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Glioma heterogeneity and the L-Amino acid transporter-1 (LAT1): A first step to stratified BPA-based BNCT? D. Ngoga1; C. L. Schütz1; A. Detta1; S. Green2; G. Cruickshank1 1University of Birmingham, School of Cancer Sciences, Queen Elizabeth Hospital, Department of Neurosurgery 2University of Birmingham, Queen Elizabeth Hospital, Department of Medical Physics ICNCT-16, June 2014, Helsinki Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Glioma Genetics To date, glioblastoma subject to the most extensive genomic profiling of any cancer (Dunn, et al Genes Dev. 2012 26: 756-784) The Cancer Genome Atlas Research Network (Parsons et al. 2008) and other studies have enabled us to systematically and comprehensively define the genomic landscape of glioblastoma. Malignant gliomas are characterized by genetic instability and complex alterations in: Chromosome structure Copy number. Variation in post translational modification. ICNCT-16, Helsinki, June 2014 / Desire Ngoga 2 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Glioma Genetics Patterns of gene expression have been collated to identify molecular subgroups with putative prognostic or predictive significance. Verhaak, et al. 2010 ICNCT-16, Helsinki, June 2014 / Desire Ngoga 3 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Isocitrate Dehydrogenase – 1 mutation Perhaps the most important of the discoveries arising from the TCGA studies. IDH-1 cytosolic component of the glycolytic pathway (Bleeker, et al. 2009) A spontaneous mutation in the gene for IDH1R132 identified in 12% of patients GBM. 12%–17% of AML (Mardis et al. 2009) Majority of central and periosteal cartilaginous tumors (Amary et al. 2011) 23% of cholangiocarcinomas (Borger et al. 2012) ICNCT-16, Helsinki, June 2014 / Desire Ngoga 4 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Isocitrate Dehydrogenase – 1 mutation Found in majority of LGG Confers a significantly improved prognosis. ICNCT-16, Helsinki, June 2014 / Desire Ngoga 5 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Methylation and treatment response The DNA repair enzyme 0-6-methylguanine-DNA methyltransferase (MGMT) is responsible for reversing the damage caused by temozolomide. Methylation of the promoter region encoding MGMT has a critical role in patients response to Temozolomide. Only ~ 50% of patients with GBM have methylated MGMT. (Esteller, et al. 2000) The remainder of patients with unmethylate, IDH WT tumours continue to have have poor prognosis. ICNCT-16, Helsinki, June 2014 / Desire Ngoga 6 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? The challenge for BNCT Understand how BNCT fit in this new framework of understanding of GBM biology? Understand and explain differences in treatment response to BNCT. Understand the impact of glioma heterogeneity on Boron uptake and therefore the effectiveness of BNCT. ICNCT-16, Helsinki, June 2014 / Desire Ngoga 7 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? BPA based BNCT 4-dihydroxyboryl-L-phenylalanine (BPA) no selectivity/specificity, but increased AA need ( LAT1) low toxicity, resistance in tumor cells, low background coupling to fructose / mannitol to increase solubility uptake mostly regulated via amino acid transporter 4F2hc/LAT1 ICNCT-16, Helsinki, June 2014 / Desire Ngoga 8 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? 4F2hc/LAT1 - Structure SLC3A2 has been shown to interact with SLC7A7 (Pfeiffer, R;et al 1999) heavy chain (also called CD98) light chain The monomers alone do not function as transporter! ICNCT-16, Helsinki, June 2014 / Desire Ngoga 9 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Study aims To understand role of LAT1 genetics in glioma To determine the influence of LAT1 gene expression of patient survival. Understand the interaction between LAT1 gene expression and know mutations relevant to GBM (IDH1 mutation) ICNCT-16, Helsinki, June 2014 / Desire Ngoga 10 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Study Method 1 Interrogate publically available gene expression databases (REMBRANDT) Genes encoding the constituent proteins of the LAT1 transporter (SLC3A2 and SLC7A5) as well as related transporter SLC7A7 were analysed. REMBRANDT - Repository for Molecular Brain Neoplasia Data Home Help Support Tutorials ICNCT-16, Helsinki, June 2014 / Desire Ngoga Cite Data Disclaimer 15/ 06/ 2014 11:11 Login 11 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 1 – SLC3A2 (Heavy chain) Gene Expression Plot (SLC3A2) ALL GLIOMA (454) ASTROCYTOMA (148) GBM (228) MIXED: (11) NON_TUMOR: (28) OLIGODENDROGLIOMA: (67) UNKNOWN: (67) ICNCT-16, Helsinki, June 2014 / Desire Ngoga Kaplan-Meier Survival Plot for Samples with Differential SLC3A2 Gene Expression (All Glioma) Number of samples in group Up-Regulated: 96 Intermediate: 247 Log-rank p-value: Up-Regulated vs. Intermediate: 9.322837E-4 12 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 1 – SLC3A2 (Heavy chain) Kaplan-Meier Survival Plot for Samples with Differential SLC3A2 Gene Expression (Oligodendroglioma) Number of samples in group: Up-Regulated: 14 Intermediate: 36 Log-rank p-value Up-Regulated vs. Intermediate: p=0.0062 ICNCT-16, Helsinki, June 2014 / Desire Ngoga 13 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 1 – SLC7A5 (Light chain) Gene Expression Plot (SLC7A5) ALL GLIOMA (454) ASTROCYTOMA (148) GBM (228) MIXED: (11) NON_TUMOR: (28) OLIGODENDROGLIOMA: (67) UNKNOWN: (67) ICNCT-16, Helsinki, June 2014 / Desire Ngoga Kaplan-Meier Survival Plot for Samples with Differential SLC7A5 Gene Expression (All Glioma) Number of samples in group: Up-Regulated: 8 Down-Regulated: 30 Intermediate: 305 Log-rank p-value Up-Regulated vs. Down-Regulated: 0.073 14 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 1 – SLC7A7 (y+LAT1) Gene Expression Plot (SLC7A7) ALL GLIOMA (454) ASTROCYTOMA (148) GBM (228) MIXED: (11) NON_TUMOR: (28) OLIGODENDROGLIOMA: (67) UNKNOWN: (67) ICNCT-16, Helsinki, June 2014 / Desire Ngoga Kaplan-Meier Survival Plot for Samples with Differential SLC7A7 Gene Expression (All Glioma) Number of samples in group: Up-Regulated: Intermediate: Down-Regulated: Log-rank p-value Up-Regulated vs. Intermediate: 192 149 2 2.16x10-8 15 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 1 – SLC7A7 (y+LAT1) Kaplan-Meier Survival Plot for Samples with Differential SLC7A7 Gene Expression (Astrocytoma) Number of samples in group: Up-Regulated: 51 Intermediate: 54 Log-rank p-value(for significance of difference of survival between group of samples) Up-Regulated vs. Intermediate: 6.68x10-4 ICNCT-16, Helsinki, June 2014 / Desire Ngoga 16 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Summary – Results 1 SLC3A2 Increased expression in GBM compared with normal brain and Low grade glioma Up-regulation is associated with a significantly worse prognosis when considering all glioma Particular prognostic significance in oligodendroglioma. SLC7A5 Expression not upregulated in GBM increased expression possibly associated with better prognosis (Not significant) SLC7A7 Increased expression in GBM compared with normal brain and Low grade glioma Particular prognostic significance in astrocytoma. ICNCT-16, Helsinki, June 2014 / Desire Ngoga 17 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Study Method 2 Identified patients treated at the Queen Elizabeth Hospital, Birmingham for low grade glioma who had an overall survival of > 5 years (Long survival) and <5 years (short survival). RNA extraction from paraffin embedded tumour samples Performed whole exome sequencing (Oxford Gene Technology) Correlated gene expression of SLC3A2, SLC7A5 and SLC7A7 to patient survival. Identify if there was any association of LAT1 gene expression with IDH1 mutation. ICNCT-16, Helsinki, June 2014 / Desire Ngoga 18 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 2 – SLC3A2 (Heavy chain) ICNCT-16, Helsinki, June 2014 / Desire Ngoga 19 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 2 – SLC7A5 (Light chain) ICNCT-16, Helsinki, June 2014 / Desire Ngoga 20 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 2 – SLC7A7 ICNCT-16, Helsinki, June 2014 / Desire Ngoga 21 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Results 2 – IDH1 status ICNCT-16, Helsinki, June 2014 / Desire Ngoga 22 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Summary – Results 2 SLC3A2 Increased expression in these grade 2 glioma samples did not appear to influence survival. SLC7A5 Increased expression in was associated with a significantly worse prognosis. (p = 0.001) SLC7A7 Increased expression in was associated with a significantly worse prognosis. (p = 0.016) ICNCT-16, Helsinki, June 2014 / Desire Ngoga 23 Glioma heterogeneity and the LAT-1: A first step to stratified BPA-based BNCT? Discussion Though numbers of samples were small, we were able to show the significant impact of the gene expression of the LAT1 transporter on the treatment and survival of glioma patients. The fact that transporter up-regulation is associated with IDH1 wild type patients and a significantly worse prognosis offers the potential to stratify these patients for BNCT ICNCT-16, Helsinki, June 2014 / Desire Ngoga 24 Thank you for your attention Further questions? [email protected]