The MUC1-C cytoplasmic domain contains a CQC motif that is necessary and sufficient for MUC1-C (i) homodimerization, (ii) nuclear localization and (iii) function as an oncoprotein. Based on these findings, we developed cell-penetrating peptides that target the MUC1-C CQC motif and thereby block MUC1-C homodimerization. Our work has demonstrated that targeting MUC1-C with (i) genetic silencing, (ii) expression of the dominant-negative CQC→AQA mutant, or (iii) treatment with GO-203 peptide is associated with the reversal of EMT, and inhibition of self-renewal capacity and tumorigenicity. The genetic approaches for targeting MUC1-C thus provided support for the results obtained with the GO-203 inhibitor, indicating that blocking the MUC1-C CQC motif is an innovative approach for targeting cancer cells.
GO-203
Genus Oncology is developing first-in-class agents that interact directly with MUC1-C and block its function. A cell-penetrating MUC1-C peptide inhibitor (GO-203) has been synthesized that targets the MUC1-C cytoplasmic domain CQC motif and thereby MUC1-C homodimerization and function. Importantly, treatment of human breast, lung, prostate and other types of cancer cells with GO-203 in vitro is associated with induction of late apoptotic/necrotic cell death. Consistent with the demonstration that MUC1 protects cells against disruption of redox balance, direct targeting of MUC1-C is associated with increases in ROS and activation of the DNA damage response. The finding that GO-203 is selective against MUC1-expressing cells indicates that this agent is an attractive candidate for treating carcinoma cells that are addicted to MUC1-C for maintaining the malignant phenotype. Another question of importance was whether GO-203 could be delivered in vivo with an effective therapeutic index. In models of human tumor xenografts growing in nude mice, administration of GO-203 was well tolerated and associated with complete regressions that were prolonged after completing treatment. These findings thus provided proof-of-principle that MUC1-C is a druggable target and that blocking MUC1-C function is effective in inducing death of human carcinoma cells.
GO-203/NPs (GO-203/Nanoparticles)
GO-203 was selected for Phase I evaluation as the first-in-man MUC1-C inhibitor. However, administration of GO-203 has been limited by a short circulating half-life that necessitated daily dosing and precluded adequate tumor drug exposure. Accordingly, we developed an alternative and highly novel approach for the sustained delivery of peptide drugs by their encapsulation in polymeric nanoparticles (NPs).
The development of peptidyl drugs for treating cancer can be a challenge because of unfavorable pharmacokinetic parameters and cell penetrating capabilities. Genus Oncology has therefore encapsulated the GO-203 inhibitor in novel polymeric NPs to circumvent these challenges. Genus’s studies have shown that loading of GO-203 into tetra-block polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and enhanced by increasing PEG chain length. Additionally, we found that release of GO-203 from these NPs is sustained over at least 7 days. Importantly, GO-203/NPs treatment of MUC1-C-positive breast and lung cancer cells was more active with less frequent dosing than that achieved with non-encapsulated GO-203. Moreover, treatment with GO-203/NPs blocked MUC1-C homodimerization, suppressed AKT activation and down-regulated TIGAR expression, consistent with on-target effects. GO-203/NP treatment was also effective in conferring ROS-induced late apoptosis/necrosis and in inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/NPs to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable to that found when dosing GO-203 on a daily basis (Fig. 1A and B). These findings have thus defined an effective approach for sustained administration of GO-203 in novel PLA-PEG-PPG-PEG tetra-block NPs to target MUC1-C in cancer cells.
The development of peptidyl drugs for treating cancer can be a challenge because of unfavorable pharmacokinetic parameters and cell penetrating capabilities. Genus Oncology has therefore encapsulated the GO-203 inhibitor in novel polymeric NPs to circumvent these challenges. Genus’s studies have shown that loading of GO-203 into tetra-block polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and enhanced by increasing PEG chain length. Additionally, we found that release of GO-203 from these NPs is sustained over at least 7 days. Importantly, GO-203/NPs treatment of MUC1-C-positive breast and lung cancer cells was more active with less frequent dosing than that achieved with non-encapsulated GO-203. Moreover, treatment with GO-203/NPs blocked MUC1-C homodimerization, suppressed AKT activation and down-regulated TIGAR expression, consistent with on-target effects. GO-203/NP treatment was also effective in conferring ROS-induced late apoptosis/necrosis and in inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/NPs to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable to that found when dosing GO-203 on a daily basis (Fig. 1A and B). These findings have thus defined an effective approach for sustained administration of GO-203 in novel PLA-PEG-PPG-PEG tetra-block NPs to target MUC1-C in cancer cells.
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Figure 1. A. Nude mice with subcutaneous ZR-75-1 hormone-dependent breast tumors (~100 mm3) were treated IP with vehicle control (closed squares) or 18 mg/kg GO-203 each day for 21 days (closed circles). Tumor volumes were determined on the indicated days of treatment. The results are expressed as tumor volumes (mean ± SEM). B. Nude mice with subcutaneous ZR-75-1 breast tumors (~60 mm3) were treated IP with vehicle control (closed squares) or 20 mg/kg GO-203/NPs (closed circles) once a week for 3 weeks. Tumor volumes were determined on the indicated days of treatment. The results are expressed as tumor volumes (mean ± SEM).
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