Translational research is a humbling process. It is about turning a scientific idea into a treatment that will hopefully one day change the lives of real patients. It’s almost two years since I started working for Remedy Plan Therapeutics. From day one, there have been some really big questions thrown my way. Friends, family and colleagues all want to know how a new cancer drug is discovered and most importantly when it will reach the clinic. I love these big picture questions, and I appreciate when people ask them. Cancer is so deeply rooted in our culture; we all probably know someone who has been affected by this pervasive disease. With that in mind, who wouldn’t be excited about a new approach to treating cancer in the near future? In a special Bench to Bedside series, my goal is to share with you an overview of the drug development process, in a way that is simple and easy to digest. This first post will describe step one of the process: drug discovery.

Drug discovery like other forms of research, follows the scientific method throughout each stage. The first step is a clinical need or some sort of observation. Scientists and researchers look at clinical trends and start to ask questions: why haven’t there been considerable improvements in treating cancer? What makes cancer so hard to treat? There are a seemingly infinite number of questions that are generated.

In response, researchers investigate data generated by their colleagues in order to see what approaches have been previously tested and what the results of those experiments were. Based upon the findings of previous studies, new hypotheses start to form. For example: “inhibiting protein ‘X’ in pathway ‘Z’ might lead to therapeutic effect in cancer type ‘Y’. The subsequent big picture goals are to identify drugs that when treated produce the desired biological response on the bio marker/target (in this example inhibiting protein ‘x’). Before a drug can be discovered, we need to be sure that the activity protein ‘x’ is a suitable indicator for measuring a therapeutic response. In order to test this initial hypothesis, scientists develop a series of experiments to both test and validate the activity of the bio marker of interest within the context of the disease (cancer type).

High throughput screening (HTS) is a method used to test thousands of ‘druggable’ molecules (usually small synthetic molecules) against the activity of the selected biological target. These small molecules may be commercially available for researchers from a variety of scientific disciplines to test against their target in order to identify a biological or therapeutic response to a particular disease (these are referred to as ‘hits’).

At Remedy Plan Therapeutics, we use our novel platform (technology) to measure embryonic-like properties in cancer cells (cancer stem cells).  These embryonic-like properties in cancer cells are what make cancer so hard to treat; they help cancer cells to continue to grow, spread and potentially develop resistance to current treatments. When we screen thousands of small molecules, we are testing them against our biological target in order to identify hits that lower these embryonic properties in cancer cells. At the end of the high throughput screen, we analyze data from thousands of potential therapeutic drugs and identify hundreds of initial hits that lower some of the most dangerous properties in cancer cells! This is really exciting, but all great results must be reproducible. In order to rule out false positives, the original high throughput assay or experiment is re-run in order to reconfirm the biological activity of selected hits.

Another important aspect of validation might involve designing experiments to measure off-target effects of each ‘hit’. An off-target effect is when a drug binds to different cellular targets than were originally intended to. This could potentially lead to unexpected side effects that may be harmful. It can take a matter of years to reach this point, where thousands of potential drugs filter into a handful of lead candidates to build a drug development program around. The discovery process is, of course, just the beginning of a long road from the laboratory bench to a patient’s bedside. The next Lab Notes piece focuses on the lead development phase. It’s during this stage that new cancer drugs are characterized further both biologically (in-vitro studies) and chemically (lead optimization).

Featured Image Cited: Fleming, N. (2018). How artificial intelligence is changing drug discovery. Nature, 557(7706), S55-S55.