A pre clinical study to investigate the potential for a novel drug combination for treating colorectal cancer (Year 2)
Professor Peter Shepherd – Professor in Department of Molecular Medicine and in the Auckland Cancer Society Research Centre
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 resiatnce to these drugs is already inherent in the tumour. A good example of this is the lack of efficact 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 harbor 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 clnical 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.
Based on the data gathered from the first project, we aim to bring the study to the next stage in order to find answers for two important questions:
(1) could the efficacy we observed from these combinations be also associated with improved survival and
(2) what is the mechanism for this synergy.
We plan to look into this by performing a long-term experiment in which the combination will be maintained for at least 100 days or when the tumour volumes reach to ethical endpoint. This experiment is also important in preparing for our clinical trial in the next steps as this will also provide data about the safety of the combinations when they are used in extended periods of time.
To understand the mechanism of the synergy, we plan to extract the RNA from the tumours and sequence them to understand the signaling pathway changes. Since the tumours are composed of both human melanoma cells and mouse stromal cells, this experiment will provide essential information about how the combination will affect the tumour cells themselves and the stromal cells in the tumour microenvironment.
These data, together with our current results will provide a solid evidence about the efficacy in the tumour and survival time as well as safety profile of the combination, which are key data for preparing for a clinical trial afterward. Since both these drugs are approved for clinical use it would make it relatively easy to then develop this to the stage of a formal clinical trial proposal.
In year 1 of a proposed 2 year study we have focussed on setting up and validating the animal tumour models that were proposed and to understand whether the dosing regimens proposed would be effective. The summary of this is that the combination of the BRAF inhibitor and the VEGFR inhibitor did not work in the colorectal cancer model that had normal BRAF (CT26) but it did work in the tumour model that had mutant BRAF (Colo205).
The MEK inhibitors trametinib was also used for the first time in our studies as this targets MEK which is immediately downstream of BRAF and combinations of BRAF and MEK inhibitors are widely used in melanoma. In the CT26 model the trametinib was also essentially without effect, alone or in combination with the BRAF and VEGFR inhibitors. However, in the BRAF mutant Colo205 there is a strong additive or synergistic effect of the BRAF inhibitor and the VEGFR inhbitor. This supported our previous findings in HT29 tumours but here we add new data also by showing the combination effect is further improved by addition of the MEK inhibitor Trametinib to give a very impressive suppression of tumour growth.
Overall our findings support finding we have made in earlier Gut Cancer Foundation funded work by showing the combination of BRAF and VEGFR inhibitors are specifically only effective in lines containing a BRAF mutation so this is where we will focus future effort. Our findings add extra information though by showing that the addition of trametinib has potential to further boost the efficacy of the combination therapy. This really provides a strong rationale to further investigate how these drug combinations achieve these effects as this will provide valuable insights into potential new therapies or to identify biomarkers that can guide our understanding of how effective a treatment is. It also sends an important signal that any clinical trial should use a precision medicine approach and really focus only on the 10% of patients who have colorectal tumours that contain a BRAF mutation as these are the ones who are most likely to benefit.