This is the second year of the project, the first year of which starting in May 2018 was gratefully funded by the Gut Cancer Foundation. Our analysis using the latest data from the Global Burden of Disease Study shows that colorectal cancer is currently the second leading cause of death from cancers in New Zealand, with approximately 586 years of life being lost per 100,000 people each year due to premature death caused by this disease.
Current treatments are not as effective as might be hoped and one problem is that drugs used tend to have only short term effects and then resistance develops or resistance to these drugs is already inherent in the tumour. A good example of this is the lack of efficacy of BRAF inhibitors even though around 10% of bowel cancers have mutations in this gene.
One way to address such resistance issues is to add a second drug as combinations of drugs targeting different aspects of tumour biology can often achieve much greater effects. We have recently found that combining an inhibitor of mutant BRAF with an inhibitor of vascular endothelial derived growth factor receptor (VEGFR) achieved spectacular synergistic effects in pre-clinical models of melanoma, even in cases where each drug alone had no effect.
Surprisingly the combination even worked in melanomas that do not have BRAF mutations. This has lead us to start exploring whether such effects might also be seen in colorectal cancer models. The rationale for this was that about 10-15% of metastatic colorectal cancers harbour BRAF mutations and yet standard BRAF inhibitor therapy had little or no effect in this type of cancer when used as a single agent in clinic. We rationalised that the addition of the VEGF inhibitor might also achieve the same synergistic effects in colorectal as we have seen in melanoma.
Therefore we have worked with Dr Sanjeev Deva (Oncologists and head of phase-1 clinical trials unit at Auckland City Hospital) to develop experimental strategies to investigate this. A pilot project was been funded by the Gut Cancer Foundation and starting in May 2018. First, we have repeated the experimental combination twice in one animal model of colorectal cancer that has a BRAF mutation and both times we have found very clear evidence of synergistic interactions between these two classes of drugs.
Since the combination of BRAF and MEK inhibitors are currently a standard treatment option of BRAF mutant melanomas, we investigated whether the combination of BRAF/MEK inhibitors could also be effective in suppressing the growth of colorectal cancer tumours and if so what the magnitudes are in comparison to the BRAF and VEGFR inhibitors. Indeed, we found that both the BRAF/MEK and MEK/VEGFR inhibition combinations could significantly suppressed the growth of the HT29 colorectal cancer tumours, which in itself is an interesting finding as this offers a new treatment option for patients of colorectal cancers using existing drugs.
Importantly, the BRAF/VEGFR inhibition combination could suppress the growth of the tumours to even greater extent in that they not only just slowed down the tumour growth but also caused the tumour volume decrease compared to the original volume.
Interestingly, our trial using all triple combination of BRAF/VEGFR/MEK inhibition achieved nearly identical efficacy compared to BRAF/VEGFR inhibition combination (see graphs on following pages). Together, these data provide solid evidence that BRAF/VEGFR inhibition combination synergistically suppresses the growth of BRAF mutant colorectal tumours to the extent very similar to BRAF/VEGFR/MEK combination, and BRAF/MEK and MEK/VEGFR inhibition combination are also effective in slowing down the growth of the tumours.