Soluble Mesothelin-Related Peptides Levels in Patients with Malignant Mesothelioma

Franko, Alenka; Dolžan, Vita; Kovač, Viljem; Arnerić, Niko; Dodic-Fikfak, Metoda

doi:10.1155/2012/430689

Cited by 28 publications

(48 citation statements)

References 42 publications

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“…[30][31][32][33][34] The presence of SMRP can also alter the binding capacity of mesothelin-targeting therapeutic agents. 22,23 On the basis of these data, we used the serum of 21 patients with metastatic colon and pancreatic cancers in competition assays with selected Fabs.…”

Section: Competition Tests With Smrp In Patients' Serum and Cell Supementioning

confidence: 99%

A new anti-mesothelin antibody targets selectively the membrane-associated form

Asgarov

Balland

Tirole

et al. 2017

mAbs

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Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that shows promise as a target for antibody-directed cancer therapy. High levels of soluble forms of the antigen represent a barrier to directing therapy to cellular targets. The ability to develop antibodies that can selectively discriminate between membrane-bound and soluble conformations of a specific protein, and thus target only the membrane-associated antigen, is a substantive issue. We show that use of a tolerance protocol provides a route to such discrimination. Mice were tolerized with soluble mesothelin and a second round of immunizations was performed using mesothelin transfected P815 cells. RNA extracted from splenocytes was used in phage display to obtain mesothelin-specific antigen-binding fragments (Fabs) that were subsequently screened by flow cytometry and ELISA. This approach generated 147 different Fabs in 34 VH-CDR3 families. Utilizing competition assays with soluble protein and mesothelin-containing serum obtained from metastatic cancer patients, 10 of these 34 VH-CDR3 families were found to bind exclusively to the membrane-associated form of mesothelin. Epitope mapping performed for the 1H7 clone showed that it does not recognize GPI anchor. VH-CDR3 sequence analysis of all Fabs showed significant differences between Fabs selective for the membrane-associated form of the antigen and those that recognize both membrane bound and soluble forms. This work demonstrates the potential to generate an antibody specific to the membrane-bound form of mesothelin. 1H7 offers potential for therapeutic application against mesothelin-bearing tumors, which would be largely unaffected by the presence of the soluble antigen.

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Section: Competition Tests With Smrp In Patients' Serum and Cell Supementioning

confidence: 99%

A new anti-mesothelin antibody targets selectively the membrane-associated form

Asgarov

Balland

Tirole

et al. 2017

mAbs

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“…So far, all efforts to implement screening and early diagnosis of mesothelioma for the high-risk populations have failed, or are still in the investigative phase 2. Our survey proves that very few patients are diagnosed at an early stage when multi-modality treatment with a curative intent is a realistic option.…”

Section: Discussionmentioning

confidence: 70%

“…Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumour arising from mesothelial surfaces of pleura 1,2…”

Section: Introductionmentioning

confidence: 99%

“…However, due to the long latent period between exposure to asbestos and the development of the disease, the incidence of mesothelioma is expected to increase for at least another decade. Since the risk for development of mesothelioma persists for several decades after professional or environmental exposure, the burden of the disease will shift to the older population 2–6…”

Section: Introductionmentioning

confidence: 99%

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Improved survival after introduction of chemotherapy for malignant pleural mesothelioma in Slovenia: Population-based survey of 444 patients

Kovač¹,

Zwitter²,

Žagar³

2012

Radiology and Oncology

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BackgroundMalignant pleural mesothelioma is a rare tumour with increasing frequency throughout the world. Due to long latency after exposure to asbestos, restrictions in the production and use of asbestos have not yet alleviated the burden of mesothelioma. During the last decade, several trials confirmed the benefit of systemic treatment with drugs such as doublets with cisplatina and gemcitabine or pemetrexed for carefully selected patients in good performance status. The purpose of this survey was to assess the impact of systemic treatment for the whole national population of patients with mesothelioma.Patients and methods.A retrospective study included all patients in Slovenia with histologically confirmed diagnosis of malignant pleural mesothelioma in the period from 1974 till 2008. Data from the Cancer Registry of Slovenia were supplemented by review of clinical records of the Institute of Oncology in Ljubljana where virtually all non-surgical treatment for mesothelioma was performed. We analysed the incidence, treatment, and survival of patients treated in the era of infrequent chemotherapy (1974–2003, the first period) and after it (2004–2008, the second period).ResultsThe survey included 444 patients, of whom 325 and 119 were diagnosed in the first and second period, respectively. Joinpoint regression analysis showed that after 1995 the trend in crude incidence rates increased more rapidly; the annual change was 0.03 per 100,000 per year before 1995 and 0.06 per 100,000 per year after. There was clear male predominance (70%) throughout the period covered by the survey. The proportion of patients above 65 years of age increased from 41.8% to 54.6% for the first and second period, respectively (p = 0.02). With a total of 52 (11.7%) operated patients, surgical treatment was rare and used only for selected patients with early disease and without comorbidity, leading to their relatively long median survival of 13.6 months. Chemotherapy was applied to 56 (17.2%) and to 96 (80.7%) patients during the first and second period, respectively. While a variety of older drugs were used in the first period, the most common regimen in the second period (applied to 91 patients) was doublet of low-dose gemcitabine in prolonged infusion and cisplatin. For the whole population of patients regardless the mode of treatment, median survival was 7.4 and 12.6 months (p-value = 0.037) for the first and second period, respectively.ConclusionsIncreasing incidence, male predominance and increased proportion of older patients confirm that the burden of mesothelioma persists in spite of a 15-years old ban in the production of asbestos. Modern chemotherapy, and in particular treatment with low-dose gemcitabine in prolonged infusion and cisplatin significantly prolonged median survival of patients with malignant pleural mesothelioma in Slovenia.

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“…A lower probability of the presence of MPM in patients with normal SMRP levels can be considered due to the high negative predictive value of the method, but the limiting lower sensitivity cannot entirely excluded the presence of disease (16). Several findings suggest that SMRP may be a useful tumor marker for detecting the progression of malignant mesothelioma and evaluating tumor response to treatment (17).…”

Section: Soluble Mesothelin-related Peptides (Smrp)mentioning

confidence: 99%

Serum mesothelin and other biomarkers: what have we learned in the last decade?

et al. 2018

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In the last decade there is been much interest in noninvasive, economic and well-accepted diagnostic tests for screening of subjects exposed to asbestos, and in patients with malignant pleuric mesothelioma (MPM) for diagnosis or monitoring response to treatment. Several biomarkers have been suggested as tools for screening and early diagnosis of MPM. Currently, in patients with MPM, have been reported high levels of soluble mesothelin-related peptides (SMRP), plasmatic osteopontin (pOPN), vimentin, fibulin-3 and many others as promising marker for diagnosis, even their use in prevention monitoring is still discussed. In this type of disease, a key role could be played by miRNAs, which expression has been investigated in a large series of MPM to examine new pathways useful in diagnosis, prognosis and therapy. An altered expression of some proteins has been reported, useful as biomarkers, in comparative proteomic analysis of malignant pleural mesothelioma. New promising markers are nowadays under study and alone or better in combination, they'll be very helpful in diagnosing, monitoring mesothelioma patients or for screening of risk groups.

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Soluble Mesothelin-Related Peptides Levels in Patients with Malignant Mesothelioma

Cited by 28 publications

References 42 publications

A new anti-mesothelin antibody targets selectively the membrane-associated form

A new anti-mesothelin antibody targets selectively the membrane-associated form

Improved survival after introduction of chemotherapy for malignant pleural mesothelioma in Slovenia: Population-based survey of 444 patients

Serum mesothelin and other biomarkers: what have we learned in the last decade?

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