Using human genetics to make new medicines

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1 Using human genetics to make new medicines Dr. Maya Ghoussaini Open targets, Wellcome Trust Sanger Institute, UK ELRIG, Drug Discovery, Liverpool, 3 rd -4 th October 2017

2 Drug development rarely succeeds Nearly 85% of candidate drugs that enter clinical trials fail Failure happens often in late phase due to lack of efficacy

3 How can we reduce drug failure?

4 A wealth of genetic information to be taken advantage of Rare Mendelian diseases Explosion of genes identified Complex diseases Whole genome/exome sequencing Genome Wide Association Studies (GWAS)

5 Genome Wide Association Studies (GWAS) Genetic variants (Hundreds of thousands or millions) Association? A complex disease > 93% variants are outside genes

6 Genetic findings from Mendelian and complex diseases

7 Number of genes Steep increase in the number of genes underlying Mendelian diseases Year

8 Early GWAS findings

9 GWAS findings in 2017 Focus

10 Genetically supported targets significantly increase the success rate in drug development GSK Astra Zeneca Nelson et al. Nature Genetics 2015 Cook et al. Nature Reviews, 2014

11 GWAS: The pros and cons Pros: No hypothesis needed Useful in pointing to new disease mechanisms Cons: Most associated variants/regions do not overlap with genes Target gene is not necessarily the closest gene Very often, several genes are being targeted Long process moving from the genetic association to the target gene

12 Linking variants to causal genes : A long process Expression data (GTEx, etc.) Chromatin conformation/looping (Promoter Capture HI-C, 3C, 4C, 5C) Genetic variant Target gene Epigenetic profile Genome editing

13 Genetic information is a powerful tool in guiding drug discovery Target identification and prioritisation Target genes emerging from GWAS Multiple variants One disease/phenotype Drug repurposing Phenome Wide Association Studies (PheWAS) A single variant Multiple diseases/phenotypes

14 Example from my previous work (Department of Oncology, University of Cambridge)

15 BCAC (Breast Cancer Association Consortium) - International consortium of 84 breast cancer studies worldwide - Including over 119,000 breast cancer patients and a similar number of controls - Two custom array chips: icogs (200 k SNPs) and Oncoarray (570 k SNPs)

16 Number of susceptibility regions/genes Genetic findings in breast cancer Pre-GWAS Era BRCA1 BRCA2 Year 173 breast cancer susceptibility variants since 2007

17 Genes near associated loci are important for breast cancer development Ghoussaini et al. Am. J.Pathol. 2013

18 FGFR2 FGFR2 Intronic variants in FGFR2 increase breast cancer susceptibility (germline) (Easton et al. Nature 2007) They increase susceptibility through increasing the expression of FGFR2 (Meyer et al. PLoS Genet. 2008) FGFR2 is somatically mutated in breast cancer and amplified in 5-10% of breast tumours Lucitanib (INN) is a drug that is being investigated in clinical trials (Phase II) for the treatment of breast cancer and other solid tumours

19 (Ghoussaini et al., unpublished) Target genes confirmed for 7/173 of the susceptibility regions using robust functional experiments FGFR2 ESR1 TBX3 MAP3K1 CCND1 IGFBP5 TERT Somatic Somatic Somatic Somatic Somatic None Somatic Lucitanib (Phase II) FULVESTRANT (Phase IV) No drugs No drugs Candidate targets? PALBOCICLIB, (Phase IV) IGF DUSIGITUMAB (Phase II) IMETELSTAT (Phase I)

20 Genetics of Rheumatoid arthritis (Okada et al., Nature, 2014) >100,000 individuals, 101 risk variants mapped to nearest genes, 98 genes Any of these genes targets for existing drugs (approved and experimental)? 27 were targets for approved drugs for rheumatoid arthritis Additional genes have drugs for other indications potential drug repurposing opportunities Ex: CDK4 and CDK6 identified as candidate genes Palbociclib: A compound that inhibits CDK4 and CDK6 and has been recently approved for breast cancer - Potential drug repurposing opportunity

21 PheWAS: Drug repurposing opportunities Hyperlipidemia rs near PSRC1 gene

22 Lots of potential drug repurposing opportunities Lots of drug repurposing opportunities once biology understood

23 Examples of drug repurposing opportunities based on GWAS and PheWAS knowledge Rastegar-Mojarad et al. Nature Technology, 2015

24 Take home messages Human genetics gives us a therapeutic hypothesis to test Use the growing wealth of human genetics to prioritise and select the best targets Deprioritise programs that do not have genetic support Naturally occurring genetic variations could : Help identify and prioritise drug targets Offer opportunities for drug repurposing

25 The big challenge Systematic strategy to integrate disease-associated variants with diverse functional genomic and drug data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits Poster number 95, Dr. Denise Carvalho-Silva

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27 What do we do? We integrate large-scale genetics and genomics data together with drug information

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29 Example of data integration: Oncology Integration for Target ID RNA-seq for gene fusions 1000 Cancer Cell Lines Genetics of clinical trial samples TF Networks Mathew Garnett Fiona Behan Francesco Iorio Luz Alonso Garcia Julio Saez-Rodriguez Targets

30 An example of how Open Targets could help linking a genetic variant to a target gene

31 Validating the platform Association with Breast Cancer Open Targets helps find the target gene Epigenetic marks Chromatin looping (Promoter Capture Hi-Seq) eqtls (Expression data in tissues) rs is associated with breast cancer What is the target gene? Open Targets: IGFBP5 (not the nearest gene!) Results confirmed through functional experiments (Ghoussaini et al., Am J. Hum. Genet. 2016)

32 BCAC consortium Acknowledgements