Mucins as contrast agent targets for fluorescence-guided surgery of pancreatic cancer

Muilenburg, Kathryn M.; Isder, Carly C.; Radhakrishnan, Prakash; Batra, Surinder K.; Ly, Quan P.; Carlson, Mark A.; Bouvet, Michael; Hollingsworth, Michael A.; Mohs, Aaron M.

doi:10.1016/j.canlet.2023.216150

Cited by 8 publications

(6 citation statements)

References 194 publications

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“…For example, Muilenburg et al targeted the cleaved portion of MUC1, CA19.9, by two antibody probes for fluorescence guided surgery (FSG) of PDAC in which they observed minimal background signal, with a much stronger signal at least 25 times greater in the tumor as compared to background organs. 35 In another study, a commercially available MUC1 antibody was used to target both subcutaneous and orthotopic pancreatic tumors, and researchers found higher tumor signals in both tumor models as compared to background noise. 36 Furthermore, MUC1 expression is highly uniform despite the heterogenicity of PDAC, and it is present on the cell surface, thus providing easy access to targeted formulations.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine–Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice

Shrestha,

Ghanwatkar,

Mahto

et al. 2024

ACS Appl. Mater. Interfaces

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Gemcitabine (GEM) is a nucleoside analogue approved as a first line of therapy for pancreatic ductal adenocarcinoma (PDAC). However, rapid metabolism by plasma cytidine deaminase leading to the short half-life, intricate intracellular metabolism, ineffective cell uptake, and swift development of chemoresistance downgrades the clinical efficacy of GEM. ONC201 is a small molecule that inhibits the Akt and ERK pathways and upregulates the TNF-related apoptosis-inducing ligand (TRAIL), which leads to the reversal of both intrinsic and acquired GEM resistance in PDAC treatment. Moreover, the pancreatic cancer cells that were able to bypass apoptosis after treatment of ONC201 get arrested in the G1-phase, which makes them highly sensitive to GEM. To enhance the in vivo stability of GEM, we first synthesized a disulfide bond containing stearate conjugated GEM (lipid− GEM), which makes it sensitive to the redox tumor microenvironment (TME) comprising high glutathione levels. In addition, with the help of colipids 1,2-dioleoyl-glycero-3-phosphocholine (DOPC), cholesterol, and 1,2-distearoyl-glycero-3-phosphoethanolamine-poly(ethylene glycol)-2000 (DSPE-PEG 2000), we were able to synthesize the lipid−GEM conjugate and ONC201 releasing liposomes. A cumulative drug release study confirmed that both ONC201 and GEM showed sustained release from the formulation. Since MUC1 is highly expressed in 70−90% PDAC, we conjugated a MUC1 binding peptide in the liposomes which showed higher cytotoxicity, apoptosis, and cellular internalization by MIA PaCa-2 cells. A biodistribution study further confirmed that the systemic delivery of the liposomes through the tail vein resulted in a higher accumulation of drugs in orthotopic PDAC tumors in NSG mice. The IHC of the excised tumor grafts further confirmed the higher apoptosis and lower metastasis and cell proliferation. Thus, our MUC1 targeting binary drug-releasing liposomal formulation showed higher drug payload, enhanced plasma stability, and accumulation of drugs in the pancreatic orthotopic tumor and thus is a promising therapeutic alternative for the treatment of PDAC.

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Section: Discussionmentioning

confidence: 99%

Gemcitabine–Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice

Shrestha,

Ghanwatkar,

Mahto

et al. 2024

ACS Appl. Mater. Interfaces

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“…Thus, other mucins can be employed in combination with MUC16 or potential targets. 24,29,43 We are collaboratively pursuing MUC4 and MUC5AC as targets for FGS. These mucins have shown strong potential as targets for pancreatic cancer.…”

Section: Future Directionsmentioning

confidence: 99%

“…10,11,22,23 Many proteins show promise as a target for FGS in pancreatic cancer, particularly the mucin family of proteins. 5,7,9,[24][25][26][27][28][29] The mucin family consists of transmembrane and secretion proteins, which are upregulated or uniquely expressed in many cancers. 24 In pancreatic cancer, at least 12 mucin family proteins are upregulated or uniquely expressed.…”

Section: Introductionmentioning

confidence: 99%

“…5,7,9,[24][25][26][27][28][29] The mucin family consists of transmembrane and secretion proteins, which are upregulated or uniquely expressed in many cancers. 24 In pancreatic cancer, at least 12 mucin family proteins are upregulated or uniquely expressed. 24 We have chosen to actively target the mucins, in particular mucin 16 (MUC16), for FGS of pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

“…24 In pancreatic cancer, at least 12 mucin family proteins are upregulated or uniquely expressed. 24 We have chosen to actively target the mucins, in particular mucin 16 (MUC16), for FGS of pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting mucins for fluorescence-guided surgery of pancreatic cancer

Mohs,

Muilenburg,

Ehrhorn

2024

Molecular-Guided Surgery: Molecules, Devices, and Applications X

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Oncogenic KRAS, Mucin 4, and Activin A‐Mediated Fibroblast Activation Cooperate for PanIN Initiation

Hu,

Huang,

Hsu

et al. 2023

Advanced Science

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Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic‐clear 3D histology is used to analyze entire pancreases of 2‐week‐old Pdx1‐Cre; LSL‐KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN‐associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+‐driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.

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Mucins as contrast agent targets for fluorescence-guided surgery of pancreatic cancer

Cited by 8 publications

References 194 publications

Gemcitabine–Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice

Gemcitabine–Lipid Conjugate and ONC201 Combination Therapy Effectively Treats Orthotopic Pancreatic Tumor-Bearing Mice

Targeting mucins for fluorescence-guided surgery of pancreatic cancer

Oncogenic KRAS, Mucin 4, and Activin A‐Mediated Fibroblast Activation Cooperate for PanIN Initiation

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