Differentiation therapy with hepatocyte nuclear factor 4α for patients with hepatocellular carcinoma

Differentiation therapy is an approach designed to revert tumor cells to a normal cellular state, thereby adopting benign characteristics. 1 This approach has achieved hallmark success in treating acute promyelocytic leukemia (APL) but has limited effectiveness in solid tumors. This difference in therapeutic efficacy may be due to the genetic complexity of the development of most solid tumors, which involve multiple oncogenic pathways, in contrast to the genetic simplicity of APL development, which is predominantly driven by PML-RARα. 2 Transcription factors (TFs) recognize specific DNA motifs in the genome to regulate gene expression and determine cell fates, with the upregulation of a single TF capable of triggering significant cellular transformations. 3 Hepatocyte nuclear factor 4α (HNF4α) is a master TF regulating hepatocyte differentiation. 4 Restoring HNF4α expression induces the differentiation of hepatocellular carcinoma (HCC) cells into mature hepatocytes and has demonstrated significant therapeutic efficacy in various HCC animal models. 5 , 6 Lipid nanoparticles (LNPs), widely employed for RNA delivery, offer hepatocyte specificity, effectively minimizing systemic exposure and toxicity. Self-replicating RNA (srRNA), with the self-amplifying nature, allows for a lower RNA dose for the treatment. 7 A recent study reported that systemic injection of LNP-encapsulated srRNA achieves significantly prolonged expression of the target gene specifically within tumors but not in normal organs of mice. 8 These characteristics make LNP-encapsulated srRNA an ideal candidate for clinical therapy in HCC. However, to date, no studies have been reported on the use of srRNA for the treatment of human cancers. In this study, we reported the development and preclinical evaluation of CD-801, a LNP-encapsulated srRNA encoding HNF4α. A subsequent first-in-human, first-in-class, dose-escalation trial was conducted to assess the safety, tolerability, and efficacy of CD-801 in patients with advanced HCC.