François Fauteux, National Research Council Canada, Emerging strategies for computational ADC target selection and prioritization, World ADC 2017, San Diego

1. Emerging strategies for computational
ADC target selection and prioritization
François Fauteux, Ph.D.
National Research Council Canada
Information and Communication Technologies
World ADC, San Diego
September 20, 2017

2. Outline
2
• Data warehousing
• Tumor classification
• ADC target selection
• Alternative splicing
• Genomic alterations
• Business intelligence

3. Molecular data
3
• NGS
• Illumina HiSeq
• STAR 2-pass (RNA-seq)
• BWA-MEM (WXS)
• GENCODE 22
• GRCh38.p2
• Microarray
• HG-U133 Plus 2.0
• BrainArray 20
Whole exome
Cancer Normal Cancer Normal Paired
Blood 1490 2212 134 507 54
Bone marrow 4678 274 151 0 149
Brain 2753 1735 667 1261 396
Breast 6173 584 1097 327 1044
Colon 3858 669 635 395 590
Heart 0 117 0 408 0
Kidney 1185 392 887 160 405
Liver 506 503 371 168 375
Lung 2391 501 1026 428 1066
Muscle 0 381 0 427 0
Ovary 1351 135 374 97 443
Pancreas 286 113 177 174 183
Prostate 356 157 499 158 498
Skin 84 834 103 891 470
Stomach 955 97 375 224 441
Uterus 293 124 603 118 542
Microarray RNA-seq

4. Data sources
4
• Microarray data & metadata
• GEO https://www.ncbi.nlm.nih.gov/geo
• GEOmetadb https://gbnci-abcc.ncifcrf.gov/geo
• NGS data & metadata
• GDC https://gdc.cancer.gov
• dbGap https://www.ncbi.nlm.nih.gov/gap
• SRA https://www.ncbi.nlm.nih.gov/sra
• Gene/protein annotations
• HGNC http://www.genenames.org
• Entrez Gene https://www.ncbi.nlm.nih.gov/gene
• GENCODE https://www.gencodegenes.org
• UniProt http://www.uniprot.org
• GOA http://www.ebi.ac.uk/GOA
• Projects
• TCGA https://cancergenome.nih.gov
• GTEX https://www.gtexportal.org
• TARGET https://ocg.cancer.gov/programs/target
• Publications
• PubMed https://www.ncbi.nlm.nih.gov/pubmed
• Patents
• USPTO https://www.uspto.gov
• EBI http://www.ebi.ac.uk/patentdata
• Clinical trials
• ClinicalTrials.gov https://clinicaltrials.gov

5. Cancer mortality
5
World Health Organization. 2012. GLOBOCAN.
American Cancer Society. 2015. Cancer Facts.
Canadian Cancer Society. 2015. Cancer Statistics.
World USA Canada
Brain 189,000 15,320 2,081
Breast 522,000 40,730 5,073
Cervix uteri 266,000 4,100 370
Colorectum 694,000 49,700 9,339
Corpus uteri 76,000 10,170 1,036
Gallbladder 142,000 3,700 265
Kidney 144,000 14,080 1,773
Leukemia 265,000 24,450 2,705
Liver 745,000 24,550 1,120
Lung 1,590,000 158,040 20,896
Melanoma 55,000 9,940 1,145
Multiple myeloma 80,000 11,240 1,367
NH lymphoma 200,000 19,790 2,656
Oesophagus 400,000 15,590 2,043
Oral 145,000 8,650 1,227
Ovary 152,000 14,180 1,739
Pancreas 331,000 40,560 4,590
Prostate 307,000 27,540 4,141
Stomach 723,000 10,720 2,048
Urinary bladder 165,000 16,000 2,306

6. Lung cancer
6
• Major histological subtypes
• ADC, SQC, LCC, SCC
• Heterogeneity within, between
subtypes
• Opportunities for target discovery
• Molecular classification
• Clean signal for target selection
Herbst et al. 2008. N Engl J Med.
Travis et al. 2015. J Thorac Oncol.

7. Class discovery
• Batch effect correction
• Unsupervised feature selection
• Consensus clustering
• Relevant number of clusters
Leek et al. 2012. Bioinformatics.
Wilkerson et al. 2012. Bioinformatics.
Charrad et al. 2014. J Stat Softw.
ADC k=3 SQC k=2

8. 8
Fauteux et al. 2016. Oncotarget.
Class prediction

9. ADC target selection
9

10. Protein annotation
10

11. Alternative splicing
11
TCGA Research Network. 2014. Nature.
Ritchie et al. 2015. Nucleic Acids Res.
• The majority of multi-exon genes
are alternatively spliced
• µ = 7.25 transcripts/protein-coding gene
• Exon-based method
• edgeR/limma:
𝑙𝑜𝑔𝐹𝐶𝑒𝑥𝑜𝑛 − µ 𝑙𝑜𝑔𝐹𝐶 𝑜𝑡ℎ𝑒𝑟 𝑒𝑥𝑜𝑛𝑠
• Exon to TM/EC domain mapping
• 2,800 TM proteins
• 6,800 EC domains
• 28,500 exons

12. Differential exon usage
12

13. Genomic alterations
13
• Somatic variant calls
• VarScan2 MAF
• LUAD: 334,879
• LUSC: 307,378
• VEP: moderate/high impact
Kobolt et al. 2012. Genome Res.
McLaren et al. 2016. Genome Biol.

14. Business intelligence
14
• Database
• Patents (class 424)
• 130.1 (antibodies): 3,700
• 178.1 (conjugates): 1,400
• Publications: 530,000
• Clinical trials (mAb, ADC): 13,000
• Gene & protein synonyms,
aliases
• HGNC, Entrez, Uniprot
• Automated document retrieval
• String cleaning, matching
• English dictionary used as decoy

15. Conclusion
15
• We work with industry
• Focus on Canadian companies
• Co-development, services
• NRC ADC pipeline
• 60 ADC targets, 2,000 mAbs
• Breast, lung colon, pancreas, ovary
• Current work
• Isoform-level targets
• Antigen sequence optimization
• Immuno-oncology

16. Acknowledgements
16
• Ottawa (HHT)
• Jennifer Hill
• Jianjun Li
• Maria Moreno
• Ottawa (ICT)
• Anu Surendra
• Mira Cuperlovic-Culf
• Youlian Pan
• Montreal (HHT)
• André Nantel
• Anne Marcil
• Maria Jaramillo
• Richard Marcotte
• Jean Labrecque
• Vincent Dodelet

17. 1717
Thank you
François Fauteux
Research Officer, Scientific Data Mining
Information and Communication Technologies
Tel: 613-993-0875
Francois.Fauteux@nrc-cnrc.gc.ca
www.nrc-cnrc.gc.ca