Abstract 5634: Macrocycle drug conjugate NOVO-111 induces ribosome biogenesis stress and is efficacious in colorectal cancer xenografts

Abstract Purpose: NOVO-111 is a novel macrocycle drug conjugate (MDC) comprised of an expanded porphyrin conjugated to a lipophilic Pt(IV) analogue of oxaliplatin. NOVO-111 has been shown to overcome both multifactorial and transport-defective mechanisms of platinum resistance. While platinum agents often induce DNA damage repair pathways, it has recently been demonstrated that certain agents such as oxaliplatin induce ribosomal biogenesis stress (RBS) as its primary anticancer mechanism. To further assess the clinical translational potential of NOVO-111, ribosome functional assays and efficacy studies involving human colorectal cancer (CRC) models were evaluated. Procedures: HCT116 cells with both copies of RPL28 SNAP-tagged at the endogenous locus were assessed for RBS. HCT116+L28SNAP tagged cells were cultured and SNAP-tagged RPL28 was labeled with benzylguanine. Cells were then incubated with 2.5uM NOVO-111 at variable time points then incubated with benzylguanine Oregon Green, fixed with 4%PFA, labeled with Hoechst and mounted in anti-fade Vectashield media. For a given cell (N=43 cells), the number of Oregon Green spots observed in the nucleus was recorded and analyzed. Athymic Nude-Foxn1nu female mice (8 mice/group), with subcutaneously implanted (flank) patient derived xenografts (PDX) using CTG-0401 and CTG-0066 received maximum tolerated doses of oxaliplatin (6 mg/kg) and NOVO-111 (70 mg/kg) i.v. on days 1, 5, 9, and 13. The body weights and tumor volumes were monitored. Mice that had reached maximum tumor burden were euthanized. Results: The data indicate NOVO-111 induces RBS in HCT116+L28 SNAP cells. The number of puncta and mean intensity of RiboSNAP signal in the puncta increase with NOVO-111 treatment while puncta size is reduced. NOVO-111 and control oxaliplatin were further evaluated in nude mice bearing CRC PDX tumors. Minimal to no body weight loss was observed for either treatment group. The treatments resulted in tumor growth inhibitions (TGI) of 94% and 62% for NOVO-111 and oxaliplatin for CTG-0066, respectively. Survival >80 days revealed a significant increase in survival for the NOVO-111 treatment group. Treatment of CTG-0401 bearing mice resulted in TGIs of 59% and 18% for NOVO-111 and oxaliplatin, respectively. Survival >80 days revealed that a mere 25% of the oxaliplatin treatment group survived, compared to a survival of 88% for the NOVO-111 treatment group. Conclusions: Results indicate that NOVO-111 is capable of inducing RBS as a potential anticancer mechanism in human CRC cells. In addition, NOVO-111 was found to induce a statistically significant tumor growth delay and increase survival in CRC PDX models compared to oxaliplatin. These data demonstrate that NOVO-111, as an MDC, has a distinct advantage over the current standard of care for CRC. Citation Format: Jonathan Arambula, Garrett Kimble, Calvin Chau, Michael Buszczak, Jonathan Sessler, Krystle Karoscik, Zahid Siddik, Adam Sedgwick. Macrocycle drug conjugate NOVO-111 induces ribosome biogenesis stress and is efficacious in colorectal cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5634.