scholarly journals Abstract 4172: Radiation-induced blood-tumor barrier permeability in a preclinical model of lung cancer brain metastasis

2018 ◽  
Author(s):  
Samuel A. Sprowls ◽  
Neal Shah ◽  
Afroz S. Mohammad ◽  
Marc Pinti ◽  
Rachel M. Tallman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Preclinical Model ◽  
Barrier Permeability ◽  
Radiation Induced

scholarly journals Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Neal Shah ◽  
Zhongwei Liu ◽  
Rachel M. Tallman ◽  
Afroz Mohammad ◽  
Samuel A. Sprowls ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Brain Metastasis ◽  
Preclinical Model

scholarly journals Proteomic Reveals Reasons for Acquired Drug Resistance in Lung Cancer Derived Brain Metastasis Based on a Newly Established Multi-Organ Microfluidic Chip Model

2020 ◽  
Vol 8 ◽  
Author(s):  
Mingxin Xu ◽  
Yingyan Wang ◽  
Wenzhe Duan ◽  
Shengkai Xia ◽  
Song Wei ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Brain Metastasis ◽  
Microfluidic Chip ◽  
Kinase Inhibitors ◽  
Primary Lung Cancer ◽  
Chemotherapeutic Agents ◽  
Preclinical Model ◽  
Acquired Drug Resistance ◽  
Gsh Metabolism

Anti-tumor drugs can effectively shrink the lesions of primary lung cancer; however, it has limited therapeutic effect on patients with brain metastasis (BM). A BM preclinical model based on a multi-organ microfluidic chip has been established proficiently in our previous work. In this study, the BM subpopulation (PC9-Br) derived from the parental PC9 cell line was isolated from the chip model and found to develop obvious resistance to antineoplastic drugs including chemotherapeutic agents (cisplatin, carboplatin, pemetrexed) and tyrosine kinase inhibitors (TKIs) which target epidermal growth factor receptor (EGFR); this suggested that the acquisition of drug-resistance by brain metastatic cells was attributable to the intrinsic changes in PC9-Br. Hence, we performed proteomic and revealed a greatly altered spectrum of BM protein expression compared with primary lung cancer cells. We identified the hyperactive glutathione (GSH) metabolism pathway with the overexpression of various GSH metabolism-related enzymes (GPX4, RRM2, GCLC, GPX1, GSTM4, GSTM1). Aldehyde dehydrogenases (ALDH1A1, ALDH3A1) were also found to be upregulated in BM. What's more, loss of EGFR and phosphorylated EGFR in PC9-Br gave reasons for the TKIs resistance. Collectively, our findings indicated potential mechanisms for the acquirement of drug resistance occurred in BM, providing new strategies to overcome therapeutic resistance in lung cancer BM.

OS2 - 166 A Novel Model of Human Lung-to-Brain Metastasis and its Application to the Identification of Essential Metastatic Regulatory Genes

2016 ◽  
Vol 43 (S4) ◽  
pp. S2-S2
Author(s):  
M Singh ◽  
C Venugopal ◽  
T Tokar ◽  
K R Brown ◽  
N McFarlane ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Functional Characterization ◽  
Primary Lung Cancer ◽  
Predictive Biomarkers ◽  
Preclinical Model ◽  
Tumor Initiation ◽  
Human Patient ◽  
Pdx Model

Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.

scholarly journals Systematic Review and Network Meta-Analysis of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Treatment-Naïve ALK-Positive Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1966
Author(s):  
Cheng-Hao Chuang ◽  
Hsiao-Ling Chen ◽  
Hsiu-Mei Chang ◽  
Yu-Chen Tsai ◽  
Kuan-Li Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Anaplastic Lymphoma Kinase ◽  
Low Dose ◽  
Meta Analysis ◽  
Phase Iii ◽  
Pairwise Comparisons ◽  
Anaplastic Lymphoma ◽  
Treatment Naïve ◽  
Alk Positive

Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.

scholarly journals Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 279
Author(s):  
Tine N. Christensen ◽  
Seppo W. Langer ◽  
Gitte Persson ◽  
Klaus Richter Larsen ◽  
Annemarie G. Amtoft ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Fdg Pet ◽  
Tumor Volume ◽  
High Dose ◽  
Flt Pet ◽  
Pet Ct ◽  
Radiation Induced ◽  
Fdg Pet Ct ◽  
Induced Changes

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-uptake. The 3′-deoxy-3′-[18F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUVmax and FLT-SUVmax were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUVmax: 12.8 vs. 4.2; p < 0.001; median FLT-SUVmax 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUVpeak (median FDG-SUVpeak: 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV50%): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV50%) was prognostic for the overall survival (hazard ratio: 1.07 pr cm3 [1.01–1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUVmax and FLT-SUVmax may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

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