Successful Targeting of the NRG1 Pathway Indicates Novel Treatment Strategy for Metastatic Cancer
This week we profile a recent publication in Annals of Oncology from Dr. Janessa Laskin
(front, sixth from right) at the BC Cancer Agency.
Can you provide a brief overview of your lab’s current research focus?
The historical model of oncology drug development has been to base the treatment of an individual on the outcomes and experience of those who have had similar appearing cancers, at least from the perspective of their cell of origin. Although this has met with variable success using cytotoxic agents it can also mean that many patients, including the majority with advanced cancer, receive expensive and toxic chemotherapy that result in little or no clinical benefit. The last decade of clinical trials using targeted agents has clearly demonstrated the need to identify specific targets within individual cancers to effectively employ targeted therapies. This approach has demonstrated success in the clinic, and limited genomic tests to guide cancer management are already standard of care for niche subpopulations (e.g. advanced lung cancer and melanoma). The challenge is to identify such targets for all cancer patients and the inherent genomic heterogeneity of cancers implies the requirement to assess each individual cancer and match it to a biologically relevant targeted therapy.
The timely production of genome scale data sets for individual cancer patients is something that was only theoretical a few years ago, but in the last 5 years our Personalized Oncogenomics (POG) project has demonstrated that: it is possible to identify and consent patients for whole genome analysis; sequence their “normal” and cancer genomes and transcriptomes; analyze and report somatic and relevant germ-line alterations; identify potential actionable targets and work with clinicians to understand and apply this information to their patients. POG is a translational research study which involves a close collaboration between the BC Cancer Agency (BCCA) clinical team and the BCCA Genome Sciences Centre.
This recent POG publication is an example of the power to innovate and discover new targets in cancer and how this approach can successfully repurpose drugs already in our armamentarium.
What is the significance of the findings in this publication?
Oncogenic gene fusions involving Neuregulin 1 (NRG1) have been described as recurrent aberrations in lung adenocarcinomas and had been proposed to represent a druggable signaling axis but this hypothesis had yet to be tested. In the overall POG project, we identified two patients with NRG1 fusion-positive cancers. The first had a primary lung adenocarcinoma, while the second had a primary intrahepatic cholangiocarcinoma, a disease type in which NRG1 fusions have not previously been described. Both were treated with the HER-family kinase inhibitor afatinib and both displayed significant and durable responses. These observations represent the first reported demonstration of a pan-HER tyrosine kinase inhibitor (TKI) response in NRG1 fusion-positive cancers in a clinical setting and the identification of a new target-drug combination has significant implications for cancer care.
What are the next steps for this research?
Advances in technology have provided insight into the complexity and diversity of cancer drivers suggesting that the future of cancer medicine will include the characterization of hundreds or perhaps thousands of cancer-driving pathways. Given the rarity of these novel cancer target-treatment subgroups these data need to be quickly and efficient shared throughout the global cancer community. POG is a catalyst for translational research and the project will continue to characterize the genomic and transcriptomic findings of patients with metastatic cancers and when possible we will test the clinical hypotheses this research uncovers.
If you’d like us to mention your funding sources, please list them.
This work would not be possible without the participation of our patients and families and the generous support of the BC Cancer Foundation. We also acknowledge contributions towards equipment and infrastructure from Canada Foundation for Innovation and the BC Knowledge Development Fund, as well as the support of the Canada Research Chairs and CIHR Foundation (FDN-143288) programs.