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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

2224 - 9-ING-41, a clinically relevant inhibitor of Glycogen Synthase Kinase-3 (GSK-3), is active pre-clinically in human bladder and renal cell cancers

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Presenters

Hiroo Kuroki

Citation

Annals of Oncology (2018) 29 (suppl_8): viii1-viii13. 10.1093/annonc/mdy268

Authors

H. Kuroki1, T. Anraku1, V. Bilim1, M. Tasaki1, D. Schmitt2, A. Mazar3, A. Ugolkov4, Y. Tomita1

Author affiliations

  • 1 Urology, Niigata University Medical and Dental Hospital, 951-8520 - Niigata/JP
  • 2 Actuate Therapeutics, Actuate Therapeutics, 76107 - Fort Worth/US
  • 3 Monopar Therapeutics, Monopar Therapeutics, 60091 - Wilmette/US
  • 4 Developmental Therapeutic Program, Division Of Hematology/oncology, Feinberg School of Medicine, Northwestern University, 60611 - Chicago/US
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Resources

Abstract 2224

Background

Glycogen Synthase Kinase-3b (GSK-3b) is a serine/threonine protein kinase that has been established as a therapeutic target in a broad spectrum of human malignancies. We have previously identified aberrant GSK-3b nuclear expression in urothelial cancer (UC) and renal cell carcinoma (RCC), and demonstrated that GSK-3b positively regulated UC and RCC cell survival and proliferation. Our objective was to evaluate the antitumor effects of clinically viable agent 9-ING-41, a maleimide-based ATP-competitive GSK-3 inhibitor, which demonstrated broad spectrum antitumor activity and marked activity in reversing chemoresistance in a variety of human cancers.

Methods

We used flow cytometry, Western immunoblotting, quantitative RT-PCR, BrDU incorporation and MTS assays to examine the pre-clinical antitumor activity of 9-ING-41 in UC (T24, HT1376 and RT4 cell lines) and RCC (ACHN, Caki2, A498 and KRC/Y cell lines).

Results

A dose-dependent decrease in cancer cell proliferation was observed by MTS assay and BrdU incorporation assay with GI50 ranging from 0.7 to 4.7 mM (UC) and 7.2 to 11.5 mM (RCC). Treatment with 9-ING-41 induced prominent cell cycle arrest (predominantly G2 arrest) in UC and RCC cell lines. Expression of cell cycle related proteins, including Cyclin D, and anti-apoptotic proteins, such as XIAP and Bcl-2, were decreased as detected by Western immunoblotting and real time RT-PCR. Treatment with 9-ING-41 significantly potentiated the growth inhibitory effect of cisplatin and gemcitabine in both UC and RCC cell lines.

Conclusions

Our data provide a rationale for the inclusion of patients with advanced and/or chemo-refractory UC or RCC in 9-ING-41 clinical studies.

Clinical trial identification

Legal entity responsible for the study

Hiroo Kuroki.

Funding

D. Schmitt: President, CEO, equity interest: Actuate Therapeutics, Inc. A. Mazar: Equity interest, scientific advisor: Actuate Therapeutics, Inc. A. Ugolkov: Equity interest, consulting scientific Director: Actuate Therapeutics, Inc.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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