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Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. (Gustav Ullenhag)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. (Gunilla Enblad)ORCID iD: 0000-0002-0594-724X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Tobias Sjöblom)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Fredrik Pontén)
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2017 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 143, no 6, p. 961-970Article in journal (Refereed) Published
Abstract [en]

Purpose Tyrosine kinase inhibitors like sunitinib and sorafenib are commonly used to treat metastatic renal cell cancer patients. Cubilin is a membrane protein expressed in the proximal renal tubule. Cubilin and megalin function together as endocytic receptors mediating uptake of many proteins. There is no established predictive marker for metastatic renal cell cancer patients and the purpose of the present study was to assess if cubilin can predict response to treatment with tyrosine kinase inhibitors.

Methods Cubilin protein expression was analyzsed in tumor tissue from a cohort of patients with metastatic renal cell cancer (n = 139) using immunohistochemistry. One hundred and thirty six of the patients were treated with sunitinib or sorafenib in the first- or second-line setting. Thirty of these were censored because of toxicity leading to the termination of treatment and the remaining (n = 106) were selected for the current study.

Results Fifty-three (50%) of the tumors expressed cubilin in the membrane. The median progression-free survival was 8 months in patients with cubilin expressing tumors and 4 months in the cubilin negative group. In addition, the overall survival was better for patients with cubilin positive tumors. We also found that the fraction of cubilin negative patients was significantly higher in the non-responding group (PFS ≤3 months) compared to responding patients (PFS >3 months).

Conclusions We show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib.

Place, publisher, year, edition, pages
2017. Vol. 143, no 6, p. 961-970
Keywords [en]
Cubilin, Predictive marker, Renal cancer, Tissue microarray, Tyrosine kinase inhibitor
National Category
Clinical Medicine Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-318129DOI: 10.1007/s00432-017-2365-yISI: 000401411200005PubMedID: 28260162OAI: oai:DiVA.org:uu-318129DiVA, id: diva2:1084175
Funder
Knut and Alice Wallenberg FoundationAvailable from: 2017-03-23 Created: 2017-03-23 Last updated: 2019-04-02Bibliographically approved
In thesis
1. Intratumoral Predictive Markers in Metastatic Renal Cancer Patients
Open this publication in new window or tab >>Intratumoral Predictive Markers in Metastatic Renal Cancer Patients
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is no established predictive marker for the treatment of metastatic renal cell cancer (mRCC) patients. With a predictive marker, patients unlikely to respond could be selected upfront and offered other therapy options. Thereby, unnecessary toxicity could be avoided and costs would be reduced. Tyrosine kinase inhibitors (TKI) are the cornerstone in the treatment of mRCC. The aim of the thesis was to evaluate and hopefully define tumoral predictive markers for treatment with the common TKIs sunitinib and sorafenib.

The studies are based on immunohistochemical analyses of renal cancer tissues from 139 primary tumors sampled in a tissue microarray. Three proteins with a specific and differential expression in RCC were chosen in co-operation with the Human Protein Atlas project. Since TKIs block vascular endothelial growth factor receptors (VEGFR) on tumor vessels, angiogenesis associated proteins were also analysed as putative predictive biomarkers.

In two studies, the renal proteins cubilin (CUBN) and pyruvate kinase L/R (PKLR) were investigated. Our results indicate that these membranous proteins are positive predictive factors for sunitinib and sorafenib therapies. Patients with high membranous expressions of CUBN and PKLR respectively experienced significantly longer progression free survivals (PFS) and overall survivals (OS) compared to the other patients. Combining CUBN and PKLR negative tumors, a patient group with a particularly short PFS could be defined, possibly consisting of patients not benefitting at all from treatment with sunitinib or sorafenib.

Studies of tumoral annexin A1 (ANXA1) and epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) demonstrated predictive potential for sunitinib but not for sorafenib treatment. A low cytoplasmic expression of ANXA1 was significantly associated with longer PFS and OS in patients treated with sunitinib. A combined analysis with CUBN and ANXA1 expression indicated a higher predictive value than the expressions of either marker alone. We further observed that a high vascular endothelial expression of ELTD1 is predictive for a longer PFS and OS in sunitinib treated patients. The expressions of CD34 which is a marker of the number of vessels and the sunitinib target VEGFR2 failed to demonstrate significant associations with PFS.

To conclude, our real world studies indicate that CUBN, PKLR, ANXA1 and ELTD1 are potential tumoral biomarkers, to predict benefit from treatment with sunitinib (all four proteins) and sorafenib (CUBN and PKLR) in patients suffering from mRCC.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1504
Keywords
Renal cell cancer, predictive marker, tyrosine kinase inhibitor, tissue microarray, cubilin, annexin A1, PKLR, ELTD1
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-360251 (URN)978-91-513-0467-0 (ISBN)
Public defence
2018-12-01, Enghoffsalen, Akademiska Sjukhuset, ingång 50, Uppsala, 09:15 (Swedish)
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Available from: 2018-11-07 Created: 2018-10-09 Last updated: 2018-11-19

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Niinivirta, MarjutEnblad, GunillaEdqvist, Per-HenrikPontén, FredrikDragomir, AncaUllenhag, Gustav J.

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