A novel combination of a tyrosine kinase inhibitor and a MEK inhibitor has been demonstrated to impede the growth of kidney cancer in preclinical studies carried out by a team at The Institute of Cancer Research (London, UK). The work, published recently in Molecular Cancer Therapeutics, demonstrated that this combination could work together to suppress tumor angiogenesis more effectively than current therapies.
Angiogenesis is known to be one of the driving forces in kidney cancer and angiogenesis inhibitors such as sunitinib are licensed for the treatment of kidney cancer. Most kidney tumors, however, swiftly develop resistance to these antiangiogenic agents via mechanisms that are not well understood. This study involved the study of the blood vessels within such resistant tumors.
In tumors that had acquired resistance to sunitinib, the team discovered that the Ras-Raf-MEK-ERK1/2 signaling pathway was hyperactive within tumor blood vessels. This finding prompted them to investigate the use of MEK inhibitors in combination with such inhibitors in these resistant tumors.
After investigations with several MEK inhibitors, it was established that trametinib was particularly effective. In mouse models, the combination of trametinib and sunitinib was found to be more effective in suppressing tumor growth than either drug alone.
Specifically, following 40 days of the combination treatment, average tumor volume was lower than it had been at the start of the study. By contrast, in those treated with sunitinib alone over the same time period, tumor volume tripled compared with the start of the study.
Realizing that the combination of trametinib and sunitinib could promote toxic adverse events, the investigators also introduced a treatment break into some of the studies. The addition of these breaks did not affect the efficacy of the therapy – an important finding meaning that patients could benefit from this therapy without developing unmanageable side effects if it were to reach the clinic.
This work also encompassed the investigation of trametinib with pazopanib, which was also effective. This combination has already been proven to be safe in a Phase I trial, so this study could provide evidence for the study of this combination in patients with advanced kidney cancer.
“Our results show the clear potential of combining drugs to treat drug-resistant renal cell carcinoma, which claims several thousand lives in the UK each year. Our study provides a strong rationale for clinical trials of the combination in people affected by the disease,” commented study lead Andrew Reynolds of The Institute of Cancer Research.