Summary
Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1–12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m2, with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m2. The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.
Similar content being viewed by others
References
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
Londin E, Loher P, Telonis AG et al (2015) Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. PNAS 23:E1106–E1115Epub February
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233
Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866
Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6:259–269
Kasinski AL, Slack FJ (2011) MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 11:849–864
Jansson MD, Lund AH (2012) MicroRNA and cancer. Mol Oncol 6:590–610
Bader AG (2012) miR-34–a microRNA replacement therapy is headed to the clinic. Front Genet 3: article 120
Cortez MA, Ivan C, Valdecanas D, Wang X et al (2016) PDL1 regulation by p53 via miR-34. J Natl Cancer Inst 108:djv303
Bader AG, Brown D, Winkler M (2010) The promise of microRNA replacement therapy. Cancer Res 70:7027–7030
Trang P, Wiggins JF, Daige DL et al (2011) Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther 19:1116–1122
Bader AG, Brown D, Stoudemire J et al (2011) Developing therapeutic microRNAs for cancer. Gene Ther 18:1121–1126
Daige CL, Wiggins JF, Priddy L et al (2014) Systemic delivery of a miR-34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 13:2352–2360
Kelnar K, Peltier HJ, Leatherbury N et al (2014) Quantification of therapeutic miRNA mimics in whole blood from non-human primates. Anal Chem 86:1534–1542
He L, He X, Lim LP et al (2007) A microRNA component of the p53 tumor suppressor network. Nature 447:1130–1134
Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199
Zhao J, Lammers P, Torrance CJ et al (2013) TP53-independent function of miR-34a via HDAC1 and p21(CIP1/WAF1). Mol Ther 21:678–686
Lee CH, Subramanian S, Beck AH et al (2009) MicroRNA profiling of BRCA1/2 mutation-carrying and non-mutation-carrying high-grade serous carcinomas of ovary. PLoS One 4:e7314
Hagman Z, Larne O, Edsjo A et al (2010) miR-34c is downregulated in prostate cancer and exerts tumor suppressive functions. Int J Cancer 127:2768–2776
Nakatani F, Ferracin M, Manara MC et al (2012) miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy. J Pathol 226:796–805
Jamieson NB, Morran DC, Morton JP et al (2012) MicroRNA molecular profiles associated with diagnosis, clinicopathologic criteria, and overall survival in patients with resectable pancreatic ductal adenocarcinoma. Clin Cancer Res 18:534–545
Hiyoshi Y, Schetter AJ, Okayam H et al (2015) Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer. PLoS One 10:e0124899
Wang J, Dan G, Zhao J et al (2015) The predictive effect of overexpressed miR-34a on good survival of cancer patients: a systematic review and meta-analysis. Onco Targets Ther 8:2709–2719
Shin J, Danli X, Zhong XP (2013) MicroRNA-34a enhances T cell activation by targeting Diacylglycerol kinase ζ. PLoS One 8:e77983
Cortez MA, Valdecanas D, Niknam S et al (2015) In vivo delivery of miR-34a sensitizes lung tumors to radiation through RAD51 regulation. Molecular Therapy—Nucleic Acids 4:e270
Wang X, Li J, Dong K et al (2015) Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal 27(3):443–452
Ji Q, Hao X, Zhang M et al (2009) MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 4:e6816
Li N, Fu H, Tie Y et al (2009) miR-34a inhibits migration and invasion by down-regulation of c-met expression in human hepatocellular carcinoma cells. Cancer Lett 275:44–53
Liu C, Kelnar K, Liu B et al (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17:211–215
Di Martino MT, Leone E, Amodio N et al (2012) Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. Clin Cancer Res 18:6260–6270
Zhao J, Kelnar K, Bader AG (2014) In-depth analysis shows synergy between erlotinib and miR-34a. PLOS One Feb 14:e8910
Wiggins JF, Ruffino L, Kelnar K et al (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res 70:5923–5930
Craig VJ, Tzankov A, Flori M et al (2012) Systemic microRNA-34a delivery induces apoptosis and abrogates growth of diffuse large B-cell lymphoma in vivo. Leukemia 26:2421–2424
Tolcher AW, Rodrigueza WV, Rasco DW et al (2014) A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors. Cancer Chemother Pharmacol 73:363–371
Kelnar K , Bader, AB (2015) A qRT-PCR method for determining the biodistribution profile of a miR-34a mimic. Chapter 8. In: Gene therapy of solid cancers: methods and protocols, Methods in Molecular Biology, Walther W, Stein U, eds 1317:125–33
Szebeni J, Muggia F, Gabizon A et al (2011) Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev 63:1020–1030
Robbins M, Judge A, Ambegia E et al (2008) Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation. Hum Gene Ther 19:991–999
Chattopadhyay S (2014) Sen GC: dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interf Cytokine Res 34(6):427–436
Chiappinelli KB, Strissel PL, Desrichard A et al (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162:974–986
Dear AE (2016) Epigenetic modulators and the new immunotherapies. N Engl J Med 374:684–686
Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982
Acknowledgements
We thank the patients and their families as well as the co-investigators and study teams for making this study possible. Assistance with medical writing and editing was provided by David E. Egerter, PhD, funded by Mirna Therapeutics.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
Muhammad S. Beg has consulting/advisory roles at Bayer, Celgene, and Ipsen, and has received research funding from Celgene, Mirna, and Precision Biologics, and travel expenses from Mirna and Precision Biologics. Andrew J. Brenner has consulting/advisory roles at NanoTX and Teleflex Medical, holds intellectual property with NanoTX, and has received research funding from Mirna and Threshold, and travel expenses from Vascular Biogenics. Jasgit Sachdev has a consulting/advisory role at Celgene and has received honoraria from Celgene. Mitesh Borad has no relationships to disclose. Yoon-Koo Kang has consulting/advisory roles at Lilly/ImClone, Novartis, Ono, Genentech, and Taiho, and has received research funding from Bayer, Novartis, and Genentech. Jay Stoudemire, Susan Smith, Andreas G. Bader, and Sinil Kim are, or were at the time of the study, employed by Mirna and own stock in Mirna; Dr. Bader additionally is an inventor on patents and patent applications assigned to Mirna, and Dr. Kim additionally owns stock in Pfizer. David S. Hong has received research funding from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Genentech, Lilly, Merck, Mirati, Mirna, Novartis, and Pfizer, and travel expenses from Loxo and Mirna.
Statement of human rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Electronic supplementary material
ESM 1
(DOCX 26 kb)
Rights and permissions
About this article
Cite this article
Beg, M.S., Brenner, A.J., Sachdev, J. et al. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest New Drugs 35, 180–188 (2017). https://doi.org/10.1007/s10637-016-0407-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-016-0407-y