Abstract A031: A combined degrader-antisense therapeutic for fibrolamellar carcinoma

Introduction: Many pediatric cancers, are driven by fusion oncoproteins. Since each fusion partner originates from a native protein with essential functions, it is important but difficult to selectively target fusion oncoproteins while sparing native components. FLC is a usually lethal primary liver tumor of adolescents and young adults driven by an oncogenic fusion between the first exon of DNAJB1, a heat shock protein, to the bulk of the coding region of PRKACA, the catalytic subunit of protein kinase A (PKA), forming DNAJB1::PRKACA. Since the active sites of the DNAJB1::PRKACA and native PRKACA are structurally indistinguishable, designing inhibitors specific to the fusion protein is challenging. Currently, there is no accepted therapy for FLC. Brief summary: We present a new therapeutic strategy that is applicable to other Fusion Oncoprotein-driven Malignancies. We designed a single molecule that encodes both a degrader to eliminate the oncoprotein and an antisense to eliminate the mRNA encoding the oncoprotein. Results: The degrader is based on a peptide that binds exclusively to PRKACA or DNAJB1::PRKACA, expressed as a fusion to an E3 ligase. The peptide-E3 selectively eliminates just the fusion oncoprotein without affecting the native kinase. This design allows the choice of E3 that is optimized for the tumor and location of the oncoprotein. This degrader is sufficient not only to eliminate the fusion oncoprotein but to eliminate patient tumors growing in mice, with no detectable effects on the physiology of the mouse or the healthy liver. This degrader was delivered as an mRNA. This empowered using the same mRNA to then encode an siRNA against the oncoprotein. Together the degrader-antisense combo more rapidly and completely eliminated the fusion oncoprotein and, together, greatly reduce the opportunities for mutational escape. Conclusion: This combined approach can be adopted to any target mutant protein driving other pediatric tumors. Citation Format: Mahsa Shirani, Ronaldo Shaquille Bowie, Michael Tomasini, Denise Ng, Ruth Hook, Barbara Lyons, Philip Coffino, Sanford Simon. A combined degrader-antisense therapeutic for fibrolamellar carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A031.