Our results demonstrate that anti-miR-17 therapy may have efficacy for the treatment of MYC-driven HCC. We found that an anti-miR-17 LNP, in a transgenic mouse model of MYC-driven HCC, impeded tumor progression without overt signs of hepatic or systemic toxicity. We have evaluated the feasibility of liver-specific anti-miR delivery to achieve sustained target de-repression in the liver tumor without general liver toxicity. Recently, a novel approach for targeting miR-17 with a tough decoy (TuD) antisense miR17 delivered via systemic lipid nanoparticle (LNP) has been shown to be effective in HCC cell lines. However, several challenges exist in achieving drug stability and ensuring tissue-specific drug delivery. Targeting microRNAs has been considered a desired approach in cancer therapeutics. We therefore hypothesized that miR-17 is a promising therapeutic target for MYC-driven HCCs.
The miR 17 family (miR 17, miR 20a, miR 20b, miR106a, miR106b, miR 93) is a part of this cluster and few studies have shown that over-expression of miR-17 family promotes HCC progression and cancer metastasis. Recently, we reported that MYC’s ability to maintain proliferation, survival and self-renewal were regulated via its induction of miR17~92 cluster. However, no existing therapies directly inactivate the MYC oncogene, so identifying critical downstream gene products that are essential for MYC to maintain a neoplastic state can help us indirectly target MYC. Hence, therapies against MYC have the potential to be highly effective treatment for liver cancer. Experimentally, inactivation of MYC oncogene in HCC is sufficient to lead to tumor regression associated with proliferative arrest, differentiation, and apoptosis. MYC is a transcription factor that modulates the gene expression of thousands of genes that regulate many programs which are hallmarks of cancer including: metabolism, proliferation, self-renewal, and survival. MYC genomic amplification and/or overexpression is a common molecular event in HCC. Therefore, it is imperative to develop novel effective therapeutics and biomarker stratification strategies for selecting the right drug for the right patient.
Targeted therapies like Sorafenib or Regorafenib improve life expectancy only by a few months Several other drugs have failed in phase 3 clinical trials for HCC likely due to the failure to identify subpopulations amenable to targeted therapy. Conventional chemotherapy has limited efficacy. Hepatocellular carcinoma (HCC) is a generally lethal cancer with increasing frequency in the Unites States and world-wide. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Treatment with anti-miR-17 in vivo, but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. Unfortunately, currently there are no direct drug therapies against MYC. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Received: JAccepted: AugPublished: NovemAbstract Keywords: liver cancer HCC miR MYC lipid nanoparticle (LNP) Felsher 2,3ġ Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USAĢ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USAģ Division of Oncology, Department Pathology, Stanford University School of Medicine, Stanford, CA, USAĤ Regulus Therapeutics, San Diego, CA, USA Renumathy Dhanasekaran 1,2,3, Meital Gabay-Ryan 2,3, Virginie Baylot 2,3, Ian Lai 2,3, Adriane Mosley 2,3, Xinqiang Huang 4, Sonya Zabludoff 4, Jian Li 4, Vivek Kaimal 4, Priya Karmali 4 and Dean W.