👤 Richard B Lock

Limited targeted agents are approved for pediatric sarcomas. Tyrosine kinase (TK) inhibitors have shown clinical efficacy in some, but not all, young sarcoma patients. A major obstacle preventing further advances and clinical implementation is the lack of predictive response biomarkers to guide TK-targeted treatments. TK-activating fusions or mutations are rare in these patients. RNA overexpression of TKs is a frequent feature. The unresolved question is when upregulated TK expression is associated with kinase activation and signaling dependence. We explored the TK molecular landscape of 107 sarcoma patients from the ZERO Childhood Cancer precision medicine program (ZERO) using whole genomic and transcriptomic sequencing. Phosphoproteomic analyses of tyrosine phosphorylation (pY) and functional in vitro and in vivo assays were performed in cell lines and patient-derived xenografts (PDXs). Our analysis shows that although novel genomic driver lesions are rare, when present they are therapeutically actionable as exemplified by a novel LSM1-FGFR1 fusion identified in an osteosarcoma patient. We further show that in certain contexts, TK RNA expression can indicate TK pathway activity and predict TK-inhibitor sensitivity. We highlight the utility of FGFR-inhibitors in PAX3-FOXO1 fusion-positive rhabdomyosarcomas (FP-RMS) characterized by high FGFR4 and FGF8 RNA expression levels, and FGFR4 activation (FGFR4_pY). We demonstrate marked tumor growth inhibition in all FP-RMS PDXs treated with single agent FGF401 (FGFR4-specific inhibitor) and single agent lenvatinib (multi-kinase FGFR-inhibitor), and report a clinical response to lenvatinib in a relapsed metastatic FP-RMS patient. Altogether, we identified new sarcoma patients who may benefit from FGFR-inhibitors, most notably FP-rhabdomyosarcoma via FGFR4/FGF8 co-expression. Show less

Bats carry many zoonotic pathogens without showing pronounced pathology, with a few exceptions. The underlying immune tolerance mechanisms in bats remain poorly understood, although information-rich omics tools hold promise for identifying a wide range of immune markers and their relationship with infection. To evaluate the generality of immune responses to infection, we assessed the differences and similarities in serum proteomes of wild vampire bats ( Show less

Metastatic cancer cells exploit Epithelial-mesenchymal-transition (EMT) to enhance their migration, invasion, and resistance to treatments. Recent studies highlight that elevated levels of copper are implicated in cancer progression and metastasis. Clinical trials using copper chelators are associated with improved patient survival; however, the molecular mechanisms by which copper depletion inhibits tumor progression and metastasis are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Here, we propose that copper chelation inhibits metastasis by reducing TGF-β levels and EMT signaling. Given that many drugs targeting TGF-β have failed in clinical trials, partly because of severe side effects arising in patients, we hypothesized that copper chelation therapy might be a less toxic alternative to target the TGF-β/EMT axis. Our cytokine array and RNA-seq data suggested a link between copper homeostasis, TGF-β and EMT process. To validate this hypothesis, we performed single-cell imaging, protein assays, and in vivo studies. Here, we used the copper chelating agent TEPA to block copper trafficking. Our in vivo study showed a reduction of TGF-β levels and metastasis to the lung in the TNBC mouse model. Mechanistically, TEPA significantly downregulated canonical (TGF-β/SMAD2&3) and non-canonical (TGF-β/PI3K/AKT, TGF-β/RAS/RAF/MEK/ERK, and TGF-β/WNT/β-catenin) TGF-β signaling pathways. Additionally, EMT markers of MMP-9, MMP-14, Vimentin, β-catenin, ZEB1, and p-SMAD2 were downregulated, and EMT transcription factors of SNAI1, ZEB1, and p-SMAD2 accumulated in the cytoplasm after treatment. Our study suggests that copper chelation therapy represents a potentially effective therapeutic approach for targeting TGF-β and inhibiting EMT in a diverse range of cancers. Show less