Disease Gallery – Breast Cancer
precisionlife analysed genetic data from BRCA2 positive patients (contrasting those affected by breast cancer at < 40 years old) and “healthy” individuals (not affected by age of 40 years old). We found multiple new drug targets, stratification biomarkers and repurposing opportunities.
We assessed multiomics data from 1,576 patients (affected by breast cancer at < 40 years old) and 6,402 “healthy” individuals (not affected by age of 40 years old). Our precisionlife platform analysed more than 200,000 SNPs.
From these data, we found 3,045 novel disease signatures (shown in grey) as well as:
- Novel drug targets: genes not previously associated with breast or other cancers
- Drug repurposing candidates: compounds showing strong potential for drug repurposing
- Key genetic modifiers: BRCA2 positive cases whose breast cancer risk is normal
- Patient stratification biomarkers: personalized risk scores and biomarkers predicting responders / non-responders, selecting the best available therapy
In the graph below, the 762 unique SNPs discovered have been clustered by the number of patients in which those SNPs co-occur. The graph shows the detailed architecture of the sub-populations of BRCA2 positive breast cancer. By analyzing the similarities and differences between patient sub-groups we can identify new opportunities and targets for drug discovery and repurposing.
precisionlife worked with the Medicines Discovery Catapult (MDC) to validate and develop assets arising from its breast cancer studies. The networks identified contain both well-established breast cancer targets (PI3K, EGRF, CCDC170 etc) as well as several novel targets. There is literature evidence of the correlation & potential causation of breast cancer with expression of these targets and in many cases, also known development compounds against these targets.
A list of 16 novel breast cancer targets was supplied to MDC with strong mechanistic hypotheses for their effects. Active chemistry was identified for many of these novel targets, including compounds that have progressed to Phase 2 in clinical trials. MDC’s results show that at least 6 of the 16 targets have good in silico validation and diverse known active chemistry, and druglike ‘hit’ compounds known to have activity at the target receptors were identified.
One of these targets is strongly modulated (low μM) by an FDA approved compound which is indicated and sold for various bone disorders. This compound shows good binding and affinity to the target. Of the others, the strongest druggability validation has multiple bioactive leads in different compound series, some with potent inhibition (low μM/nM).
This shows that precisionlife can accelerate identification of novel druggable targets with multiple bioactive ‘hit’ compounds (including drugs and drug-like development compounds), even in highly novel areas of metabolism that have not previously been directly targeted by pharmaceutical R&D.