Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014; Early Online: 1–2

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Amyotrophic lateral sclerosis onset after prolonged treatment with a VEGF receptors inhibitor Antonio Canosa1,2, Andrea Calvo1,3,4, Marco Barberis1,5, Maura Brunetti1,5, Gabriella Restagno5, Stefania Cammarosano1, Antonio Ilardi1, Maria C. Vigliani3, Adriano ChiÒ1,3,4 & Cristina Moglia1 1ALS

Centre, ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Turin, of Neuroscience, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genova, Genoa, 3Neurologia 2, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, 4Neuroscience Institute of Torino, Turin, and 5Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy 2Department

Key words: Amyotrophic lateral sclerosis, vascular endothelial growth factor, sunitinib

Introduction Amyotrophic lateral sclerosis causes upper and lower motor neurons degeneration. Respiratory failure usually leads to death within three years. ALS is considered a complex disease, involving genetic and environmental factors: 10% of cases are familial (FALS), the others appear sporadically (SALS). Genetic mutations are detected in two-thirds of FALS and ∼10% of SALS (1). In rodents, homozygous deletions of the hypoxiaresponsive element (HRE) in the vascular endothelial growth factor gene (VEGF-A) causes motor neuron degeneration (2) and the administration of VEGF-A gene or recombinant VEGF-A protein increases survival (3). No VEGF-A mutation has been reported in ALS patients, but an association with the AA genotype of the -2578C/A SNP was found in males (3). We report an apparently SALS case with onset one year after starting a chronic treatment with sunitinib, a VEGF receptors (VEGF-R) inhibitor, for a metastatic renal cell carcinoma (mRCC) and a rapid course. Case report The patient presented right hand weakness and wasting when he was 62 years of age. Three months later he showed dysarthria, dysphagia, upper limbs weakness, wasting and spasticity, hyperreflexia at four

limbs, widespread fasciculations, bilateral Hoffmann and Babinski signs. CK was 206 UI/l. Familial history was negative for neurodegenerative diseases. At age 56 years he was diagnosed with a RCC and underwent radical nephrectomy. At age 61 years, lung and adrenal metastases were discovered, and brain MRI detected a right parietal, periventricular, subcentimetric metastasis. He started sunitinib, a VEGF-R inhibitor approved for mRCC, 50 mg/day orally. At our first evaluation he was still taking sunitinib. Serum anti-Hu, -Yo, -Ri, -Ma1, -Ma2, -CV2, -amphiphysin antibodies were absent. Six months after ALS onset he showed normal cognition, spastic tetraparesis, diffuse muscle atrophy and respiratory failure. Thirteen months from onset he died from respiratory failure, refusing non-invasive ventilation. Clinic and radiologic follow-up excluded neoplasm progression along the whole course of ALS and sunitinib was not discontinued. A written informed consent for genetic analysis was collected. The screening of c9orf72, SOD1, TARDBP, FUS,VCP, OPTN and ANG was negative. Three VEGF SNPs, previously identified to be associated with ALS (-2578C/A, -1154G/A, -634G/C) (3) were tested; the genotype was CGG/AGG. Discussion We report an apparently SALS case with onset after a prolonged treatment with sunitinib, a VEGF-R

Correspondence: A. Canosa, ALS Centre, ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, via Cherasco 15, 10126 Turin, Italy. E-mail: [email protected] (Received 6 June 2014; accepted 20 September 2014) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.969274

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inhibitor. The possible role of VEGF in ALS has been suggested by the observation that homozygous HRE deletions in the VEGF-A gene cause mainly lower motor neuron disease in mice (2). The intramuscular administration of VEGF-A gene to SOD1G93A mice via lentiviral transfer and the treatment of SOD1-G93A rats with intracerebroventricular recombinant VEGF-A prolonged survival (3). Subjects carrying AAG/AAG or AGG/AGG haplotypes of VEGF SNPs -2578C/A, -1154G/A, -634G/C were first reported to have increased risk of ALS (3). Subsequent studies refuted this finding, but a metaanalysis showed an increased risk of ALS in males carrying the -2578AA genotype (3). Although conclusive evidence is lacking, the literature suggests a role of VEGF in ALS. Our patient carried neither the previously hypothesized at-risk haplotypes nor the -2578/AA genotype. He started sunitinib, an inhibitor of all VEGF-R isoforms, one year before ALS onset. VEGF inhibitors are the first-line therapy in ∼77% of patients with mRCC in the USA, of which ∼67% receive sunitinib (4). In phase III trials with sunitinib in mRCC, median progression-free survival was 11 months (5), median duration of treatment was 7.6 months (6). Neurological adverse events of sunitinib are rare (7), but data on long-term follow-up are lacking because it is indicated only in advanced neoplasms. Our patient did not display neoplasm progression during the ALS course but we cannot exclude that mRCC contributed to clinical deterioration. The existence of paraneoplastic ALS is debated, although the association between ALS and tumours, including RCC (8), has been reported. Nevertheless, the worsening despite cancer treatment makes this possibility less likely. Currently, there are no reports of ALS associated with VEGF-R inhibitors treatment, but the monitoring of chronic administration has been advocated (2). Prolonged treatments with VEGF-R antagonists might accelerate motor neuron degeneration, in agreement with the observation that SOD1-G93A mice carrying HRE deletions show a worse and faster course than SOD1-G93A mice without deletions (3). Such therapies might also trigger motor neuron degeneration. Sunitinib has multiple targets, including PDGF-R a/b and GDNF-R (9); their inhibition could contribute to its deleterious effect. This is in agreement with data from animal models on the involvement of GDNF in ALS by itself and in synergy with VEGF (3). In apparent contrast with data reported here, sunitinib slightly increases survival of primary cortical neurons in vitro (10). Further data

are necessary to confirm a causal link between VEGF inhibitors administration and ALS and to elucidate the underlying mechanisms. Declaration of interest:  The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This work was in part supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata), the European Community’s Health Seventh Framework Programme, the Joint Programme – Neurodegenerative Disease Research (Sophia Project), granted by Italian Health Ministry, the Fondazione Mario ed Anna Magnetto and the Associazione Piemontese per l’Assistenza alla SLA (APASLA). References 1. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17:17–23. 2. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, et  al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001;28:131–8. 3. Pronto-Laborinho ACI, Pinto SI, de Carvalho M. Roles of vascular endothelial growth factor in amyotrophic lateral sclerosis. Biomed Res Int. 2014;2014:947513. doi: 10.1155/2014/947513. Epub 2014 Apr 29. 4. Jonasch E, Signorovitch JE, Lin PL, Liu Z, Culver K,Pal SK, et al. Treatment patterns in metastatic renal cell carcinoma: a retrospective review of medical records from US community oncology practices. Curr Med Res Opin. 2014;9:1–10. 5. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et  al. Sunitinib versus interferonalpha in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24. 6. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renalcell carcinoma. N Engl J Med. 2013;369:722–31. 7. Aparicio-Gallego G, Blanco M, Figueroa A, GarcíaCampelo R, Valladares-Ayerbes M, Grande-Pulido E, et al. New insights into molecular mechanisms of sunitinib-associated side-effects. Mol Cancer Ther. 2011;10:2215–23. 8. Evans BK, Fagan C, Arnold T, Dropcho EJ, Oh SJ. Paraneoplastic motor neuron disease and renal cell carcinoma: improvement after nephrectomy. Neurology. 1990;40:960–2. 9. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, et al. In vivo anti-tumour activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9:327–37. 10. Sanchez A, Tripathy D, Yin X, Luo J, Martinez JM, Grammas P. Sunitinib enhances neuronal survival in vitro via NF-kB-mediated signalling and expression of cyclooxygenase-2 and inducible nitric oxide synthase. J Neuroinflammation. 2013;10:93.

Amyotrophic lateral sclerosis onset after prolonged treatment with a VEGF receptors inhibitor.

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