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CYP3A5 mediates resistance to small molecule inhibitors in pancreatic cancer

Noll E.M. ; Eisen C. ; Stenzinger A. ; [et al.]

Nature Medicine

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Type of Publication: Journal article epub ahead of print

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=67047

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CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma

Noll EM ; Eisen C ; Stenzinger A ; [et al.]

Nature Medicine 22 (3), 278-287

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Abstract: Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers-HNF1A and KRT81-that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.

Type of Publication: Journal article published

PubMed ID: 26855150

Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=69602

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Anpassung der Wickbold-Apparatur an die Verbrennung schwerer Öle und gebrauchter Schmieröle für die Spurenbestimmung anorganischer Elemente (1977)

Kulke, M. ; Umland, F.

Springer

Fresenius' Zeitschrift für analytische Chemie 288 (1977), S. 273-276

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ISSN: 1618-2650

Keywords: Best. von Vanadium, Elementen in Schmierölen ; Spektralphotometrie, Atomabsorption ; flammenlos, Anpassung der Wickbold-Apparatur

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Description / Table of Contents: Zusammenfassung Die Verbrennungsapparatur nach Wickbold wurde durch Veränderungen am Saugbrenner, am vorderen Flammenrohr, am Kühlsystem und durch Verwendung von Wirbelrohren und eines Überdruckventils der Verbrennung von Erdölprodukten, speziell von gebrauchten Schmierölen, angepaßt. Zur Überprüfung der Apparatur wurde Vanadium in einer synthetischen Testlösung bestimmt. Die Endbestimmung nach der Verbrennung erfolgte durch flammenlose Atomabsorptionsspektrometrie in einer Graphitrohrküvette nach Massmann.

Notes: Summary The Wickbold combustion apparatus has been modified for decomposition of petroleum products, especially of used lubricating oils. Modifications were made concerning the suction burner, the front of the combustion chamber and the cooling system in conjunction with adding a mixing tube and a pressure limiting valve. The improved apparatus was tested by the vanadium determination in a synthetic sample. After combustion the measurement was performed by flameless atomic absorption spectroscopy using a Massmann graphite tube.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00539394

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Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors (2018)

Hope, T. A., Bergsland, E. K., Bozkurt, M. F., Graham, M., Heaney, A. P., Herrmann, K., Howe, J. R., Kulke, M. H., Kunz, P. L., Mailman, J., May, L., Metz, D. C., Millo, C., O'Dorisio, S., Reidy-Lagunes, D. L., Soulen, M. C., Strosberg, J. R.

The Society of Nuclear Medicine (SNM)

In: Journal of Nuclear Medicine

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Publication Date: 2018-01-03

Print ISSN: 0022-3123

Topics: Medicine

Published by The Society of Nuclear Medicine (SNM)

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Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial (2018)

Pavel, M., Gross, D. J., Benavent, M., Perros, P., Srirajaskanthan, R., Warner, R. R. P., Kulke, M. H., Anthony, L. B., Kunz, P. L., Horsch, D., Weickert, M. O., Lapuerta, P., Jiang, W., Kassler-Taub, K., Wason, S., Fleming, R., Fleming, D., Garcia-Carbonero, R.

The Society for Endocrinology

In: Endocrine-Related Cancer

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Publication Date: 2018-02-10

Description: Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with 〈4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients ( N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges–Lehmann estimators of median treatment differences from placebo of –54.0% (95% confidence limits, –85.0%, –25.1%, P 〈 0.001) and –89.7% (95% confidence limits, –113.1%, –63.9%, P 〈 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).

Print ISSN: 1351-0088

Electronic ISSN: 1479-6821

Topics: Medicine

Published by The Society for Endocrinology

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