131TiP ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886

Dean, A.; Price, T.J.; Sjoquist, K.; Aryal, N.; Mumford, J.; Day, F.; Yip, S.; Walsh, A.; Siu, D.; Jackson, C.; Padinharakam, S.; Lee, B.; Burge, M.; Lynam, J.; Tebbutt, N.; Wong, Z.W.J.; Lam, L.L.; Lee, J.; Chantrill, L.; Harris, M.

doi:10.1016/j.annonc.2022.10.167

Annals of Oncology

2022

DOI: 10.1016/j.annonc.2022.10.167

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131TiP ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886

A. Dean

T.J. Price²,

K. Sjoquist³

et al.

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2024

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Protease-activated CendR peptides targeting tenascin-C: mitigating off-target tissue accumulation

Tobi,

Haugas,

Rabi

et al. 2024

Drug Deliv. and Transl. Res.

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To achieve precision and selectivity, anticancer compounds and nanoparticles (NPs) can be targeted with affinity ligands that engage with malignancy-associated molecules in the blood vessels. While tumor-penetrating C-end Rule (CendR) peptides hold promise for precision tumor delivery, C-terminally exposed CendR peptides can accumulate undesirably in non-malignant tissues expressing neuropilin-1 (NRP-1), such as the lungs. One example of such promiscuous peptides is PL3 (sequence: AGRGRLVR), a peptide that engages with NRP-1 through its C-terminal CendR element, RLVR.Here, we report the development of PL3 derivatives that bind to NRP-1 only after proteolytic processing by urokinase-type plasminogen activator (uPA), while maintaining binding to the other receptor of the peptide, the C-domain of tenascin-C (TNC-C). Through a rational design approach and screening of a uPA-treated peptide-phage library (PL3 peptide followed by four random amino acids) on the recombinant NRP-1, derivatives of the PL3 peptide capable of binding to NRP-1 only post-uPA processing were successfully identified. In vitro cleavage, binding, and internalization assays, along with in vivo biodistribution studies in orthotopic glioblastoma-bearing mice, confirmed the efficacy of two novel peptides, PL3uCendR (AGRGRLVR↓SAGGSVA) and SKLG (AGRGRLVR↓SKLG), which exhibit uPA-dependent binding to NRP-1, reducing off-target binding to healthy NRP-1-expressing tissues. Our study not only unveils novel uPA-dependent TNC-C targeting CendR peptides but also introduces a broader paradigm and establishes a technology for screening proteolytically activated tumor-penetrating peptides. Graphical Abstract

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Protease-activated CendR peptides targeting tenascin-C: mitigating off-target tissue accumulation

Tobi,

Haugas,

Rabi

et al. 2024

Drug Deliv. and Transl. Res.

View full text Add to dashboard Cite

show abstract

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131TiP ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886

Cited by 1 publication

References 0 publications

Protease-activated CendR peptides targeting tenascin-C: mitigating off-target tissue accumulation

Protease-activated CendR peptides targeting tenascin-C: mitigating off-target tissue accumulation

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