Dr. Manley first highlighted a 2020 paper from Yuan and colleagues1 that implicated the post-translational histone modification H3K36me2 as a regulator of epithelial plasticity (lineage switching) and metastatic progression. Using a CRISPR screen from a mouse model of pancreatic cancer, the authors showed that genes like the histone methyltransferase NSD2 place methyl groups at histone 3 lysine 36, thus promoting a mesenchymal phenotype that is more invasive. Conversely, histone demetylases like KDM2A removed histone methylation marks at H3K36, promoting transition from the mesenchymal to a more epithelial phenotype that allows for metastatic site colonization. The authors show using expression data from renal papillary cell carcinoma that low expression of NSD family histone methyltransferases (meaning less H3K36 methylation and thus less mesenchymal/invasive phenotype) is associated with improved recurrence free survival compared to tumors with higher expression of NSD family member genes.
Dr. Manley then shifted to discussed molecular subtypes in metastatic renal cell carcinoma that have a differential response to angiogenic or immune checkpoint directed therapies. These studies were performed using transcriptomic analysis of patient samples from the IMmotion 150 and 151 trials of combination immune checkpoint and anti-angiogenesis therapy (atezolizumab and bevacizumab) verses anti-angiogenesis therapy (sunitinib). Dr. Manley simplified the 7 tumor clusters identified in that paper into four larger categories that are shown below. Both combination and anti-angiogenic therapies are effective and tumors that have high expression of angiogenesis gene sets or mTOR signaling, the addition of immunotherapy is uniquely beneficial in tumors expressing proliferative or T-effector gene sets. Certain subgroups are more associated with certain genomic alterations, for example, PBRM1 and KDM5C mutations are associated with high angiogenesis transcription programs.
Finally, Dr. Manley discussed ongoing work characterizing certain host immune factors that may contribute to treatment response and toxicity. Specifically, he discussed ongoing collaborative work estimating the diversity of patient T- and B-cell receptors and how this might impact selection of patients more likely to respond beyond what he already described from published molecular subtyping studies.
He concluded with optimism that future work would help further stratify patients by underlying biology to the most effective and least toxic systemic therapies.
Presented by: Brandon Manley, MD, H. Lee Moffitt Cancer Center and Research Institute
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
1. Yuan S, Natesan R, Sanchez-Rivera F, et al., Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression. Cancer Discovery, 2020; 10(6): 854-871