrez ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Halogen Bond ◽  
Phenyl Group ◽  
Advanced Lung Cancer ◽  
Titration Calorimetry ◽  
Egfr Inhibition ◽  
Egfr Mutant ◽  
Sar Study

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4’ of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.

Strategies for Overcoming Acquired Resistance to Epidermal Growth Factor Receptor–Targeted Therapies in Lung Cancer

2012 ◽  
Vol 136 (10) ◽  
pp. 1205-1209 ◽  
Author(s):  
Geoffrey R. Oxnard
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Targeted Therapies ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Egfr Inhibition ◽  
Epidermal Growth ◽  
Egfr Mutant

Acquired resistance to targeted therapy in epidermal growth factor receptor (EGFR)–mutant lung cancer represents a valuable model for considering strategies of overcoming different types of cellular resistance mechanisms. Using existing data on resistance in EGFR-mutant lung cancer, this review will discuss 3 basic approaches for overcoming resistance to EGFR-targeted therapies: intensification of EGFR inhibition, combination of EGFR inhibitors with other targeted therapies, and changing to anticancer therapies acting via alternate pathways.

Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer.

1998 ◽  
Vol 16 (6) ◽  
pp. 2150-2156 ◽  
Author(s):  
S Wojtowicz-Praga ◽  
J Torri ◽  
M Johnson ◽  
V Steen ◽  
J Marshall ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Plasma Concentrations ◽  
Study Drug ◽  
Advanced Lung Cancer ◽  
Pharmacokinetic Analysis ◽  
Antiinflammatory Drugs ◽  
Concurrent Administration ◽  
Inflammatory Polyarthritis

PURPOSE This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.

scholarly journals Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: from bed to bench

2020 ◽  
Vol 12 ◽  
pp. 175883592093033
Author(s):  
Rui Jin ◽  
Jing Zhao ◽  
Lexin Xia ◽  
Qin Li ◽  
Wen Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant

Targeted therapies are efficient in the context of oncogenic driver mutations. Epidermal growth factor receptor (EGFR)-mutant lung cancers represent a distinct subset of non-small-cell lung cancer (NSCLC) with marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the high response rate to EGFR TKIs in EGFR-mutant lung cancer, resistance and tumor recurrence are unavoidable. Therapeutic options are restricted in patients after exhaustion of targeted therapies. Immune checkpoint inhibitors (ICIs) represent a novel therapeutic option for advanced NSCLC with significant overall survival benefit in registration trials. No superiority in terms of long-term survival was observed in the EGFR mutation subgroup when ICIs were given as monotherapy in second-line treatment in earlier studies. Thus, the appropriate application of ICIs to patients harboring EGFR mutations remains an important field of ongoing research. Here, we discuss different immune checkpoint blockade strategies, including ICIs alone and in combination with TKIs, chemotherapy, radiation, and antiangiogenic agents in EGFR-mutant NSCLC as first-line and subsequent treatments. We also summarize the evidence concerning the heterogeneous molecular features and immune signatures of EGFR mutations and their associations with ICI therapy outcomes. This study was performed to improve our understanding of the optimal mode of immune-based treatment approaches in EGFR-mutant NSCLC.

scholarly journals Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhimin Zhang ◽  
Xiaojuan Lian ◽  
Wei Xie ◽  
Jin Quan ◽  
Maojun Liao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Advanced Lung Cancer ◽  
Tki Resistance ◽  
Geo Dataset ◽  
Epidermal Growth

AbstractResistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.

Delay of chemotherapy through use of post-progression erlotinib in patients with EGFR-mutant lung cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7547-7547 ◽  
Author(s):  
Geoffrey R. Oxnard ◽  
Peter Lo ◽  
David Michael Jackman ◽  
Mohit Butaney ◽  
Stephanie Heon ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Lung Cancer ◽  
Systemic Therapy ◽  
Acquired Resistance ◽  
Local Treatment ◽  
Treatment Modalities ◽  
Advanced Lung Cancer ◽  
Egfr Mutant ◽  
Exon 19

7547 Background: 1st-line tyrosine kinase inhibitor (TKI) therapy for patients (pts) with EGFR-mutant lung cancer prolongs progression free survival (PFS) and improves quality of life. When pts develop acquired resistance to TKI, chemotherapy is the only approved systemic treatment. Anecdotal evidence suggests that change of therapy can be delayed in some pts through continued TKI beyond progression (PD), but the effectiveness of this approach has not been quantified. Methods: Through an IRB-approved mechanism, pts with advanced lung cancer and EGFR sensitizing mutations treated on 3 prospective trials of 1st-line erlotinib were identified. Only pts with RECIST PD while on erlotinib were studied. Time from PD until use of an alternate systemic therapy (or death) and characteristics at PD (development of new extra-thoracic metastases or cancer-related symptoms) were assessed. Results: 42 eligible pts were identified with the following characteristics: median age 70, 86% female, 93% non-Asian, 50% never-smokers, 83% adenocarcinoma, 100% EGFR-mutant (55% exon 19, 36% exon 21, 9% exon 18). Median PFS on erlotinib was 13 months. After PD, alternate systemic therapy was delayed >3 months in 19 pts (45%; 95%CI: 31%-60%), through a combination of post-PD erlotinib (16 pts), radiation (6 pts), and/or surgery (3 pts), or on observation alone (2 pts). These 19 pts commonly had exon 19 deletions and were more likely to have no cancer-related symptoms at PD (Table), and had a median post-PD survival of 29 months. Alternate systemic therapy was delayed >12 months in 8 pts (19%). Conclusions: In a subset of pts with EGFR-mutant lung cancer and acquired resistance to TKI, chemotherapy can be delayed with the aid of post-PD TKI and local treatment modalities. This indolent PD is likely due to ongoing tumor EGFR dependence. In pts who are tolerating TKI and have asymptomatic progression, we recommend this palliative treatment strategy as an option for delaying chemotherapy and maximizing quality of life. [Table: see text]

scholarly journals Personalized drug testing in a patient with non-small-cell lung cancer using cultured cancer cells from pleural effusion

2020 ◽  
Vol 48 (9) ◽  
pp. 030006052095505
Author(s):  
Ming Wu ◽  
Guodai Hong ◽  
Yu Chen ◽  
Lina Ye ◽  
Kang Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Pleural Effusion ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Drug Testing ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung

Objective Patients with non-small-cell lung cancer (NSCLC) and primary or acquired resistance do not respond to targeted drugs. We explored whether cancer cells can be cultured from liquid biopsies from patients with primary resistance to tyrosine kinase inhibitors (TKIs). We aimed to predict patients’ responses to drugs according to in vitro drug testing results. Methods Cancer cell cultures were established from the pleural effusion of a patient with TKI-resistant NSCLC using a conditional reprogramming technique. Phenotypic drug sensitivity tests were performed using the Cell Counting Kit-8 assay. We tested individual drugs and compared the synergistic and inhibitory effects of drug combinations. Results The results of our in vitro sensitivity test using the combination of cisplatin and pemetrexed were correlated with the patient’s response. Conclusion This represents the first successful report of predictive testing for combination therapy in patients with epidermal growth factor receptor-mutant NSCLC and primary TKI resistance. This strategy should be applicable to both chemotherapies and targeted therapies, and it will significantly improve the clinical treatment and management of patients with NSCLC and primary or acquired resistance to targeted therapies, as well as patients lacking targetable mutations.

scholarly journals Hypothesis generative head-to-head study comparing efficacy of afatinib and osimertinib based on immunological biomarkers in Japanese NSCLC patients with EGFR mutations (Heat on Beat study)

2020 ◽  
Vol 12 ◽  
pp. 175883592096725
Author(s):  
Kei Morikawa ◽  
Hisashi Tanaka ◽  
Hidetoshi Itani ◽  
Saori Takata ◽  
Satoshi Watanabe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Japanese Patients ◽  
Advanced Lung Cancer ◽  
Treatment Naïve ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82–2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients. Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients ( N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up. Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Trial registration Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221

Pilot trial of molecular profiling and targeted therapies in advanced thoracic malignancies: Non-small cell lung cancer, small cell lung cancer and thymic malignancies (CUSTOM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS7609-TPS7609
Author(s):  
Ariel Lopez-Chavez ◽  
Arun Rajan ◽  
Anish Thomas ◽  
Mark Raffeld ◽  
Liqiang Xi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Targeted Therapies ◽  
Response Rate ◽  
Molecular Profiling ◽  
Small Cell ◽  
Advanced Lung Cancer ◽  
Small Cell Lung

TPS7609 Background: For decades, clinical trial design strategies have relied upon the broad classification of tumors into tumor site and histopathology. Several lines of evidence have shown that a molecular approach to patient selection may be better in its capacity to improve patient outcomes. CUSTOM is an innovative clinical trial that allows for the parallel evaluation of multiple targeted therapies in molecularly selected patients with multiple cancer histological subtypes and the prospective evaluation of multiple molecular biomarkers. Methods: All patients with advanced lung cancer and thymic malignancies and a good performance status are eligible independently of previous lines of treatment. The trial begins with tumor biopsy and molecular profiling using a multi-platform approach to identify oncogenic alterations in more than 34 genes for treatment allocation (12 genes) and exploratory purposes. Depending upon the specific biomarker identified, patients are then triaged into 5 experimental arms. Erlotinib for sensitizing EGFR mutations; AZD6244 for KRAS, NRAS, HRAS and BRAF mutations; MK2206 for PIK3CA, AKT and PTEN mutations and PIK3CA amplification; Lapatinib for ERBB2 mutations or amplification; Sunitnib for KIT mutations and PDGFRA mutations and amplification. Patients not eligible for the experimental treatment arms are enrolled into a standard treatment arm. Upon disease progression patients are eligible for repeat biopsy and molecular profiling in order to identify molecular changes and mechanisms of resistance. All patients are followed until death. The primary endpoint is response rate and secondary endpoints include progression-free survival, duration of response and overall survival. With three disease types and five experimental drugs, there are 15 possible treatment arms which will be under active consideration. For each of these, the study will be conducted as an optimal two-stage phase II trial in order to rule out an unacceptably low 10% clinical response rate in favor of a modestly high response rate of 40%. As of January 11, 2012, two hundred and sixteen patients have been enrolled.

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