Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors

Keding, Stacy J.

doi:10.1073/pnas.0401894101

Cited by 93 publications

(60 citation statements)

References 36 publications

(39 reference statements)

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“…The O-glycosidically linked oligosaccharides of mucins are being investigated in cancer as diagnostic and prognostic markers (Baldus et al 2004;Byrd and Bresalier 2004). Targeting immune response to simple mucin-type O-glycan chains (Tn, TF, and sialyl-Tn antigens) represents a promising approach for development of therapeutic vaccines against cancers (Keding and Danishefsky 2004;Lo Man et al 2004).…”

mentioning

confidence: 99%

UDP-N-Acetyl-d-Galactosamine: Polypeptide N-Acetylgalactosaminyltransferase-6 as a New Immunohistochemical Breast Cancer Marker

Berois

Mazal

Ubillos

et al. 2006

J Histochem Cytochem.

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S U M M A R Y Mucin O-glycosylation is characterized in cancer by aberrant expression of immature carbohydrate structures (Tn, T, and sialyl-Tn antigens). The UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-T) family enzymes regulate the initial steps of mucin O-glycosylation and could be responsible for the altered glycosylation observed in cancer. Considering that we recently found the ppGalNAc-T6 mRNA expressed in breast carcinomas, we produced a highly specific monoclonal antibody (MAb T6.3) to assess the expression profile of ppGalNAc-T6 protein product in breast tissues. The expression of ppGalNAc-T6 by breast carcinoma cells was confirmed on MCF-7 and T47D cell lines. In formalin-fixed tissues, ppGalNAc-T6 expression was observed in 60/74 (81%) breast cancers, 21/23 (91.3%) adjacent ductal carcinoma in situ (DCIS), 4/20 benign breast lesions (2/2 sclerosing adenosis and 2/13 fibroadenoma), and in 0/5 normal breast samples. We observed a statistically significant association of ppGalNAc-T6 expression with T1 tumor stage. This fact, as well as the observation that ppGalNAc-T6 was strongly expressed in sclerosing adenosis and in most DCIS, suggests that ppGalNAc-T6 expression could be an early event during human breast carcinogenesis. Considering that an abnormal O-glycosylation greatly contributes to the phenotype and biology of breast cancer cells, ppGalNAc-T6 expression could provide new insights about breast cancer glycobiology. polypeptide N-acetylgalactosaminyltransferases ppGalNAc-T6

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confidence: 99%

UDP-N-Acetyl-d-Galactosamine: Polypeptide N-Acetylgalactosaminyltransferase-6 as a New Immunohistochemical Breast Cancer Marker

Berois

Mazal

Ubillos

et al. 2006

J Histochem Cytochem.

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“…Inhibition of it would have limited consequences on normal healthy tissue, helping to reduce the side effects encountered with many current treatments. It has also been suggested that altered O-glycans in tumours could be targeted by vaccines [60][61][62]. However, there are some drawbacks to targeting pp-GalNAc-T6.…”

Section: Potential As a Drug Targetmentioning

confidence: 99%

UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

Banford¹,

Timson

2016

CCDT

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UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-6 (pp-GalNAc-T6) is a member of the N-acetyl-D-galactosamine transferase family. It catalyzes the addition of N-acetyl-D-galactosamine to proteins, often the first step in Oglycosylation of proteins. Glycosylated proteins play important roles in vivo in the cell membrane. These are often involved in cell-cell adhesion, cytoskeleton regulation and immune recognition. pp-GalNAc-T6 has been shown to be upregulated in a number of types of cancer. Abnormally glycosylated forms of mucin 1 (substrate of the enzyme), are used clinically as a biomarker for breast cancer. There is potential for other products of the pp-GalNAc-T6 catalyzed reaction to be used. It is also possible that pp-GalNAc-T6 itself could be used as a biomarker, since levels of this protein tend to be low in nonmalignant tissues. pp-GalNAc-T6 has been implicated in malignant transformation and metastasis of cancer cells. As such, it has considerable potential as a target for chemotherapy. To date, no selective inhibitors of the enzyme have been identified. However, general inhibitors of the enzyme family result in reduced cell surface Olinked glycosylation and induce apoptosis in cultured cells. Thus, a selective inhibitor of pp-GalNAc-T6 is likely to target cancer cells and could be developed into a novel anticancer therapy.

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“…Data available from this trial indicated that 94% (17/18) and 100% (18/18) of the patients with stage III and IV breast cancer, respectively, survived for five years after initiation of treatment (151,152). This impressive survival advantage led others to develop T and Tn antigen-based vaccination strategies that involved the activation of the immune response by the Keyhole Limpet Hemocyanin and other adjuvants or by using synthetic constructs of T and Tn antigens (153,154). Clinical trials are currently underway to determine the efficacy of these T and Tn antigen based vaccination approaches.…”

Section: Thomsen-friedenrich (T or Tf) Antigen-the Tn Antigen Was Firmentioning

confidence: 99%

The immunomodulating roles of glycoproteins in epithelial ovarian cancer

Felder¹

2012

Front Biosci

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The complexity of the immune system demands an intricate defense mechanism by tumors. Ovarian and other tumors employ specific glycoproteins and the associated glycan sequences to modulate immune responses. Glycoproteins enable tumor cells that express or secrete these molecules to evade immune cell attack and induce the immune system to promote tumor growth. This review focuses first on the immune environment in ovarian cancer, and the mechanisms of activation and inhibition that immune cells undergo in order to either attack or ignore a target cell. Next we illustrate the immunomodulatory roles of ovarian cancer-associated glycans and glycoproteins in 1. preventing immune synapse formation, 2. serving as ligands of immune cell receptors, 3. scavenging cytokines and chemokines, and 4. participating in the formation of autoantibodies against the tumor. The importance of these immunomodulating strategies from the view points of understanding the tumor immunology of ovarian tumors, potential origin of such mechanisms, and specific strategies to circumvent the glycoconjugate-mediated suppression of immune responses is discussed in this review. KeywordsGlycoproteins; T cells; NK cells; Epithelia Ovarian Cancer; MUC16; Glycodelin; MUC1; Mucins; Immune Synapse; Review INTRODUCTIONOvarian cancer is a highly insidious disease that is usually detected at a very late stage when the possibility of an efficient therapeutic management of the cancer is relatively low (1-3). Therefore, in most women with advanced ovarian cancer the five year survival rate is around 30-55% (4). Specific biomarkers that can detect the cancer at an early stage (when the survival rate after treatment is 80%) are not available (5,6). In women with advanced disease, the standard of care includes an initial surgical debulking of the tumor followed by an intense chemotherapy with platinum or taxol based compounds. Under these treatment conditions the cancer regresses and the low level of the tumor is monitored by measuring the Send correspondence to: Manish S. Patankar, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, 600 Highland Avenue, H4/657 CSC, Madison, patankar@wisc.edu. NIH Public Access Author ManuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 2015 February 12. Published in final edited form as:Front Biosci (Elite Ed). ; 4: 631-650. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript serum concentration of the biomarker CA125 (7-10). A steady elevation in serum CA125 levels from this nadir is indicative of recurrent disease (10).The progression of ovarian cancer requires the cancer cells to first develop on the surface of the ovary or along the walls of the fallopian tubes and then metastasize to other sites within the peritoneum (11)(12)(13)(14)(15)(16)(17)(18). Starting with the initiation of the cancer to metastasis, the tumor cells encounter distinct immunologic environments and therefore have to adapt at each site to not only overcome immune recognition but al...

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Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors

Cited by 93 publications

References 36 publications

UDP-N-Acetyl-d-Galactosamine: Polypeptide N-Acetylgalactosaminyltransferase-6 as a New Immunohistochemical Breast Cancer Marker

UDP-N-Acetyl-d-Galactosamine: Polypeptide N-Acetylgalactosaminyltransferase-6 as a New Immunohistochemical Breast Cancer Marker

UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

The immunomodulating roles of glycoproteins in epithelial ovarian cancer

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