Modeling the Diversity of Epithelial Ovarian Cancer through Ten Novel Well Characterized Cell Lines Covering Multiple Subtypes of the Disease

Sauriol, Alexandre; Simeone, Kayla; Portelance, Lise; Meunier, Liliane; Leclerc-Desaulniers, Kim; Ladurantaye, Manon de; Chergui, May; Kendall‐Dupont, Jennifer; Rahimi, Kurosh; Carmona, Eurı́dice; Provencher, Diane; Mes-Masson, Anne-Marie

doi:10.3390/cancers12082222

Cited by 12 publications

(11 citation statements)

References 106 publications

(174 reference statements)

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“…To evaluate PODO447-ADC cytotoxic activity, we selected a panel of Podxl-expressing human cancer cell lines, including SKOV3 (ovarian, ascites-derived), MIA PaCa-2 (pancreatic, primary tumor-derived), A-172 (glioblastoma, primary tumor-derived), ONS-76 (medulloblastoma, primary tumor-derived), THP-1 (acute monocytic leukemia), and patient tumor-derived TOV3133D and OV3331 [ovarian, primary solid tumor- and ascites-derived, respectively ( 35 , 36 )] ( Figure 4A ; Supplementary Figure 4 ). Cells were treated with serial dilutions of PODO447- or palivizumab-ADC for 6 days and then evaluated for cell viability.…”

Section: Resultsmentioning

confidence: 99%

“…HEK-293 WT, HUVEC, SKOV3, A-172, MIA PaCa-2, THP-1 and MDA-MB-231 cells were obtained from the American Tissue Culture Collection (ATCC). Glycosylation-mutant HEK-293 cells ( 33 , 34 ) and patient tumor-derived epithelial high grade serous ovarian OV3331 and TOV3133D cancer cell lines ( 35 , 36 ) were previously described. ONS-76 medulloblastoma cell line was generously provided by Dr. Sorensen from the University of British Columbia.…”

Section: Methodsmentioning

confidence: 99%

“…Human ovarian cancer SKOV3 cells were grown in DMEM F-12 with 15 mM HEPES (Sigma, #D6421) supplemented with 10% FBS, 0.2 mM L-glutamine (Gibco, #25030-081) and 10 U/ml P/S. OV3331 and TOV3133D cells were grown in complete OSE medium ( 36 ). ONS-76 cells were grown in RPMI (Gibco, #11875093) supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

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Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models

Hernaez

Hughes

et al. 2022

Front. Oncol.

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Podocalyxin (Podxl) is a CD34-related cell surface sialomucin that is normally highly expressed by adult vascular endothelia and kidney podocytes where it plays a key role in blocking adhesion. Importantly, it is also frequently upregulated on a wide array of human tumors and its expression often correlates with poor prognosis. We previously showed that, in xenograft studies, Podxl plays a key role in metastatic disease by making tumor initiating cells more mobile and invasive. Recently, we developed a novel antibody, PODO447, which shows exquisite specificity for a tumor-restricted glycoform of Podxl but does not react with Podxl expressed by normal adult tissue. Here we utilized an array of glycosylation defective cell lines to further define the PODO447 reactive epitope and reveal it as an O-linked core 1 glycan presented in the context of the Podxl peptide backbone. Further, we show that when coupled to monomethyl auristatin E (MMAE) toxic payload, PODO447 functions as a highly specific and effective antibody drug conjugate (ADC) in killing ovarian, pancreatic, glioblastoma and leukemia cell lines in vitro. Finally, we demonstrate PODO447-ADCs are highly effective in targeting human pancreatic and ovarian tumors in xenografted NSG and Nude mouse models. These data reveal PODO447-ADCs as exquisitely tumor-specific and highly efficacious immunotherapeutic reagents for the targeting of human tumors. Thus, PODO447 exhibits the appropriate characteristics for further development as a targeted clinical immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models

Hernaez

Hughes

et al. 2022

Front. Oncol.

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“…OV3331 cells were grown in complete OSE medium. 36 All cell lines were maintained at 37°C, 5% CO 2 and high humidity.…”

Section: Methodsmentioning

confidence: 99%

PODO447: a novel antibody to a tumor-restricted epitope on the cancer antigen podocalyxin

Hernaez

Hughes

Dean

et al. 2020

J Immunother Cancer

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BackgroundThe success of new targeted cancer therapies has been dependent on the identification of tumor-specific antigens. Podocalyxin (Podxl) is upregulated on tumors with high metastatic index and its presence is associated with poor outcome, thus emerging as an important prognostic and theragnostic marker in several human cancers. Moreover, in human tumor xenograft models, Podxl expression promotes tumor growth and metastasis. Although a promising target for immunotherapy, the expression of Podxl on normal vascular endothelia and kidney podocytes could hamper efforts to therapeutically target this molecule. Since pathways regulating post-translational modifications are frequently perturbed in cancer cells, we sought to produce novel anti-Podxl antibodies (Abs) that selectively recognize tumor-restricted glycoepitopes on the extracellular mucin domain of Podxl.MethodsSplenic B cells were isolated from rabbits immunized with a Podxl-expressing human tumor cell line. Abs from these B cells were screened for potent reactivity to Podxl+ neoplastic cell lines but not Podxl+ primary endothelial cells. Transcripts encoding heavy and light chain variable regions from promising B cells were cloned and expressed as recombinant proteins. Tumor specificity was assessed using primary normal tissue and an ovarian cancer tissue microarray (TMA). Mapping of the tumor-restricted epitope was performed using enzyme-treated human tumor cell lines and a glycan array.ResultsOne mAb (PODO447) showed strong reactivity with a variety of Podxl+ tumor cell lines but not with normal primary human tissue including Podxl+ kidney podocytes and most vascular endothelia. Screening of an ovarian carcinoma TMA (219 cases) revealed PODO447 reactivity with the majority of tumors, including 65% of the high-grade serous histotype. Subsequent biochemical analyses determined that PODO447 reacts with a highly unusual terminal N-acetylgalactosamine beta-1 (GalNAcβ1) motif predominantly found on the Podxl protein core. Finally, Ab–drug conjugates showed specific efficacy in killing tumor cells in vitro.ConclusionsWe have generated a novel and exquisitely tumor-restricted mAb, PODO447, that recognizes a glycoepitope on Podxl expressed at high levels by a variety of tumors including the majority of life-threatening high-grade serous ovarian tumors. Thus, tumor-restricted PODO447 exhibits the appropriate specificity for further development as a targeted immunotherapy.

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“…Ovarian cancer represents a complex and heterogeneous malignant gynecological pathology ( 15 ) with a high mortality rate, with and a 5-year survival rate <45% ( 16 ), which is considered to be the second most common gynecologic malignancy in developed countries ( 17 ). The risk of ovarian cancer development is ~1% among patients during lifetime in developed countries ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Ovarian endometriosis, a precursor of ovarian cancer: Histological aspects, gene expression and microRNA alterations (Review)

et al. 2021

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Ovarian endometriosis is a frequent chronic gynecological disease with an uncertain evolution regarding its progression or association with ovarian malignant lesions. The present review summarized the histological aspects, gene expression and microRNA (miRNA/miR) alterations associated with ovarian endometriosis and cancer and their possible interaction. The endometriosis-ovarian cancer interaction has been proposed by certain researchers as a single entity. Histological results indicated that endometriosis has been in different circumstances coexisting with ovarian cancer, with reference to endometrioid and clear cell carcinoma. Endometriosis with moderate and severe atypia can influence cell proliferation and architecture, resulting in a possible malignant transformation. Gene expression analysis indicated that the pathologies of both endometriosis and ovarian cancer are characterized by genetic instability from a molecular point of view, as several important genetic mutations, including ARID1A, PI3KCA, PTEN, BRCA1, BRCA2, TP53 and KRAS genes, were identified. miRNA alterations have been implicated in the regulation of gene expression. Common dysregulated miRNAs, such as miR-331, miR-335, miR-891, miR-548, miR-124, miR-148, miR-215, miR-192, miR-337, miR-153, miR-155, miR-144, miR-221 and miR-3688 were extensively investigated in understanding endometriosis and ovarian cancer evolution. From a combined viewpoint including histological aspects, gene expression and miRNA alterations, it is reasonable to speculate that endometriosis is associated with ovarian cancer. Ovarian endometriosis lesions may present a risk for ovarian malignant lesions, which supports a model of endometriosis as a malignant precursor. However, the endometriosis-ovarian cancer association is not widely accepted in the literature and additional studies are required to validate this association.

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Modeling the Diversity of Epithelial Ovarian Cancer through Ten Novel Well Characterized Cell Lines Covering Multiple Subtypes of the Disease

Cited by 12 publications

References 106 publications

Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models

Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models

PODO447: a novel antibody to a tumor-restricted epitope on the cancer antigen podocalyxin

Ovarian endometriosis, a precursor of ovarian cancer: Histological aspects, gene expression and microRNA alterations (Review)

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