Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation

Abstract

Purpose The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell penetrating capabilities. Experimental Design Encapsulation of the MUC1-C inhibitor, GO-203, in novel polymeric nanoparticles (NPs) was studied for effects on intracellular targeting of MUC1-C signaling and function. Results Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. Additionally, we found that release of GO-203 from these NPs is controllable over at least 7 days. GO-203/NP treatment of MUC1-C-positive breast and lung cancer cells in vitro 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, consistent with on-target effects. GO-203/NP treatment was also effective in downregulating TIGAR, disrupting redox balance and 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 those found when dosing on a daily basis with GO-203. Conclusions These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA-(PEG-PPG-PEG) NPs to target MUC1-C in cancer cells and (ii) the potential delivery of other anti-cancer peptide drugs.

Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas

“…The BET bromodomain inhibitors GSK525762 and TEN-010 are being evaluated in Phase I clinical trials. Moreover, a Phase I trial of GO-203 has been completed in patients with refractory solid tumors and has been formulated in nanoparticles for assessing the effectiveness of this agent in treating NSCLC (50). Based on the present results, subsequent studies that assess the activity of GO-203 with BET bromodomain inhibitors could be potentially informative in the setting of KRAS mutant NSCLC and possibly other MYC-dependent cancers.…”

MUC1-C Oncoprotein Integrates a Program of EMT, Epigenetic Reprogramming and Immune Evasion in Human Carcinomas

“…Treatment of cancer cells with these agents is associated with increases in ROS, loss of self-renewal, downregulation of MUC1-C-induced signaling pathways and induction of late apoptotic/necrotic death [13, 24, 27, 50]. Based on these and other findings, the MUC1-C inhibitor GO-203 has been studied in a Phase I trial for patients with advanced carcinomas and, as a result of a favorable safety profile, has been formulated in nanoparticles for the treatment of patients with cancers that overexpress the MUC1-C oncoprotein [51]. …”

Systemic delivery of the tumor necrosis factor gene to tumors by a novel dual DNA-nanocomplex in a nanoparticle system

“…One of the major challenges has been the systemic delivery of cationic peptide-DNA complexes to tumor cells at sufficient levels because of DNA degradation in serum (17, 21). To address this obstacle, we developed novel polymeric NPs with high molecular weight PLA for the systemic delivery of peptide cargoes to tumor cells (18, 20). Additionally, for effective DNA delivery, we designed a linear short HCR peptide that maintains DNA condensation, imparts endosomal escape properties and directs nuclear localization (16).…”

“…The plasmids pEGFP-N3 (Clontech, Palo Alto, CA, USA) and pE425-TNF (10) were purified using the GenElute HP endotoxin free plasmid maxiprep kit (Sigma, St. Louis, MO, USA). PLA-PEG block co-polymer of 75 kDa PLA was designed and synthesized as reported (18). …”