Targeting the acidic tumor microenvironment enhances antimiR delivery and oncomiR inhibition.
Major finding: Targeting the acidic tumor microenvironment enhances antimiR delivery and oncomiR inhibition.
Concept: Attachment to pHLIP transports antimiRs across the plasma membrane and escapes liver clearance.
Impact: This system may have therapeutic potential in both cancer and other pathologic conditions.
Overexpression of oncogenic miRNAs, known as oncomiRs, has been shown to drive tumor initiation and maintenance and results in dependency of some tumors on expression of these miRNAs. Recent studies have explored targeted inhibition of oncomiRs using antisense oligomers (antimiR) as a strategy to overcome this oncomiR addiction and suppress tumor growth. However, the anticancer activity of antimiRs is limited by suboptimal delivery into target tumor cells. To overcome this limitation, Cheng and colleagues developed a new antimiR delivery platform in which charge-neutral peptide nucleic acid antimiRs were attached to a low pH-induced transmembrane structure (pHLIP), which specifically localized to the acidic tumor microenvironment, but not the liver, and effectively transported antimiRs across the plasma membrane of various tumor cell types under acidic conditions. Treatment with pHLIP–antimiR-155 diminished the growth of subcutaneous miR-155–driven lymphoma tumors, prolonged survival, and suppressed metastatic spread more effectively than commercially available antimiRs and without systemic toxicity. Furthermore, targeted silencing of miR-155 via systemic administration of pHLIP–antimiR-155 also effectively inhibited lymphoma growth and liver metastasis in a transgenic mouse model of miR-155–addicted lymphoma, resulting in decreased lymph node tumor burden and restoration of splenic architecture without renal damage. RNA sequencing analysis of regressing tumors following antimiR treatment compared with miR-155–addicted tumors identified putative miR-155 target genes that are differentially expressed upon oncomiR withdrawal, including genes that regulate cell adhesion and migration, as well as a number of tumor suppressor genes that represent predicted miR-155 targets. Of note, two validated miR-155 targets, Bach1 and Mafb, were upregulated following pHLIP–antimiR-155 treatment. In sum, these data demonstrate the anticancer efficacy of this antimiR delivery platform and suggest that targeted miRNA silencing using this system may also be useful for other pathologic conditions.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.