We recently read an interesting article about the potential effects of the post-World War II Baby Boom on cancer prevalence. Baby Boomers (people born between 1946 and 1964) are growing older, and with them, the number of cancer cases is expected to grow to 22.2 million by 2030 in the U.S. alone. This has serious implications for healthcare: even though cancer death rates have been declining over the last two decades, the American Association for Cancer Research worries that we might not be able to keep up with “aging Boomers” and therefore, investing in cancer research should be a priority.
Few things are more satisfying for the scientific community than seeing the discovery of a new therapeutic target against cancer. Proof of this is that in the last 60 days, the most downloaded article in the journal Cancer Cell has been a paper reporting that Integrin Beta 3 signalling is essential for leukaemia survival. Scientists found that when the expression of Integrin Beta 3 was silenced, leukaemia cell growth and survival was significantly impaired. This looked like a hopeful finding because of its potential to avoid bone marrow toxicity, one of the major caveats of leukaemia treatment. Knockout models of this gene have normal blood counts, and in fact, patients with mutations in Integrin Beta 3 (a genetic coagulation disorder known as Glanzmann’s thrombasthenia) do not develop bone marrow failure.
Graphical abstract. Source: Cancer Cell
After confirming the relevance of the results in human samples, scientists set out to explore mediators of the Integrin Beta 3 pathway that could be amenable to pharmacological inhibition, and they identified spleen tyrosine kinase (SYK) as a possible target. This is good news, as there are several SYK inhibitors already in clinical trials –although none are being tested in Acute Myeloid Leukaemia (AML), the disease featured in the article. We can expect a lot of work in the future with the aim to assess the potential effects of new and existing SYK inhibitors for the treatment of AML, and this will involve pre-clinical trials in animal models as well as clinical trials in human subjects. So it would be interesting to know beforehand what the potential liabilities of these molecules are. What are the adverse effects that drug makers should be worried about?
SIP matrix view showing links between compounds and species where Biomedical Observations have been described.
Let’s use Instem’s Safety Intelligence Programme, a knowledgebase containing data on compounds causing adverse effects across different tissues and species, to explore the safety of SYK inhibitors. If we do a search for compounds that inhibit this protein, we identify a list of 15 molecules. Next, we can look for biomedical observations caused by these compounds in any species and tissue. This results in a list of 2760 assertions linking compounds to biomedical observations, obtained by Instem Scientific from relevant data sources such as Medline, FDA NDAs, EMC, DrugMatrix, ChEMBL or NTP. 8.19% of the resulting assertions refer to liver effects. Other major toxicities include bodily fluid (7.36%), vasculature (7.32%) and heart (6.27%). Notably, the only SYK inhibitor linked to myelosupression is Imatinib, a molecule already approved for the treatment of Chronic Myelogenous Leukaemia.
We can then use OmniViz, Instem’s visual analytics platform, to explore the major themes in our 2765 biomedical observations and get a feel of what is more important in each tissue. Using this approach, we see that skeletal muscle, heart and vasculature are enriched in assertions referring to contraction. Bodily fluid is enriched in assertions related to platelet aggregation, as we could expect from the mechanism of action, as well as effects on creatine kinase levels. Interestingly, a rise in creatine kinase can be related to muscle toxicity. Other prominent topics are mitochondrial dysfunction in liver and heart, edema in the eye and cell death in the nervous tissue. So now we can only wait and see what the results of these studies are. If the risk-benefit balance is good, we might see a new weapon against cancer that will help us beat the Aging Boom.
OmniViz CoMet plot showing enrichment of certain terms in the Biomedical Observations of different tissues. Red indicates positive association, blue indicates negative association.