Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer

Schöttle, Jakob; Chatterjee, Sampurna; Volz, Caroline; Siobal, Maike; Florin, Alexandra; Rokitta, Dennis; Hinze, Yvonne; Dietlein, Felix; Plenker, Dennis; König, Katharina; Albus, Kerstin; Heuckmann, Johannes M.; Rauh, Daniel; Franz, Thomas; Neumaier, Bernd; Fuhr, Uwe; Heukamp, Lukas C.; Ullrich, Roland T.

doi:10.18632/oncotarget.6276

Cited by 19 publications

(31 citation statements)

References 35 publications

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“…However, some studies showed Gefitinib has no benefit to chemotherapy , possibly due to incomplete inhibition of the EGFR tyrosine kinase with daily Gefitinib therapy and/or the development of resistance to chemotherapy [ 23 , 24 ]. Intermittent high-dose EGFR has shown the potential to overcome these theoretical limitations of daily dosing in several studies [ 14 , 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer

Zhang

et al. 2017

Oncotarget

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Gefitinib showed response in phase II clinical trials and with better clinical response in lung cancer with activating mutations in the tyrosine kinase domain of the EGFR. Questions of toxicity and potential dosing regimens impede the use in a prevention setting. This study will provide scientific evidence for the utility of testing and comparing weekly and daily dosing regimens in clinical trials. We employed the adenocarcinoma (AD) and squamous cell carcinoma (SCC) models to compare the efficacy of Gefitinib in daily or weekly dosing regimens. We also assessed the effectiveness of Gefitinib in altering growth of the H3255 xenograft. Bioluminescent imaging (BLI) and tumor size was evaluated. Relative expression of phospho-EGFR, phospho-ERK and phospho-AKT in the xenograft were evaluated by Western Blot analysis. In the lung AD model, Gefitinib showed significant inhibition of tumor load when treated with weekly or weekly intermittent dosing regimens in AJ/p53val135/wtmice whereas a daily dosing regimen did not decrease the tumor load significantly. In the H3255-Luciferase xenograft model, weekly treatment demonstrated better inhibition than daily treatment. The weekly dosing regimen exhibited greater inhibition of phospho-EGFR, phospho-ERK and phospho-AKT than the daily dosing regimen, which may be correlated with the antitumor effects of the different dosing regimens. Weekly dosing with Gefitinib had similar or better efficacy than the daily dosing regimen in pre-clinical models of NSCLC. The data provide scientific evidences for the utility of testing and comparing weekly and intermittent dosing regimens in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Effect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer

Zhang

et al. 2017

Oncotarget

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“…Briefly, 1.0×10 6 exponentially growing cells with ectopic expression of appropriate genes were injected subcutaneously. Tumor volume was estimated using calipers every week ((length* width^2)/2) [ 44 ], then in the sixth week after injection, animals were sacrificed. Tumor nodules were harvested and measured, then immunohistochemically stained with PCNA to assess the proliferation of cells.…”

Section: Methodsmentioning

confidence: 99%

ZYG11A serves as an oncogene in non-small cell lung cancer and influences CCNE1 expression

et al. 2016

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By analyzing The Cancer Genome Atlas (TCGA) database, we identified ZYG11A as a potential oncogene. We determined the expression of ZYG11A in NSCLC tissues and explored its clinical significance. And also evaluated the effects of ZYG11A on NSCLC cell proliferation, migration, and invasion both in vitro and in vivo. Our results show that ZYG11A is hyper-expressed in NSCLC tissues compared to adjacent normal tissues, and increased expression of ZYG11A is associated with a poor prognosis (HR: 2.489, 95%CI: 1.248-4.963, p = 0.010). ZYG11A knockdown induces cell cycle arrest and inhibits proliferation, migration, and invasion of NSCLC cells. ZYG11A knockdown also results in decreased expression of CCNE1. Over-expression of CCNE1 in cells with ZYG11A knockdown restores their oncogenic activities. Our data suggest that ZYG11A may serve as a novel oncogene promoting tumorigenicity of NSCLC cells by inducing cell cycle alterations and increasing CCNE1 expression.

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“…Schedules and dosing represent a blend of the maximally effective dose and/or maximally tolerated dose based on several experiments conducted by Charles River Discovery. Doses are in a range that reflects preclinical studies that have been seen previously in the literature [ 25 – 33 ].…”

Section: Resultsmentioning

confidence: 99%

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin

Hall

Marlow

Mathias³

et al. 2016

J Transl Med

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BackgroundPancreatic acinar cell carcinoma (PACC) is a rare malignancy, accounting for <1 % of all pancreatic neoplasms. Very few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic PACC who achieved prolonged survival following doxorubicin treatment. Personalized treatment was based on molecular and in vitro data collected from primary cells developed from their liver metastasis. We now report the characterization of a patient derived tumor xenograft (PDTX) mouse model that originated from this patient’s PACC liver metastasis.MethodsFragments of biopsy tissue (5 mm3) from PACC liver metastasis were implanted into athymic nude mice. Tumors were grown and passaged from the host mice into new mice to be tested for therapeutic response. Immuno-histochemical (IHC) biomarkers were used to confirm that the PDTX model represents human PACC. The antitumor activities of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) were tested. Tumor size was measured over 74 days or until they reached an endpoint volume of ~800 mm3. Tests to measure serum lipase levels and histological analyses of tumor tissues were also conducted to assess PACC progression and re-differentiation.ResultsThe model presented here expresses the same IHC markers found in human PACC. In the chemotherapy study, oxaliplatin produced a prolonged durable growth response associated with increased apoptosis, decreased serum lipase levels and increased healthy acinar cells. Bevacizumab also produced a significant growth response, but the effect was not prolonged as demonstrated by oxaliplatin treatment. The other chemotherapies had moderate to little effect, particularly after treatment ceased. Mutations in DNA repair genes are common in PACC and increase tumor susceptibility to oxaliplatin. To explore this we performed IHC and found no nuclear expression of BRCA2 in our model, indicating a mutation affecting nuclear localization. Gene sequencing confirms BRCA2 has a homozygous gene deletion on Exon 10, which frequently causes a protein truncation.ConclusionsIn summary, we report the development and characterization of the first and only preclinical PACC PDTX model. Here we show sustained anti-tumor activity of single agent oxaliplatin, a compound that is more effective in tumors that harbor mutations in DNA repair genes. Our data shows that BRCA2 is mutated in our PACC model, which could contribute to the oxaliplatin sensitivity observed. Further studies on this rare PACC model can serve to elucidate other novel therapies, biomarkers, and molecular mechanisms of signaling and drug resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0875-z) contains supplementary material, which is available to authorized users.

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Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer

Cited by 19 publications

References 35 publications

Effect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer

Effect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer

ZYG11A serves as an oncogene in non-small cell lung cancer and influences CCNE1 expression

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin

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