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01-08-2018 | PRECLINICAL STUDIES

Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis

Authors: Hak-Min Lee, Eunmyong Lee, So-Young Yeo, Sang Shin, Hyun-Kyu Park, Do-Hyun Nam, Seok-Hyung Kim

Published in: Investigational New Drugs | Issue 4/2018

Summary

Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval. As a result, bortezomib (BTZ), carfilzomib (CFZ), and panobinostat (PST) were identified as anti-CAF drug candidates. It was confirmed that BTZ and PST could decrease the viability of various patients derived CAFs through inducing of caspase-3 mediated apoptosis. Interestingly, combination therapy with BTZ and PST showed better efficacy of inhibiting CAFs than single treatment. The synergistic effect between BTZ and PST on viability of CAFs was observed both in vitro CAF culture and in vivo mouse model. Furthermore, combination therapy with BTZ/PST and conventional anticancer compound docetaxel strongly inhibited tumor growth in xenografts of mouse breast cancer cells with mouse CAFs. In conclusion, our present study revealed that BTZ and PST could significantly reduce the viability of CAFs. Therefore, a combination therapy with BTZ/PST and anticancer drugs might be considered as a new rational for the development of anticancer therapy.

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Title: Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis
Authors: Hak-Min Lee
Eunmyong Lee
So-Young Yeo
Sang Shin
Hyun-Kyu Park
Do-Hyun Nam
Seok-Hyung Kim
Publication date: 01-08-2018
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2018
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-017-0547-8

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Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

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Other articles of this Issue 4/2018

Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy – results of an exploratory phase I study

Nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer

Unique characteristics of regulatory approval and pivotal studies of orphan anticancer drugs in Japan

Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies

Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience

A phase I/II trial of pemetrexed plus radiotherapy in elderly patients with locally advanced non-small cell lung cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer