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Background: The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5) melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-γ or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site.

Background Patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic MET alterations, such as MET exon 14 skipping or MET amplification (MET amp), benefit from MET tyrosine kinase inhibitor (TKI) treatment. Brain metastases are common in patients with advanced NSCLC. In preclinical studies in rats, tepotinib had relatively high binding to brain tissue (fu br=0.4%, fu pl=4%) and free tepotinib concentrations in brain were 25% of the concentrations found in plasma (Kp u,u=0.25). In this study we investigated the efficacy of the MET TKIs tepotinib, capmatinib, savolitinib and crizotinib in mice implanted orthotopically with MET-dependent tumor explants derived from human NSCLC brain metastases. Methods The antitumor activity of tepotinib (30 mg/kg qd) was investigated in a screen of 21 subcutaneous lung cancer patient-derived xenograft (PDX) models of brain metastases grown in NOD-SCID mice (n=1/model). 20 of these tumors were retrospectively analyzed for cancer-specific mutations, gene copy number (GCN) and gene expression by Nanostring. 2 responding models, both found to harbor MET amp, were tested again subcutaneously in NOD-SCID mice treated with vehicle or tepotinib (125 mg/kg qd; n=5). Both models were orthotopically implanted into brains of NOD-SCID mice and tumor growth was monitored by MRI. Established tumors were treated with MET TKIs (n=10) tepotinib (125 mg/kg qd), capmatinib (30 mg/kg bid), savolitinib (60 mg/kg qd) or crizotinib (50 mg/kg qd). Results 2 of 21 subcutaneous PDX tumors (LU5406 and LU5349) regressed in response to tepotinib treatment. When implanted subcutaneously again into mice, both models regressed completely upon treatment with tepotinib. Molecular profiles revealed that these were the only tumors of the 20 models investigated by Nanostring that had MET amp (high-level increase in MET GCN of >10). Both models grew orthotopically when implanted into brains of mice. Contrast-weighted MRI indicated regions with intact and disrupted blood–brain barrier (BBB) in all implanted tumors. Tumor regression of orthotopic LU5406 tumors was observed with all MET TKIs (% median tumor volume changes [%TV]: tepotinib, –63%; capmatinib, –24%; savolitinib, –38%; crizotinib, –27%). In the orthotopic LU5349 tumors, treatment with crizotinib or savolitinib led to growth inhibition (%TV: +88% and –13%, respectively), whereas tepotinib and capmatinib induced tumor regression (%TV: –84% and –63%, respectively). Conclusions The heterogenous pattern of regions with intact and disrupted BBB in the orthotopic brain metastases models is thought to mirror the clinical situation. Tepotinib was efficacious in the two MET-driven orthotopic brain metastases PDX tumors characterized by pronounced tumor regression and may be relevant to patients with brain metastases. Relationships between efficacy and BBB leakiness will be discussed. Citation Format: Manja Friese-Hamim, Anderson Clark, Lindsey Crowley, Christof Reusch, Olga Bogatyrova, Claudia Wilm, Hong Zhang, Timothy Crandall, Jing Lin, Jianguo Ma, David Bachner, Jürgen Schmidt, Martin Schaefer, Christopher Stroh. Anti-tumor activity of tepotinib in orthotopic models of lung cancer patient-derived brain metastases with MET amplification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3407.

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Rationale: RAS genes are well-established oncogenes known to contribute to the development of cancer. Epidermal, sebaceous, and melanocytic nevi may be triggered by somatic mutations in HRAS, KRAS, and NRAS. The majority of these nevi are not associated with internal malignancies, however, a small subset have been associated with rhabdomyosarcoma (RMS). This calls into question the clinical utility of the anatomic location of the nevi for cancer risk stratification and management. Methods: A retrospective review showed 12 previously reported cases of RAS-driven nevi in conjunction with RMS. 3 additional unreported cases were collected from collaborators through the Pediatric Dermatology Research Alliance (PeDRA). Results: 15 patients with 16 primary RMS were included for analysis. 12/15 were previously reported. 1-12 All had RAS-driven birthmarks: 5 patients with epidermal nevi, 4 with congenital melanocytic nevi, 4 with phacomatosis pigmentokeratotica, and 2 with speckled lentiginous nevi/agminated Spitz. Of the 16 RMS: 8 were genitourinary, 3 were pelvic/retroperitoneal, 4 were dermal, and 1 was abdominal. 5/15 tumor-birthmark pairs had genotyping results: 3 had HRAS mutations and 2 had KRAS mutations. Body surface area did not seem to be a contributing risk factor. However, all 15 cases had involvement of the nevus on the trunk. Relevance: Truncal location of mosaic RASopathies may be a risk factor for RMS. Further prospective studies are needed to solidify appropriate monitoring guidelines for patients at risk. and 2 VA Palo Alto Healthcare System, Palo Alto, California, United States Small non-coding RNAs play fundamental roles in biology. Among them are snoRNAs, which are best studied for their role in modifying RNA nucleosides. Of the two major snoRNA classes, H/ACA box snoRNAs are known to enable RNA pseudouridylation while C/D box snoRNAs facilitate RNA methylation.137/412 annotated snoRNAs do not have defined RNA targets, and are designated as orphan snoRNAs. Recent data suggest that snoRNAs may have broader impacts relevant to human disease, including in genetic disorders, metabolic stress, and neoplasia. To identify new roles for snoRNAs in disease, we hybridized all non-clustered orphan snoRNAs consist of 26 C/D and 20 H/ACA box snoRNAs to 9200 recombinant human proteins. Unexpectedly, the H/ACA box snoRNA SNORA12 directly bound an essential kinase in the MAPK protein kinase cascade, ERK2 (MAPK1). A CRISPR/Cas9 dual-cut gRNA lentiviral vector was used to produce SNORA12snoRNA knockout clones from human cancer cell lines. SNORA12 deletion reduced ERK2 activation and in vivo tumorigeneses. These effects were due to the SNORA12 snoRNA itself, as opposed to an artifact of genome editing at the SNORA12locus, as confirmed by rescue experiments that restored SNORA12 expression. To define how SNORA12 modulates ERK2 function, we performed mass spectrometry (LC-MS/MS) to detect ERK2 proximal proteins in the presence and absence of SNORA12. In parallel, we also analyzed the status of 104 phosphorylation sites o...