Why are combination drugs important for treatment of cancer?
Overview of cHTS screening strategy
Example of cHTS screening results
Amgen MDM2 inhibitor combination activities
Combination drug leads- prioritization
Ex vivo assays
Tumor microenvironment assays
Xenografts
cHTS to identify synergies and antagonism
Immuno-oncology
2. 2
Presentation Overview
• Why are combination drugs important for treatment
of cancer?
• Overview of cHTS screening strategy
• Example of cHTS screening results
Amgen MDM2 inhibitor combination activities
• Combination drug leads- prioritization
Ex vivo assays
Tumor microenvironment assays
Xenografts
• cHTS to identify synergies and antagonism
• Immuno-oncology
• Summary
3. 3
Cancer Genome Efforts - the Complexity of Cancer
188 lung adenocarcinomas
• 623 genes sequenced, 26 mutated at high frequency
• Large number of chromosomal amplifications and deletions
Key pathways are mutated
TCGA
Somatic mutations affect key pathways in lung adenocarcinoma
NATURE| Vol 455|23 October 2008
4. 4
Brain Cancer: Frequent Genetic Alterations in Critical Signaling
NATURE| Vol 455|23 October 2008
TCGA
5. 5
The Complexity of Cell Signaling
• Hard to predict tumor cell responses to cancer drugs
• Horizon Discovery’s strategies are robust can be an agnostic approach to probe cell signaling
The color of a node signifies the phenotypic effect of
removing the corresponding protein (red, lethal; green,
non-lethal; orange, slow growth; yellow, unknown).
Source: ibis.northwestern.edu/faculty/amaral.html
RealityCartoon
Source: mayoclinicproceedings.com
ErbB1
ErbB2
ErbB3
ErbB4
PDGFR
6. 6
The Dose Matrix: Identification of Combination Activities
• Combination effects can manifest as potency
shifts or efficacy boosts
• Challenging to pick concentrations and optimal
ratios
• Dose-response matrix screening can detect both
synergy and antagonism
Effect
Concentration
Measured Activities Null Interaction Model Excess
Cytostatic
Cytotoxic
Inclusion of T0 measurement to help
distinguish cytostatic versus cytotoxic activities
7. 7
Horizon Has an Extensive Cell Line Collection Available for
Screening
>800 Core Cell Line Collection
• Core cell line collection has
extensive overlap with the
Cancer Cell Line
Encyclopedia (CCLE)
collection
• Wealth of information
accumulated about use of
cell line collection for HTS
• Augmented by X-MAN®
isogenic cell lines
Cell Line Collection
>550 X-MAN® Isogenic Cell Line Pairs
+
8. 8
Horizon has Worked with Many Leading Pharma Companies and
Research Foundations
• Many examples of multiple projects
over a multi-year time span
• Quick delivery time
• Quality of data
• Cost-effective
• CRO as a collaborator
• Expertise
• Presentations at meeting
• Publications
• Assist with IP filings
CHDI (HD)
SMA
Cystic Fibrosis
DMD
Examples of
Discovery Collaborations
Systematic identification of synergistic multi-
target mechanisms conferring selectivity and
enabling patient stratification
Drug leads
Examples of
Discovery/Translation Collaborations
9. 9
Custom Offerings
Pairwise Screening
• 100-200 compounds of diverse
mechanism and activity
• >20,000 pairwise combinations
• 50-100s of cell lines
Enhancer Screening
• One or more focus compounds
• 100-250 enhancer compounds of
diverse activity and mechanisms
• 20-100 cell lines
10. 10
Alternative Screening Patterns Are Available
• Our automated platform allows screening formats to be
adapted to best suit the experimental design
• Non-uniform sampling of combination space
Increases cHTS efficiency
Decreases cHTS-associated costs
Decreases timeline
CompoundA
Compound B
6x6 Optimized
CompoundA
Compound B
6x6 Format
CompoundA
Compound B
HFDR Format
Patch 5 4x4Diag2x2_ic20 2x62x2top
11. 11
Comparison of Full versus HFDR Dose Matrix
Validation- alternative combination dose matrices behave similarly to full dose matrices
when compared experimentally
– HFDR highly correlates with 6x6 format (mean R=0.96)
12. 12
cHTS Case Study: Amgen and MDM2 (Discovery Effort)
• MDM2 inhibitors hold great promise as cancer therapeutics
• As with many other targets, drug resistance will likely limit efficacy as single agents
• Amgen engaged Horizon to systematically identify and verify multi-target synergies
Phase 1: Primary ScreenMDM2i
X
1200 Enhancers
(SOC, Emerging Rx, Probes)
X
10 Cell Lines
> 25,000
Replicate
matrixes
Analyzed by
Chalice™
Synergy Score
Heat map showing synergy score
Identified multiple synergistic interactions
2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039142/
MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways Oncotarget 2014
16. 16
The Past and the Future of Cancer Drug Development
Development of chemotherapeutic drugs better efficacy with use of drug
combinations
• Pair drugs that exhibit single agent activity in the clinic
• Pair drugs based on knowledge of disease biology
Development of targeted drugs better efficacy with use of drug combinations
• Pair drugs that exhibit single agent activity in the clinic
• Pair drugs based on knowledge of disease biology
• Pair drugs based on combination drug activities (cHTS, preclinical models)
Development of immuno-modulatory drugs better efficacy with use of drug
combinations
• Pair drugs that exhibit single agent activity in the clinic
• Pair drugs based on knowledge of disease biology
• Pair drugs based on combination drug activities (cHTS, preclinical models)
17. 17
cHTS to Identify Immune Modulators
• Horizon Discovery has extensive experience with inflammation assays
• Example: identification of synergistic drug combinations that inhibit production of pro-
inflammatory cytokines
Measured Activities Excess
(TNFa)
0
20
40
60
80
100
0
20
40
60
80
100
%Inhibition%Inhibition
TCR activation
(anti-CD28/
anti-CD3 stimulation)
18. 18
Combination Drug Discovery
Assays need to be robust
• Known immuno-modulatory agents should exhibit activity
Capture disease complexity
• If not primary screen, with use of secondary screen(s)
Combination drug discovery is “critical path” for cancer drug
development
• Synergistic selective killing of tumor cells
• Immuno-modulatory drugs
Horizon Discovery
• More than a decade of experience with oncology and
inflammation cHTS
• Strong TIDVAL capabilities (shRNA, siRNA, sgRNA)
• Strong track record for technology development
• Proven ability to quickly deliver actionable insights
• insights
19. Your Horizon Contact:
t + 44 (0)1223 655580
f + 44 (0)1223 655581
e info@horizondiscovery.com
w www.horizondiscovery.com
Horizon Discovery, 7100 Cambridge Research Park, Waterbeach, Cambridge, CB25 9TL, United Kingdom
Richard Rickles
Senior Director, Oncology
R.Rickles@horizondiscovery.com
+1 (0)
Notes de l'éditeur
Pleasure to be here to today to tell you more about Horizon and our suite of technologies based around a core expertise in human genome editing and how we are applying this to better understand the human genome, find new validated targets and support targeted drug discovery with predictive, genetically-defined, in vitro models that accurately represent target patient groups.
The CRx cell line collection contains many of the cell lines that are also in the CCLE (currently 625, ~75% of the lines in the CRx collection). CRx uses the same sourcse for cell lines as used by the Broad Institute/Novartis and the same growth conditions. As a result, the CRx cell line collection is the most closely aligned cell line panel available outside of what the Broad Institute and Novartis are using. The CRx cell line collection is therefore the best choice for companies wanting to use CCLE information (especially gene expression data) during follow up analysis of screening efforts.
CRx has considerable experience with most of the cell lines in the collection and has a good understanding of their suitability for HTS work, including seeding densities for various plate formats and assay incubation times, cell doubling times and number of replicate data points required to generate quality data. Depending on the scope of the project CRX will use 96, 384 and 1536 well formats for screening. Also, CRx has optimized screening conditions for some of the cell lines when using 72, 96, 120 and 144 hour assays
The CRx cell line panel can be used to assess single agent and combination activities across a large and diverse cell line panel to explore drug activity in different tumor types and specific genetic contexts. The Horizon Discovery X-Man cell lines are a natural extension of the CRx cell line panel, invaluable for understanding the importance/influence of specific genomic dysregulation events on drug activity (through use of matched isogenic cell lines).