“It is our duty to test our discovery in man, for the sake of man.”
TOMMY ANDERSSON, IN BRIEF, WHAT IS YOUR BACKGROUND AND SPECIALTY?
I have been professor of experimental pathology at the Faculty of Medicine at the Lund University, since 1996. My research is focused on the areas of intracellular signalling, cell adhesion and cell migration. I have published more than 130 scientific articles, of which 38 relate to WNT5A.
HOW DID YOU SEE THAT WNT5A HAS DIFFERENT EFFECTS ON CANCER?
When we began to examine breast and colon tumours, we discovered that normal, non-cancer-transfomed tissue had a noticeable higher WNT5A expression but that it varied significantly in tumour tissue, from total absence to the same expression we found in normal tissue. We then decided to investigate whether tumours with a low WNT5A expression had a worse or better prognosis than the tumours that had a normal / higher expression.
I should clarify that the WNT5A we study primarily activates β-catenin-independent signalling. The other variant of WNT signalling is called β-catenin dependence and is primarily linked to malign transformation and tumour growth. Furthermore, the effect of WNT5A signalling varies depending on the type of cancer.
In our studies of breast, prostate and colon cancer, WNT5A signalling has an inhibitory effect on tumour spread2.
HOW DO YOU RATE WNT5A EXPRESSIONS?
Initially, we rated the intensity on a scale from 0 to 3. When we first determined the intensity in normal samples, the mean value turned out to be 2.7 and based on this, values of 2 and 3 were considered normal (often called high WNT5A) while 0 and 1 were low values1. We then further developed the method to indicate the amount of WNT5A in a tumour sample by also taking into account how much of the tumour is affected and with this method you get a scale from 0 to 12. To determine the limit between low and normal / high WNT5A expression, we first assessed the value for normal tissue.
We obtained an average value and a spread of 8.2 +/- 0.6. Assuming that the samples are normally distributed, 99% of all normal samples end up above 6.4. Thus, the limit between low and normal / high WNT5A expression was set to 6.5. Patients with breast, colon or prostate cancer whose tumours had normal / high expression were statistically found to live longer due to lower metastasis than patients with low expression. This is also supported by other studies2.
HOW WAS FOXY-5 DISCOVERED?
WNT5A is a complex protein with a long and folded chain of 360 amino acids that is not suitable as a possible drug candidate. We chose with the help of data models (in silico) to try to identify peptide sequences (chain of amino acids) that were thought to have the ability to adhere to cells and mimic the effects of the WNT5A molecule on tumour cells.
14 peptides were identified and of these, a peptide was finally identified which, after further modification, became our active pharmaceutical substance (API). We named this peptide Foxy-5 as it is a Formulated hexapeptide from WNT5A.
With Foxy-5, our research then focused on understanding its mechanisms through in vitro studies on human cancer cells, after which we performed in vivo (animal experiments) on mice. With the study data obtained, we were able to proceed to the Swedish Medicines Agency for a permit application for a clinical phase I study in humans. The primary goal of this study was to test toxicity, i.e., a safety study to clinically test different doses in humans to see if Foxy-5 is safe and has no side effects. The study result was successful when Foxy-5 was found to be safe, even at levels as high as 2.3 mg / kg body weight.
WHY ARE CLINICAL STUDIES CARRIED OUT ON JUST PATIENTS WITH COLON CANCER?
Metastases occur at different rates depending on the type of cancer. If you look at breast cancer, the process is slow. The course of colon cancer is significantly faster and thus increases the likelihood of detecting an inhibitory effect of Foxy-5 on metastasis within a shorter period. The time perspective when metastases occur is of great importance from a study perspective. Colon cancer is also the third most common type of cancer after lung and breast cancer. Finally, we regard it as our duty to investigate our discoveries in man, for the sake of man.
1 Mehdawi and co-workers. Molecular Oncology 10 (9): 1415-1429, 2016.
2 Prasad and co-workers. Cancer and Metastasis Reviews, 37 (4), 767-778, 2018.