Autoantibodies to Ezrin are an early sign of pancreatic cancer in humans and in genetically engineered mouse models

Capello, Michela; Cappello, Paola; Linty, Federica; Chiarle, Roberto; Sperduti, Isabella; Novarino, Anna; Salacone, Paola; Mandili, Giorgia; Naccarati, Alessio; Sacerdote, Carlotta; Beghelli, Stefania; Bersani, Samantha; Barbi, Stefano; Bassi, Claudio; Scarpa, Aldo; Nisticò, Paola; Giovarelli, Mirella; Víneis, Paolo; Milella, Michèle; Novelli, Francesco

doi:10.1186/1756-8722-6-67

Cited by 44 publications

(51 citation statements)

References 36 publications

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“…This alludes to the non-specific nature of the symptoms of pancreatic cancer, but also raises the possibility of an earlier diagnosis that may improve outcome. Whilst one recent study has assessed pre-diagnostic PDAC samples (from the prospective EPIC cohort), reporting that autoantibodies against ezrin appear early in PDAC development, CA19-9 levels were unfortunately not reported in the 16 cases examined (49). …”

Section: Discussionmentioning

confidence: 99%

Serum CA19-9 Is Significantly Upregulated up to 2 Years before Diagnosis with Pancreatic Cancer: Implications for Early Disease Detection

O’Brien

Sandanayake

Jenkinson

et al. 2015

Clinical Cancer Research

166

141

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Purpose Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1 and REG3A are present prior to clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis. Experimental Design This nested case control study within UKCTOCS included 118 single- and 143 serial-serum samples from 154 post-menopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched non-cancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1 and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times prior to diagnosis and for prognosis was evaluated. Results At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 yrs before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in ~20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20-23 months were estimated for test-positive cases. Pre-diagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR 2.69 and 3.15, respectively). Conclusions CA19-9 and CA125 have encouraging sensitivity for detecting pre-clinical pancreatic cancer and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is up-regulated late in the course of pancreatic cancer development.

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Section: Discussionmentioning

confidence: 99%

Serum CA19-9 Is Significantly Upregulated up to 2 Years before Diagnosis with Pancreatic Cancer: Implications for Early Disease Detection

O’Brien

Sandanayake

Jenkinson

et al. 2015

Clinical Cancer Research

166

141

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“…Further validation of the three-marker panel in independent prediagnostic cohorts will be required to demonstrate utility for pancreatic cancer screening, leading to the development of an US Food and Drug Administration-approved test for targeted screening populations. Moreover, further improvement in marker performance may result from inclusion in the panel of additional marker types other than circulating proteins (15)(16)(17)(18)(19)(20)(21)(22)46) through critical testing of marker combinations. …”

Section: Discussionmentioning

confidence: 99%

“…As a result, there is substantial ongoing effort to identify additional serological biomarkers that complement CA19-9 for the detection of early-stage PDAC. Markers investigated include proteins (9)(10)(11)(12)(13)(14), metabolites (15)(16)(17), autoantibodies (18,19), miRNAs (20)(21)(22), markers with aberrant glycosylation (CA19-9 and Tn antigens) (6,23,24), and exosomes (25). In view of the wide array of potential biomarkers, there is a need for systematic evaluation of candidates using CA19-9 as an anchor marker given its established performance.…”

mentioning

confidence: 99%

Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer

Capello

Bantis

Scélo

et al. 2016

JNCI J Natl Cancer Inst

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123

125

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Background: CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone. Methods: Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n ¼ 187), benign pancreatic disease (n ¼ 93), and healthy controls (n ¼ 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided. Results: Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] ¼ 0.917 to 0.981) and 0.887 (95% CI ¼ 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P ¼ .008, test set).

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“…26 Combined detection of antibodies to Ezrin, phosphorylated ENO1, and CA 19-9 correctly discriminates PDA from control patients with high sensitivity and specificity. 25 A cell surface proteoglycan, glypican-1, specifically enriched on PDA cell-derived exosomes, was found to be able to discriminate early stages of pancreatic cancer. 27 Validating these newly discovered markers in large cohorts of early and advanced patients with PDA, as well as in selected risk populations, and developing easy and convenient clinical tests for their detection will greatly facilitate curative surgical and immune-based therapies.…”

mentioning

confidence: 99%

“…24 A promising discovery of biomarkers for the early diagnosis of PDA came from a serological proteome approach, which identified autoantibodies as a potential diagnostic marker in patients with PDA, in a genetically engineered mouse (GEM) model of PDA and in a prediagnostic cohort. These autoantibodies recognize the cytoskeletal protein Ezrin 25 and the phosphorylated α-enolase (ENO1), a glycolytic enzyme, which also functions as a plasminogen receptor. 26 Combined detection of antibodies to Ezrin, phosphorylated ENO1, and CA 19-9 correctly discriminates PDA from control patients with high sensitivity and specificity.…”

mentioning

confidence: 99%

Pancreatic cancer vaccine: a unique potential therapy

Cappello¹,

Principe²,

Novelli³

2015

GICTT

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Pancreatic ductal adenocarcinoma (PDA) is a lethal disease and is one of the cancers that is most resistant to traditional therapies. Historically, neither chemotherapy nor radiotherapy has provided any significant increase in the survival of patients with PDA. Despite intensive efforts, any attempts to improve the survival in the past 15 years have failed. This holds true even after the introduction of molecularly targeted agents, chosen on the basis of their involvement in pathways that are considered to be important in PDA development and progression. Recently, however, FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) treatment has provided a limited survival advantage in patients with advanced PDA. Therefore, effective therapeutic strategies are urgently needed to improve the survival rate of patients with PDA. Results from the last 10 years of research in the field of PDA have helped to identify new immunological targets and develop new vaccines that are capable of stimulating an immune response. In addition, the information obtained about the role of the tumor microenvironment in suppressing the immune response and the possibility of targeting PDA microenvironment to limit immune suppression and enhance the response of effector T-cells has opened new avenues for treating this incurable disease. The time is ripe for developing new therapeutic approaches that are able to effectively counteract the progression and spreading of PDA. This review discusses the potential prospects in the care of patients with pancreatic cancer through vaccination and its combination therapy with surgery, chemotherapy, targeting of the tumor microenvironment, and inhibition of immunological checkpoints. Keywords: pancreatic cancer, vaccines, T-cells, antibody, immunotherapy Pancreatic cancerAlthough lung, breast, prostate, and colorectal cancers are considered to be the "big four" cancer types in the USA, pancreas and liver cancers are expected to surpass breast, prostate, and colorectal cancers to become the second and third leading causes of cancer-related deaths by 2030, respectively.1 Pancreatic ductal adenocarcinomas (PDAs) arise from the exocrine pancreas and account for 95% of pancreatic cancers. In the USA, there were an estimated 48,960 cases of new-onset pancreatic cancer in 2015, which led to 40,560 deaths, with a 5-year survival rate of ∼7%.3 PDA is nearly universally lethal; ,20% of patients are suitable candidates for surgery at the time of diagnosis, and the median survival rate is 3.5 months and 12.6 months for nonresected patients and resected patients, respectively.2,4 PDA evolves from noninvasive precursor lesions that do not invade the basement membrane. [5][6][7] Three precursors have been characterized, namely, pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms.

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Autoantibodies to Ezrin are an early sign of pancreatic cancer in humans and in genetically engineered mouse models

Cited by 44 publications

References 36 publications

Serum CA19-9 Is Significantly Upregulated up to 2 Years before Diagnosis with Pancreatic Cancer: Implications for Early Disease Detection

Serum CA19-9 Is Significantly Upregulated up to 2 Years before Diagnosis with Pancreatic Cancer: Implications for Early Disease Detection

Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer

Pancreatic cancer vaccine: a unique potential therapy

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