Mucin-based Targeted Pancreatic Cancer Therapy

Torres, María P.; Chakraborty, Subhankar; Souchek, Joshua J.; Batra, Surinder K.

doi:10.2174/13816128112092472

Cited by 83 publications

(83 citation statements)

References 70 publications

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“…Some have been studied as biomarkers or targeted for pancreatic cancer treatment. Clinical studies suggest a correlation between the overexpression of mucins and pancreatic cancer (10)(11)(12)(13), and have demonstrated a link between the aberrant expression and differential overexpression of mucin glycoproteins and the initiation, progression, and poor prognosis of the disease (14-16, 19, 30). However, little advancement has been made in this area.…”

Section: Discussionmentioning

confidence: 99%

“…The mucins may prevent drugs from accessing their sites of action. The expression of several mucins, including MUC1, MUC4, MUC5AC, and MUC16, is highly upregulated in pancreatic ductal adenocarcinoma (PDAC), pancreatic intraepithelial neoplasia (PanIN), intrapapillary mucinous neoplasms, and mucinous cystic neoplasms from patients with pancreatic cancer (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The extent to which the dense mucin mesh influences the antiproliferative activity of 5-fluorouracil (5-FU) was investigated using human pancreatic cancer cells (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of the Kras and EGFR signaling pathways is involved in increased cell proliferation, angiogenesis, metastasis, and decreased apoptosis. Clinical studies also suggest a correlation between overexpression of mucins and pancreatic cancers (10)(11)(12)(13). One important issue is whether synthesis of mucins by core enzymes is regulated coordinately.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

et al. 2016

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Pancreatic cancer is an aggressive neoplasm with almost uniform lethality and a 5-year survival rate of 7%. Several overexpressed mucins that impede drug delivery to pancreatic tumors have been therapeutically targeted, but enzymes involved in mucin biosynthesis have yet to be preclinically evaluated as potential targets. We used survival data from human patients with pancreatic cancer, next-generation sequencing of genetically engineered Kras-driven mouse pancreatic tumors and human pancreatic cancer cells to identify the novel core mucin-synthesizing enzyme GCNT3 (core 2 b-1,6 N-acetylglucosaminyltransferase). In mouse pancreatic cancer tumors, GCNT3 upregulation (103-fold; P < 0.0001) was correlated with increased expression of mucins (5 to 87-fold; P < 0.04-0.0003). Aberrant GCNT3 expression was also associated with increased mucin production, aggressive tumorigenesis, and reduced patient survival, and CRISPR-mediated knockout of GCNT3 in pancreatic cancer cells reduced proliferation and spheroid formation. Using in silico small molecular docking simulation approaches, we identified talniflumate as a novel inhibitor that selectively binds to GCNT3. In particular, docking predictions suggested that three notable hydrogen bonds between talniflumate and GCNT3 contribute to a docking affinity of À8.3 kcal/mol. Furthermore, talniflumate alone and in combination with low-dose gefitinib reduced GCNT3 expression, leading to the disrupted production of mucins in vivo and in vitro. Collectively, our findings suggest that targeting mucin biosynthesis through GCNT3 may improve drug responsiveness, warranting further development and investigation in preclinical models of pancreatic tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

et al. 2016

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“…These features are exploited for making specific antibodies. These antibodies serve as the guides for the vectors with the therapeutic cargo to the cancer cells [88,100,101].…”

Section: Receptors Displayed On Living Cells -Targets For Therapeuticmentioning

confidence: 99%

Frontiers in Suicide Gene Therapy of Cancer

Malecki¹

2012

J Genet Syndr Gene Ther

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The National Cancer Institute (NCI) and the American Cancer Society (ACS) predict that 1,638,910 men and women will be diagnosed with cancer in the USA in 2012. Nearly 577,190 patients will die of cancer of all sites this year. Patients undergoing current systemic therapies will suffer multiple side effects from nausea to infertility. Potential parents, when diagnosed with cancer, will have to deposit oocytes and sperms prior to starting systemic radiation or chemo-therapy for the future genetic testing and in vitro fertilization, while trying to avoid risks of iatrogenic mutations in their germ cells. Otherwise, children of parents treated with systemic therapies, will be at high risk of developing genetic disorders. According to these predictions, this year will carry another, very poor therapeutic record again.The ultimate goal of cancer therapy is the complete elimination of all cancer cells, while leaving all healthy cells unharmed. One of the most promising therapeutic strategies in this regard is cancer suicide gene therapy (CSGT), which is rapidly progressing into new frontiers.The therapeutic success, in CSGT, is primarily contingent upon precision in delivery of the therapeutic transgenes to the cancer cells only. This is addressed by discovering and targeting unique or / and over-expressed biomarkers displayed on the cancer cells and cancer stem cells. Specificity of cancer therapeutic effects is further enhanced by designing the DNA constructs, which put the therapeutic genes under the control of the cancer cell specific promoters. The delivery of the suicidal genes to the cancer cells involves viral, as well as synthetic vectors, which are guided by cancer specific antibodies and ligands. The delivery options also include engineered stem cells with tropisms towards cancers. Main mechanisms inducing the cancer cells' deaths include: transgenic expression of thymidine kinases, cytosine deaminases, intracellular antibodies, telomeraseses, caspases, DNases. Precautions are undertaken to eliminate the risks associated with transgenesis.Progress in genomics and proteomics should help us in identifying the cancer specific biomarkers and metabolic pathways for developing new strategies towards clinical trials of targeted and personalized gene therapy of cancer.

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“…Moreover, MUC1 is overexpressed on most adenocarcinomas, including breast, lung, colon, pancreas, stomach, and prostate cancers. [23][24][25] MUC1-MNP-SiO 2 (RITC) can be used to detect various cancers that are overexpressing MUC1. MUC1 is not a hallmark for ovarian cancer in general: one-step detection of CTC using MUC1 will be limited to the diagnosis of epithelial ovarian cancer.…”

mentioning

confidence: 99%

One-step detection of circulating tumor cells in ovarian cancer using enhanced fluorescent silica nanoparticles

Kim¹,

Chung²,

Jeong³

et al. 2013

IJN

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Ovarian cancer is the fifth-leading cause of cancer-related deaths among women as a result of late diagnosis. For survival rates to improve, more sensitive and specific methods for earlier detection of ovarian cancer are needed. This study presents the development of rapid and specific one-step circulating tumor cell (CTC) detection using flow cytometry in a whole-blood sample with fluorescent silica nanoparticles. We prepared magnetic nanoparticle (MNP)-SiO 2 (rhodamine B isothiocyanate [RITC]) (MNP-SiO 2 [RITC] incorporating organic dyes [RITC, λ max(ex/em) = 543/580 nm]) in the silica shell. We then controlled the amount of organic dye in the silica shell of MNP-SiO 2 (RITC) for increased fluorescence intensity to overcome the autofluorescence of whole blood and increase the sensitivity of CTC detection in whole blood. Next, we modified the surface function group of MNP-SiO 2 (RITC) from -OH to polyethylene glycol (PEG)/COOH and conjugated a mucin 1 cell surface-associated (MUC1) antibody on the surface of MNP-SiO 2 (RITC) for CTC detection. To study the specific targeting efficiency of MUC1-MNP-SiO 2 (RITC), we used immunocytochemistry with a MUC1-positive human ovarian cancer cell line and a negative human embryonic kidney cell line. This technology was capable of detecting 100 ovarian cancer cells in 50 µL of whole blood. In conclusion, we developed a one-step CTC detection technology in ovarian cancer based on multifunctional silica nanoparticles and the use of flow cytometry.

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Mucin-based Targeted Pancreatic Cancer Therapy

Cited by 83 publications

References 70 publications

Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

Frontiers in Suicide Gene Therapy of Cancer

One-step detection of circulating tumor cells in ovarian cancer using enhanced fluorescent silica nanoparticles

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