Sub theme 3.6
Neuro-oncology and Pain

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Goals of research: general outline

The overall aim of this scientific program is to study various aspects of cancer involving the nervous system, in close collaboration with many departments, including the departments of Neurology, Pathology, Neurosurgery, Immunology, Medical Oncology and Radiotherapy. The program focuses on the following three main topics:

1.1.     Primary Brain Tumors.

1.1.1   Identify molecular markers predicting prognosis and treatment response in glial tumors using large scale analysis (genomics, transcriptomics, methylomics, metabolomics and lipidomics) and high-end mass spectrometry.

1.1.2   Identify genes and proteins involved in gliomagenesis and angiogenesis.

1.1.3   Establish an effective treatment for patients with primary brain tumors.

1.2.     Paraneoplastic disorders. 

1.2.1   Identify the association between paraneoplastic autoantibodies, antigen specific T lymphocytes, clinical neurological syndrome and associated tumor.

1.2.2   Clone the target antigen of newly identified paraneoplastic autoantibodies.

1.2.3   Study the role of the paraneoplastic autoimmune response in anti-tumor immunity and neurological dysfunction.

1.3.     Pain. 

1.3.1   Study the role of neurotrophic factors in pain transmission in the superficial dorsal horn in animal models.

1.3.2   Establish an effective treatment for patients with cancer pain, focusing on neuropathic cancer pain and breakthrough pain.

Scientific achievements

2.1.     Primary Brain Tumors.

2.1.1   Using Affymetrix HU133 Plus 2.0 microarrays Gene expression profiles associated with treatment response in oligodendrogliomas were identified [3]. Subsequently, we identified differentially regulated splice variants and novel exons in glial brain tumors using exon expression arrays [2]. A large cohort of frozen glioma tissues (>300 samples) has been investigated using Affymetrix HU133 Plus 2.0 microarrays. We identified distinct molecular subgroups that are different from histological subgroups and correlate better with patient survival. The prognostic value of molecular subgroups was validated on three large independent sample cohorts. Specific genetic changes (EGFR amplification, IDH1 mutation and 1p/19q LOH) segregate in distinct molecular subgroups (Gravendeel et al. submitted).

2.1.2   Using a proteomics approach several biomarkers of glioma angiogenesis were identified, including caldesmon, fibronectin and colligin 2 [6, 10]. Using in integrated proteomics and genomics approaches several genes were identified that could be involved in gliomagenesis (e.g. fusion genes) based on functional studies (Bralten et al. submitted). A zebrafish model has been set-up to study glioma angiogenesis and blood brain barrier.

2.1.3   The department of Neurology participates in phase I trials and is coordinator/initiator of several large international phase II-III trials. Many translational projects are spin-off of these prospective and often randomized studies, which have identified several prognostic factors (1p/19q loss, MGMT promoter methylation, IDH1 mutations) [4, 5, 8, 9]. In addition, the Departments of Neurosurgery and Neurology are involved in Phase I-II clinical gene therapy studies.

2.2.     Paraneoplastic disorders. 

2.2.1   In a unique cohort of anti-Hu associated PNS patients, we have further defined the cellular immune response, both in blood and CSF [1].

2.2.3   We studied the effect of rituximab and human chorionic gonadotrophin (Sillevis Smitt et al. J Neurology, In Press) in Hu-PNS.

2.3.     Pain. 

2.3.1   In a study of neuropathic pain, the distribution of RET immunoreactivity in the rodent spinal cord and changes after nerve injury were studied.

2.3.2   We have studied the efficacy of various treatment strategies on breakthrough pain in cancer patients. In addition, we examined the effects of analgesic prescription and patient adherence on pain in a large Dutch outpatient cancer population.

Future plans: special goals and approach

3.1.     Primary Brain Tumors.

3.1.1   We will establish molecular classifiers based on expression arrays to predict survival and treatment response in glioma patients in collaboration with Skyline b.v. Classifiers will be validated in several independent international cohorts. Candidate serum protein biomarkers that correlate with glioma activity and treatment response will be validated in a large prospectively collected set of serum samples. Results will be correlated with clinical and radiological (MRI) data. State of the art proteomics approaches will be used and further developed to allow high throughput evaluation of relatively large numbers of candidate biomarkers.

3.1.2   Laser microdissection of glioma tissues and glioma vasculature will be combined with advanced mass spectrometry. The zebrafish model will be expanded to study angiogenesis in the brain and the blood brain barrier.

3.1.3   The department of neurology will participate in many (international) clinical trials. Target drugs include angiogenesis inhibitors and other small molecules. Attached to these studies are translational research projects on tissues correlates, aiming at molecular correlates of outcome. In the laboratory we will test combinations of small molecules on early glioma cultures and spheroids. The Neurosurgery department will start a new phase I-II gene therapy study.

3.2.     Paraneoplastic disorders. 

3.2.1   The humoral and cellular immunity will be further dissected using single cell PCR on CSF B cells and plasma cells.

3.2.2   Serum form autoimmune encephalitis patients that react with neuronal surface antigens will be used to identify target antigens. Technically, we will use immunoprecipitation combined with mass spectrometry, expression cloning and a candidate gene approach.

3.2.3   Sera from patients that react with identified neuronal surface antigens will be used in passive transfer studies both in vitro (slices) and in vivo (mice and rats) in collaboration with the Neuroscience department, as shown before [7].

3.3.     Pain. 

3.3.1   In collaboration with the hematology department, genes involved in chemotherapy induced neuropathic pain will be identified.

3.3.2   The department of Neurology will participate in clinical trials in cancer pain and neuropathic pain.

Most recent publications

1.            de Beukelaar JW, Milikan JC, Verjans GM, de Graaf MT, van Norden Y, Lamers CH, van den Bent MJ, Bromberg JE, Hulsenboom E, Sintnicolaas K, Gratama JW, Sillevis Smitt PA (2009) No evidence for the presence of HuD-specific T cells in the cerebrospinal fluid of patients with Hu-associated paraneoplastic neurological syndromes. J Neurol 256:279-282

2.            French PJ, Peeters J, Horsman S, Duijm E, Siccama I, van den Bent MJ, Luider TM, Kros JM, van der Spek P, Sillevis Smitt PA (2007) Identification of differentially regulated splice variants and novel exons in glial brain tumors using exon expression arrays. Cancer Research 67:5635-5642

3.            French PJ, Swagemakers SM, Nagel JH, Kouwenhoven MC, Brouwer E, van der Spek P, Luider TM, Kros JM, van den Bent MJ, Sillevis Smitt PA (2005) Gene expression profiles associated with treatment response in oligodendrogliomas. Cancer Research 65:11335-11344

4.            Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. New Engl J Med 352:997-1003

5.            Kouwenhoven MC, Gorlia T, Kros JM, Ibdaih A, Brandes AA, Bromberg JE, Mokhtari K, van Duinen SG, Teepen JL, Wesseling P, Vandenbos F, Grisold W, Sipos L, Mirimanoff R, Vecht CJ, Allgeier A, Lacombe D, van den Bent MJ (2009) Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951. Neuro Oncol Feb 17, Epub ahead of print

6.            Mustafa DA, Burgers PC, Dekker LJ, Charif H, Titulaer MK, Smitt PA, Luider TM, Kros JM (2007) Identification of glioma neovascularization-related proteins by using MALDI-FTMS and nano-LC fractionation to microdissected tumor vessels. Mol Cell Proteomics 6:1147-1157

7.            Sillevis Smitt P, Kinoshita A, DeLeeuw B, Moll W, Coesmans M, Jaarsma D, Henzen-Logmans S, Vecht C, De Zeeuw C, Sekiyama N, Nakanishi S, Shigemoto R (2000) Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. New Engl J Med 342:21-27

8.            van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27:1268-1274

9.            van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T (2006) Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715-2722

10.        Zheng PP, Hop WC, Sillevis Smitt PA, van den Bent MJ, Avezaat CJ, Luider TM, Kros JM (2005) Low-molecular weight caldesmon as a potential serum marker for glioma. Clin Cancer Res 11:4388-4392