In December 2019, reports of an atypical pneumonia emerged from the city of Wuhan, Hubei province of China. 1 The infectious agent was soon identified as a novel enveloped betacoronavirus. 2,3 Coronaviruses are enveloped non-segmented positive sense RNA viruses belonging to the family Coronaviridae. 4 This newly identified coronavirus, has been named Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) by the World Health Organization (WHO). This is the third large scale health crises caused by a betacoronavirus. Severe Acute Respiratory Syndrome CoronaVirus (SARS-CoV) and Middle East Respiratory Syndrome CoronaVirus (MERS-CoV) represent the previous health crises. Mortality rate of SARS-CoV and MERS-CoV was 10% and 37%, respectively. SARS-CoV and MERS-CoV infections were reported in 26 and 27 countries, respectively. A total 10,590 cases of infections were caused by both viruses. 5-11 On January 30, WHO declared the novel coronavirus outbreak (2019-nCoV) a public health emergency of

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM’s and MAPKAPK’s in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.

Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis.

Inspite of medication compliance, some chronic myeloid leukemia (CML) patients will relapse/progress into an accelerated phase or blast crisis. Central nervous system (CNS) involvement is a rare manifestation of such a relapse. Here, we report a case of 23-year-old female who was diagnosed with CML in the accelerated phase and subsequently treated with imatinib. She developed early relapse in her CNS, and her treatment was switched to dasatinib and intrathecal chemotherapy with cytarabine and methotrexate. Her CNS disease went into remission, and she underwent matched unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). We discuss various mechanisms of treatment failure, importance of vigilance for symptoms and signs of treatment failure/relapse, indications for use of different tyrosine kinase inhibitors (TKIs), and management of blast crises in CML.

Purpose Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab. Methods Patients were treated with escalating doses of nintedanib (150mg or 200mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes. Results Eighteen patients with advanced tumors (lung (n=9), colon (n=8), and cervical (n=1)) previously treated with at least two lines of chemotherapy including bevacizumab (n=9, 50%) were enrolled. The highest dose of nintedanib was 200mg twice a day with no observed dose limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1–3) and diarrhea (grade 1–2). Durable clinical response was observed in 55% patients pre-treated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1α. Conclusion Nintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.