Copyright
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma
Jennifer Wu, Merly Contratto, Krishna P Shanbhogue, Gulam A Manji, Bert H O’Neil, Anne Noonan, Robert Tudor, Ray Lee
Jennifer Wu, Merly Contratto, Division of Hematology and Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, United States
Krishna P Shanbhogue, Department of Radiology at New York University School of Medicine, New York, NY 10016, United States
Gulam A Manji, Division of Hematology and Oncology, Columbia University Medical Center, New York, NY 10032, United States
Bert H O’Neil, Division of Hematology and Oncology, Indiana University, Indianapolis, IN 46202, United States
Anne Noonan, Division of Hematology and Oncology, Ohio State University Medical Center, Columbus, OH 43210, United States
Robert Tudor, Roche Pharmaceutical Company, New York, NY 10016, United States
Ray Lee, Roche and Teclison Pharmaceutical Company, Montclair, NJ 07042, United States
Author contributions: Wu J provided comments on the final version of the phase 1b of the study; Contratto M provided the abstract, conclusion, references and completed the final revision; Lee R provided the concept, the outline, designed the study, and the major references for this manuscript, provided critical revisions for this manuscript; Shanbhoque KP provided analysis of all imaging studies, set up the DCE protocol (including attending the initial protocol meeting), supervised and analyzed the perfusion MRI scans, and provided comments on the results of the manuscript and revision approval; Manji GA, O’Noeal BH, Noonan A and Tudor R provided some data regarding the patients’ information that were enrolled in their facilities.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of New York University School of Medicine.
Clinical trial registration statement: This registration policy applies to prospective trials only.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare no potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jennifer Wu, MD, Associate Professor, Attending Doctor, Division of Hematology and Oncology, Perlmutter Cancer Center, New York University School of Medicine, 462 First Ave, BCD556, New York, NY10016, United States.
jennifer.wu@nyumc.org
Telephone: +1-212-2636530 Fax: +1-212-2638210
Received: November 8, 2018
Peer-review started: November 10, 2018
First decision: November 14, 2018
Revised: December 17, 2018
Accepted: January 8, 2019
Article in press: January 9, 2019
Published online: March 24, 2019
Processing time: 134 Days and 16.8 Hours
BACKGROUND
Hypoxia-inducible factor 1α (HIF-1α) is a gene that regulates tumor survival, neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma (HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC.
AIM
To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179.
METHODS
In the preclinical study of RO7070179 in a HCC xenograft model, the mice were separated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment, received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179.
RESULTS
Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and 1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies (each biopsy was divided into 2 specimens, the tip and the root).
CONCLUSION
RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity. This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either mRNA level or DCE-MRI within 1 cycle of therapy.
Core tip: Overexpression of hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in hepatocellular carcinoma (HCC) patients. HIF-1a inhibitor decreases HIF-1a mRNA and its downstream targets, it could be a potential treatment in HCC.
