Antibodies Against Specific MUC16 Glycosylation Sites Inhibit Ovarian Cancer Growth

Rao, Thapi D.; Fernández‐Tejada, Alberto; Axelrod, Abram; Rosales, Nestor; Yan, Xiu-Juan; Thapi, Sahityasri; Wang, Amy; Park, Kay J.; Nemieboka, Brandon; Xiang, Jingyi; Lewis, Jason S.; Olvera, Narciso; Levine, Douglas A.; Spriggs, David R.

doi:10.1021/acschembio.7b00305

Cited by 32 publications

(42 citation statements)

References 30 publications

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“…S6 ), an activity known from tumor cell growth regulation ( 91 , 92 ). Since Gal-3 association with synthetic glycoclusters and polyvalent cell surface ligands can initiate its self-aggregation ( 38 , 93 ) depending on the length of NT and even leading to bridging of two different counterreceptors, e.g., MUC16(CA125) and EGFR/β 1 -integrin ( 93 – 95 ), the nature of the ligand(s) appears to modulate this aspect of lectin activity. We first asked the question whether this type of protein design is capable of strong aggregation, when the CRD’s affinity to the ligand is higher than that of the Gal-3/Lac interaction.…”

Section: Resultsmentioning

confidence: 99%

Exploring functional pairing between surface glycoconjugates and human galectins using programmable glycodendrimersomes

Xiao

Ludwig

Romanò

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceCells are decorated with charged and uncharged carbohydrate ligands known as glycans, which are responsible for several key functions, including their interactions with proteins known as lectins. Here, a platform consisting of synthetic nanoscale vesicles, known as glycodendrimersomes, which can be programmed with cell surface-like structural and topological complexity, is employed to dissect design aspects of glycan presentation, with specificity for lectin-mediated bridging. Aggregation assays reveal the extent of cross-linking of these biomimetic nanoscale vesicles—presenting both anionic and neutral ligands in a bioactive manner—with disease-related human and other galectins, thus offering the possibility of unraveling the nature of these fundamental interactions.

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Section: Resultsmentioning

confidence: 99%

Exploring functional pairing between surface glycoconjugates and human galectins using programmable glycodendrimersomes

Xiao

Ludwig

Romanò

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, targeting the carboxyl-terminal domain of MUC16, which is retained by the tumor cells after cleavage, can expand the present immunotherapy. In context to this, there are more recent reports of monoclonal antibodies targeting the retained carboxy terminus that have been developed [32, 33, 146, 147]. Another hurdle in the field is the incomplete understanding of the structural and functional diversity of different MUC16 domains along with the aberrant glycoforms and possible splice variants, which are seen during disease condition.…”

Section: Expert Opinionmentioning

confidence: 99%

MUC16 as a novel target for cancer therapy

Aithal

Rauth

Kshirsagar

et al. 2018

Expert Opinion on Therapeutic Targets

168

141

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MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.

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“…It helped to explain that high MUC16 meant poor prognosis. On the contrary, presence of MUC16 neo-antigen-specific T cells in cancer patients suggested that MUC16 could serve as a potential target for cancer immunotherapy and radioimmunotherapy (16,18,19), which might possibly benefit our subject population.…”

Section: Discussionmentioning

confidence: 99%

MUC16 in non-small cell lung cancer patients affected by familial lung cancer and indoor air pollution: clinical characteristics and cell behaviors

Chen¹,

Huang²,

Kanwal³

et al. 2019

Transl. Lung Cancer Res.

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Background: Inherited susceptibility and environmental carcinogens are crucial players in lung cancer etiology, and both exhibit population heterogeneity. MUC16 is overexpressed in various cancers and often associated with poor prognosis. Present work was to investigate the clinical significance of MUC16 in non-small cell lung cancer patients affected by familial lung cancer (FLC) and indoor air pollution caused by coal use. Methods: Clinicopathologic characteristics and MUC16 expression were analyzed and evaluated in our subject population. Vectors were constructed for MUC16 gene knockout and overexpression, then we examined how MUC16 affected lung cancer cell behaviors, including proliferation, migration, invasion and chemoresistance. Results: FLC showed significant association with early-onset (P<0.01) and later stage (P<0.01). Indoor air pollution was associated with younger age (P<0.01), later stage (P<0.05) and AD histology type (P<0.05). Interestingly, two age peaks were observed in our FLC and sporadic group respectively, possibly suggesting multiple major contributors to lung cancer in our subject population. MUC16 overexpression was significantly associated with FLC (P<0.05), indoor air pollution (P<0.01) and later stage (P<0.01), additionally more metastasis cases were observed in patients with up-regulated MUC16 (18.1% vs. 10.3%). Taken together, elevated MUC16 may potentially be one molecular character of FLC in local residents. Intriguingly, patients with more MUC16 up-regulation seemed to have a lower number of white blood cells, especially neutrophils, this reflected MUC16's role in immune regulation. In cell behavior experiments, high MUC16 level could contribute to lung cancer cell proliferation, migration, invasion and chemoresistance, but there were variations among cell lines. Conclusions: MUC16 plays crucial roles in lung cancer pathogenesis, progression and chemoresistance. Interestingly, its association with FLC and indoor air pollution highlights the complexity of lung cancer etiology. Our findings provide useful information to study the intricate interaction between environmental carcinogens and population genetic background.

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Antibodies Against Specific MUC16 Glycosylation Sites Inhibit Ovarian Cancer Growth

Cited by 32 publications

References 30 publications

Exploring functional pairing between surface glycoconjugates and human galectins using programmable glycodendrimersomes

Exploring functional pairing between surface glycoconjugates and human galectins using programmable glycodendrimersomes

MUC16 as a novel target for cancer therapy

MUC16 in non-small cell lung cancer patients affected by familial lung cancer and indoor air pollution: clinical characteristics and cell behaviors

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