Phase II study of E7820 in combination with cetuximab in subjects (pts) with metastatic and refractory colorectal cancer (CRC).

Sawyer, M. B.; Iqbal, S.; Lenz, H.; Lima, C. S. Rocha; Rossignol, Daniel P.; Krivelevich, I.; Fan, Jia; El-Khoueiry, Anthony B.

doi:10.1200/jco.2010.28.15_suppl.3537

Cited by 9 publications

(6 citation statements)

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“…E7820 has undergone several clinical trials, including a phase II study in combination with cetuximab (an EGFR inhibitor) in subjects with metastatic and refractory colorectal cancer 76 . So far, a single prolonged partial response has been observed in a KRAS-mutant patient; however, this study did not meet its primary endpoint of objective response rate 76 and further results have not been published. E7820 was also used in combination with erlotinib in preclinical studies to overcome therapy resistance in non-small cell lung cancer.…”

Section: Role Of Integrin α2 In Diseasesmentioning

confidence: 94%

Regulation and functions of integrin α2 in cell adhesion and disease

2019

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Integrins are cell adhesion molecules that are composed of an alpha (α) subunit and a beta (β) subunit with affinity for different extracellular membrane components. The integrin family includes 24 known members that actively regulate cellular growth, differentiation, and apoptosis. Each integrin heterodimer has a particular function in defined contexts as well as some partially overlapping features with other members in the family. As many reviews have covered the general integrin family in molecular and cellular studies in life science, this review will focus on the specific regulation, function, and signaling of integrin α2 subunit (CD49b, VLA-2; encoded by the gene ITGA2) in partnership with β1 (CD29) subunit in normal and cancer cells. Its roles in cell adhesion, cell motility, angiogenesis, stemness, and immune/blood cell regulations are discussed. The pivotal role of integrin α2 in many diseases such as cancer suggests its potential to be used as a novel therapeutic target.

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Section: Role Of Integrin α2 In Diseasesmentioning

confidence: 94%

Regulation and functions of integrin α2 in cell adhesion and disease

2019

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“…α 2 -Integrin is therefore currently being evaluated in phase I studies as possible biomarker (4,6). In this article, we present a modeling and simulation analysis that integrates data from preclinical experiments and a phase I clinical trial to evaluate the expected efficacy of the dose levels that were studies in phase I.…”

Section: Introductionmentioning

confidence: 99%

“…The inhibition of α 2 -integrin measured on platelets provides a measure of pharmacological target modulation, and therefore would theoretically provide a better predictor of activity than measures of E7820 plasma exposure. α 2 -Integrin is therefore currently being evaluated in phase I studies as possible biomarker ( 4 , 6 ). In this article, we present a modeling and simulation analysis that integrates data from preclinical experiments and a phase I clinical trial to evaluate the expected efficacy of the dose levels that were studies in phase I.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of α2-Integrin Expression as a Biomarker for Tumor Growth Inhibition for the Investigational Integrin Inhibitor E7820 in Preclinical and Clinical Studies

Keizer

Funahashi

Semba

et al. 2011

AAPS J

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E7820 is an orally active inhibitor of α2-integrin mRNA expression, currently tested in phases I and II. We aimed to evaluate what levels of inhibition of integrin expression are needed to achieve tumor stasis in mice, and to compare this to the level of inhibition achieved in humans. Tumor growth inhibition was measured in mice bearing a pancreatic KP-1 tumor, dosed at 12.5–200 mg/kg over 21 days. In the phase I study, E7820 was administered daily for 28 days over a range of 0–200 mg, followed by a 7-day washout period. PK-PD models were developed in NONMEM. α2-Integrin expression measured on platelets, corresponding to tumor stasis at t = 21 in 50% and 90% of the mice (Iint,50, Iint,90) were calculated. It was evaluated if these levels of inhibition could be achieved in patients at tolerable doses. One hundred nineteen α2-Integrin measurements and 210 tumor size measurements were available from mice. The relationship between PK and α2-integrin expression was modeled using an indirect-effect model, subsequently linked to an exponential tumor growth model. Iinh,50 and Iinh,90 were 14.7% (RSE 7%) and 17.9% (RSE 8%). Four hundred sixty two α2-integrin measurements were available from 29 patients. Using the schedule of 100 mg qd (MTD), α2-integrin expression was inhibited more strongly than the Iint,50 and Iint,90 in greater than 95% and greater than 50% of patients, respectively. Moderate inhibition of α2-integrin expression corresponded to tumor stasis in mice, and similar levels could be reached in patients with the dose level of 100 mg qd.

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“…The aromatic sulphonamide E7820 (N-(3-Cyano-4methyl-1H-indol-7-yl)-3-cyanobenzene-sulfonamide) was initially characterised as a novel modulator of integrin α2 expression and shown to decrease integrin α2 mRNA levels and integrin α2 expression on HUVEC cell lines [4]. Since its first publication E7820 was shown to possess anti-cancer activity in vitro and in vivo and has been tested in phase I and phase II clinical trials [5][6][7][8][9]. More recently it was shown to act by stabilising PPIs and thus identified as belonging to the SPLINTS [3,10,11].…”

Section: Introductionmentioning

confidence: 99%

The small-molecule protein ligand interface stabiliser E7820 induces differential cell line specific responses of integrin α2 expression

2021

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Background The mechanism of small-molecule stabilised protein-protein interactions is of growing interest in the pharmacological discovery process. A plethora of different substances including the aromatic sulphonamide E7820 have been identified to act by such a mechanism. The process of E7820 induced CAPERα degradation and the resultant transcriptional down regulation of integrin α2 expression has previously been described for a variety of different cell lines and been made responsible for E7820’s antiangiogenic activity. Currently the application of E7820 in the treatment of various malignancies including pancreas carcinoma and breast cancer is being investigated in pre-clinical and clinical trials. It has been shown, that integrin α2 deficiency has beneficial effects on bone homeostasis in mice. To transfer E7820 treatment to bone-related pathologies, as non-healing fractures, osteoporosis and bone cancer might therefore be beneficial. However, at present no data is available on the effect of E7820 on osseous cells or skeletal malignancies. Methods Pre-osteoblastic (MC3T3 and Saos-2) cells and endothelial (eEnd2 cells and HUVECs) cells, each of human and murine origin respectively, were investigated. Vitality assay with different concentrations of E7820 were performed. All consecutive experiments were done at a final concentration of 50 ng/ml E7820. The expression and production of integrin α2 and CAPERα were investigated by quantitative real-time PCR and western blotting. Expression of CAPERα splice forms was differentiated by semi-quantitiative reverse transcriptase PCR. Results Here we present the first data showing that E7820 can increase integrin α2 expression in the pre-osteoblast MC3T3 cell line whilst also reproducing canonical E7820 activity in HUVECs. We show that the aberrant activity of E7820 in MC3T3 cells is likely due to differential activity of CAPERα at the integrin α2 promoter, rather than due to differential CAPERα degradation or differential expression of CAPERα spliceforms. Conclusion The results presented here indicate that E7820 may not be suitable to treat certain malignancies of musculoskeletal origin, due to the increase in integrin α2 expression it may induce. Further investigation of the differential functioning of CAPERα and the integrin α2 promoter in cells of various origin would however be necessary to more clearly differentiate between cell lines that will positively respond to E7820 from those that will not.

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Phase II study of E7820 in combination with cetuximab in subjects (pts) with metastatic and refractory colorectal cancer (CRC).

Cited by 9 publications

References 0 publications

Regulation and functions of integrin α2 in cell adhesion and disease

Regulation and functions of integrin α2 in cell adhesion and disease

Evaluation of α2-Integrin Expression as a Biomarker for Tumor Growth Inhibition for the Investigational Integrin Inhibitor E7820 in Preclinical and Clinical Studies

The small-molecule protein ligand interface stabiliser E7820 induces differential cell line specific responses of integrin α2 expression

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