MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC

Abstract

The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon known as oncogene addiction. However, it is unclear whether a therapy that targets the MYC oncogene could similarly elicit oncogene addiction. In this study, we report that using antisense oligonucleotides (ASOs) to target and reduce the expression of MYC impedes tumor progression and phenotypically elicits oncogene addiction in transgenic mouse models of MYC-driven primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Quantitative image analysis of MRI was used to demonstrate the inhibition of HCC and RCC progression. After 4 weeks of drug treatment, tumors had regressed histologically. ASOs depleted MYC mRNA and protein expression in primary tumors in vivo, as demonstrated by real-time PCR and immunohistochemistry. Treatment with MYC ASO in vivo, but not with a control ASO, decreased proliferation, induced apoptosis, increased senescence, and remodeled the tumor microenvironment by recruitment of CD4 + T cells. Importantly, although MYC ASO reduced both mouse Myc and transgenic human MYC, the ASO was not associated with significant toxicity. Lastly, we demonstrate that MYC ASO inhibits the growth of human liver cancer xenografts in vivo. Our results illustrate that targeting MYC expression in vivo using ASO can suppress tumorigenesis by phenotypically eliciting both tumor-intrinsic and microenvironment hallmarks of oncogene addiction. Hence, MYC ASO therapy is a promising strategy to treat MYC-driven human cancers.

Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

“…Lipid nanoparticle-based formulations (DCR-MYC) have been used to deliver siRNA into tumor cells, leading to inhibition of translation and expression of the c-Myc protein [ 41 ]. This approach was later found to not meet therapeutic expectations and was halted, however work using antisense oligonucleotides to target c-Myc mRNA continues [ 42 ]. More recently, the inhibitor Omomyc, a c-Myc dominant negative protein [ 43 – 45 ], has shed light on the impact of directly inhibiting c-Myc-mediated malignancy.…”

Therapeutic targeting of “undruggable” MYC

“…Several approaches have attempted to inhibit MYC directly or indirectly at all levels of its regulation. Some strategies that have shown promising results in vivo have focused on preventing MYC gene expression using antisense oligonucleotides (ASOs) that target MYC mRNA 14 or G4-quadruplex binders that stabilize these DNA secondary structures. Other strategies are based on inhibiting MYC synthetic lethal genes required for tumorigenesis or tumor maintenance such as BUD31, 15 NUAK1 (ARK5) 16 or eIF4F.…”

MYC Overexpression Drives Immune Evasion in Human Cancer that is Reversible Through Restoration of Pro-Inflammatory Macrophages

“…MRI was performed using a 7T small animal MRI (Agilent conversion) with a 40 mm Varian Millipede RF coil (ExtendMR LLC, Milpitas, CA) at the Stanford Small Animal Imaging Facility as previously described (40,41). Briefly, animals were anesthetized with 1-3% isoflurane and placed into the MRI scanner containing a 40 mm Varian Millipede RF coil (ExtendMR LLC, Milpitas, CA).…”