The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors.
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Rossman, Zabka et al. Mol Cancer Ther 2021;20:2177–88
Summary of the findings
BRAF gene mutations, especially BRAFV600E, drive up to 8% of all human cancer across cancer types. Drugs targeting BRAF mutations can induce dramatic remissions in human cancer patients, however, drug resistance consistently develops. There is considerable interest in identifying clinically-relevant, immunocompetent animal models to test strategies to overcome drug resistance and advance BRAF-targeted therapies. This work focused on naturally-occurring canine urothelial carcinoma, a heterogenous aggressive cancer which interestingly, harbors the dog homologue of BRAFV600E. In a canine phase I/II clinical trial of the BRAF-targeted drug, vemurafenib, remission occurred in 38% of dogs. As in humans, drug resistance developed with median progression free interval of 6 months. Transcriptomic analyses of tumor tissues collected by cystoscopic biopsy before, during, and at relapse on therapy were very informative. Upregulation of genes in the classical and alternative MAPK-related pathways occurred in subsets of dogs at cancer progression, providing important clues to mechanisms contributing to drug resistance. The most consistent transcriptomic changes, however, were the increase in patterns of immune infiltration during the first month of vemurafenib, and immune failure at relapse. The results support the inclusion of dogs with BRAF-mutated cancer to complement experimental models in research to improve BRAF-targeted therapies in humans.
Future impact of the findings
The canine model can be used in research to improve BRAF-targeted therapy. Insights into transcriptomic changes in tumor signaling and immune activity with therapy can be leveraged to develop better therapies, especially targeted drug-immunotherapy combinations. The transcriptomic, pharmacokinetic, and case data have been deposited in the US National Cancer Institute’s Integrated Canine Data Commons with expected release by March 2022. This data can be analyzed in parallel with human cancer data to test emerging hypotheses. In addition to work aimed at helping humans, the work is expected to lead to new cancer therapies for pet dogs with cancer.
