tbuckley/cabot-search huggingface dataset:
Regorafenib Dose Optimization Study (ReDOS): Randomized phase II trial to evaluate escalating dosing strategy and pre-emptive topical steroids for regorafenib in refractory metastatic colorectal cancer (mCRC) – An ACCRU Network study
Authors: T. Bekaii-Saab, F. Ou, D. Anderson, D. Ahn, P. Boland, K. Ciombor, N. Jacobs, R. Desnoyers, J. Cleary, J. Meyers, E. Chiorean, K. Pedersen, A. Barzi, J. Sloan, J. McCune, M. Lacouture, H. Lenz, A. Grothey
Journal: Annals of Oncology (2018)

Introduction: Regorafenib (Rego) confers a survival benefit in refractory mCRC patients (pts). Toxicities such as palmar-plantar erythrodysesthesia syndrome (PPES) have limited its use. Despite absence of supportive data, various dosing variations are used in clinical practice. Methods: Patients with mCRC were randomized to Arm A: 80 mg/day (d), weekly escalation if no significant drug-related toxicity, up to 160 mg/d vs. Arm B: 160 mg/d for 21 ds of a 28-d cycle. Randomization was 1:1:1:1 to arms A1 and B1 (Arm 1 Pre-emptive topical Clobetasol [CL] for 12 weeks); A2 and B2 (Arm 2 Reactive CL for PPES). Primary endpoint was the proportion of pts who initiate a 3rd cycle in Arm A (A1 + A2) vs. Arm B (B1 + B2). Superiority for Arm A is declared if one-sided p-value with Fisher's exact method was less than 0.2. Quality of Life (QoL) was collected using Linear Analogue Self-Assessment over 8 weeks. Plasma pharmacokinetic (PK) analysis of Regorafenib and its M2 and M5 metabolites were performed prior to dosing (Cmin, trough levels) on cycle 1 days 7,14, 21 and cycle 2 days 1 and 21. Results: A total of 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Median age of 61 years and ECOG PS 0/1 (37/63%). The study met its primary endpoint with 43% of pts in Arm A initiating the 3rd cycle vs. only 25% of pts in Arm B [one-sided p-value 0.028]. Most common reason for not initiating cycle 3 was progressive disease (35% in A vs. 47% in B). Median overall survival was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median progression free survival was 2.5 mos vs 2.0 mos for Arm A vs. Arm B (p = 0.55). In cycle 1, rates of common dose modifying toxicities such as PPES (grade [G] 2-3) and fatigue or hypertension (G3) were more favorable in Arm A vs. Arm B. Pts on Arm 1 vs. Arm 2 experienced less G2-3 PPES in the first 2 cycles (28% vs. 35% in cycle 1 and 13% vs. 34% in cycle 2, in Arm 1 vs. Arm 2 respectively). Multiple QoL parameters were favorable in A vs. B primarily at week 2 of cycle 1. Conclusion: A strategy with weekly dose escalation of Rego from 80 to 160 mg/d was found to be superior to a starting dose of 160 mg/day. These results conceivably establish a new standard for optimizing Rego dosing through dose escalation. A preemptive strategy with CL may decrease the risk of PPES warranting further investigation. PK analysis and correlation with clinical parameters of interest will be reported at the meeting.
Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses
Authors: Neil Romberg, Carole Le Coz, Salomé Glauzy, Jean-Nicolas Schickel, Melissa Trofa, Brian E. Nolan, Michele Paessler, Mina L. Xu, Michele P. Lambert, Saquib A. Lakhani, Mustafa K. Khokha, Soma Jyonouchi, Jennifer Heimall, Patricia Takach, Paul J. Maglione, Jason Catanzaro, F. Ida Hsu, Kathleen E. Sullivan, Charlotte Cunningham-Rundles, Eric Meffre
Journal: Journal of Allergy and Clinical Immunology (2018)
Inactivation of Citron Kinase Inhibits Medulloblastoma Progression by Inducing Apoptosis and Cell Senescence
Authors: Gianmarco Pallavicini, Francesco Sgrò, Francesca Garello, Mattia Falcone, Valeria Bitonto, Gaia E. Berto, Federico T. Bianchi, Marta Gai, Alessandra M.A. Chiotto, Miriam Filippi, Juan C. Cutrin, Ugo Ala, Enzo Terreno, Emilia Turco, Ferdinando Di Cunto
Journal: Cancer Research (2018)

Medulloblastoma is the most common malignant brain tumor in children. Current treatment for medulloblastoma consists of surgery followed by irradiation of the whole neuraxis and high-dose multiagent chemotherapy, a partially effective strategy associated with highly invalidating side effects. Therefore, identification and validation of novel target molecules capable of contrasting medulloblastoma growth without disturbing brain development is needed. Citron kinase protein (CITK), encoded by primary microcephaly gene MCPH17, is required for normal proliferation and survival of neural progenitors. Constitutive loss of CITK leads to cytokinesis failure, chromosome instability, and apoptosis in the developing brain, but has limited effects on other tissues. On this basis, we hypothesized that CITK could be an effective target for medulloblastoma treatment. In medulloblastoma cell lines DAOY and ONS-76, CITK knockdown increased both cytokinesis failure and DNA damage, impairing proliferation and inducing cell senescence and apoptosis via TP53 or TP73. Similar effects were obtained in the NeuroD-SmoA1 transgenic mouse model, in which CITK deletion increased apoptotic cells and senescence markers such as P21CIP1, P27KIP1, and P16INK4A Most importantly, CITK deletion decreased tumor growth and increased overall survival in these mice, with no apparent side effects. These results suggest that CITK can be a useful molecular target for medulloblastoma treatment.Significance:In vitro and in vivo proof of concept identifies citron kinase protein as a suitable target for medulloblastoma treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4599/F1.large.jpg Cancer Res; 78(16); 4599-612. ©2018 AACR.
Abstract 108: C1q-TNF Related Protein-9, a Novel Cardioprotective Cardiokine, Requires Proteolytic Cleavage to Generate a Biologically Active Globular Domain Isoform
Authors: Yuanhui Du, Yuexing Yuan, Wayne Lau, Theodore Christopher, Bernard Lopez, Yajing Wang, Xinliang Ma
Journal: Circulation Research (2015)

The discovery of the cardiac secretomes, known as “cardiokines”, significantly enhanced appreciation of the local microenvironment’s influence upon disease development. We previously reported cardiomyocytes produce cardioprotective adiponectin (APN). However, cardiac APN levels are several orders of magnitude below adipocytes, thereby making APN an unlikely physiologically relevant cardiokine. C1qTNF-related proteins (CTRP1-15) is a newly descovered family of APN paralogs. However, whether any of the CTRP members may function as a “true” cardiokine remains unknown. Here we demonstrated that several CTRPs (CTRP1,4,7,9,13) were expressed in the heart at levels significantly greater than APN. Most notably, the mRNA level of CTRP9 exceeded APN by &gt;100-fold in cardiac tissue. Adult cardiac cells were isolated and cultured in vitro. Conditioned medium was collected 1-8 hours after culture and CTRP9 protein levels were determined by ELISA. A significant increase of CTRP9 in conditioned medium was detected as early as 1 hour in culture, steadily accumulating thereafter. These results indicate CTRP9 is secreted by cardiac cell at levels that may function as a cardiokine. Addional experiemnt unexpectedly demonstarted that CTRP9 circulates in the plasma primarily in the globular domain isoform (gCTRP9), opposing from APN which circulates as full length multimers. Recombinant full length CTRP9 (fCTRP9) was cleaved when incubated with cardiac tissue extracts, generating gCTRP9, a process inhibited by protease inhibitor cocktail. To gain more insight into the biological significance of gCTRP9 production, isolated adult cardiomyocytes were treated with gCTRP9 or fCTRP9. gCTRP9 rapidly activates cardiac survival kinases, including AMPK, Akt, and eNOS. However, fCTRP9-mediated kinase activation is much less potent, and significantly delayed. Kinase activation by fCTRP9, but not gCTRP9, is inhibited by protease inhibitor cocktail. These results demonstrate for the first time CTRP9 is a novel cardiokine undergoing proteolytic cleavage to generate cardioprotective isoform, gCTRP9. Enhancing cardiac CTRP9 production and/or its proteolytic post-translational modification are of therapeutic potential, attenuating cardiac injury.
Influence of Smoking, Body Mass Index, and Other Factors on the Preventive Effect of Nonsteroidal Anti-Inflammatory Drugs on Colorectal Cancer Risk
Authors: Xiaoliang Wang, Andrew T. Chan, Martha L. Slattery, Jenny Chang-Claude, John D. Potter, Steven Gallinger, Bette Caan, Johanna W. Lampe, Polly A. Newcomb, Niha Zubair, Li Hsu, Robert E. Schoen, Michael Hoffmeister, Hermann Brenner, Loic Le Marchand, Ulrike Peters, Emily White
Journal: Cancer Research (2018)

Nonsteroidal anti-inflammatory drugs' (NSAID) use has consistently been associated with lower risk of colorectal cancer; however, studies showed inconsistent results on which cohort of individuals may benefit most. We performed multivariable logistic regression analysis to systematically test for the interaction between regular use of NSAIDs and other lifestyle and dietary factors on colorectal cancer risk among 11,894 cases and 15,999 controls. Fixed-effects meta-analyses were used for stratified analyses across studies for each risk factor and to summarize the estimates from interactions. Regular use of any NSAID, aspirin, or nonaspirin NSAIDs was significantly associated with a lower risk of colorectal cancer within almost all subgroups. However, smoking status and BMI were found to modify the NSAID-colorectal cancer association. Aspirin use was associated with a 29% lower colorectal cancer risk among never-smokers [odds ratios (OR) = 0.71; 95% confidence intervals (CI): 0.64-0.79], compared with 19% and 17% lower colorectal cancer risk among smokers of pack-years below median (OR, 0.81; 95% CI, 0.71-0.92) and above median (OR, 0.83; 95% CI, 0.74-0.94), respectively (
MBCL-15. TOXICITY PROFILE AND RESPONSE TO HIGH DOSE METHOTREXATE, BEVACIZUMAB, AND TEMOZOLOMIDE CHEMOTHERAPY REGIMEN IN CHILDREN WITH RECURRENT MALIGNANT PEDIATRIC BRAIN TUMORS: SINGLE INSTITUTION EXPERIENCE
Authors: Margaret Page, Sumit Singh, Sasha Ramini, Kara Kachurak, Jessica Edmondson, Rong Li, Emily Waite, Joshua Bernstock, Elizabeth Alva, Alyssa Reddy, Gregory Friedman
Journal: Neuro-Oncology (2018)

Standard, effective therapies for recurrent malignant pediatric brain tumors do not exist. High-dose methotrexate (HDMTX), bevacizumab, and temozolomide have been studied alone or with other agents, but a regimen combining these agents has not been described. We report the toxicity and tumor response for patients treated with this regimen. We conducted a retrospective review of patients at Children’s of Alabama with recurrent tumors treated with up to six 28-day cycles of HDMTX (8 grams/m2 IV on day 2), bevacizumab (5-10 mg/kg IV on day 1, 14), and temozolomide (200 mg/m2 po daily for 5 days after clearance of HDMTX). Response was measured by RANO criteria. Patients who responded to therapy received additional cycles of bevacizumab and temozolomide. Primary diagnoses included 5 medulloblastoma, 2 supratentorial PNETs, 1 choroid plexus carcinoma, and 1 ependymoma. Median age at diagnosis was 11 years (range 2-19). All patients received prior standard-of-care chemotherapy and/or radiation. Six had disseminated disease at recurrence. A total of 43 courses of therapy were administered (median 5.5 cycles/patient [range 2-6]). Toxicities included neutropenia (18.6%), thrombocytopenia (18.6%), hypertension (13.9%), skin rash (9.3%), and dysuria (7.0%). No hospitalizations for toxicity or leukoencephalopathy occurred. Four patients with medulloblastoma (80%) had a partial response with mean response time of 16 months (range 14-18). The combination of HDMTX, bevacizumab and temozolomide was well-tolerated in heavily pretreated children with recurrent malignant brain tumors. Partial responses lasting over a year were achieved in 80% of medulloblastoma patients. Further evaluation of this regimen is warranted.
MBRS-64. SURPRISING ROLE FOR WNT SIGNALING IN SONIC HEDGEHOG DRIVEN MEDULLOBLASTOMA
Authors: Jezabel Rodriguez-Blanco, Lina Pednekar, Clara Penas, Bin Li, Vanesa Martin, Jun Long, Ethan Lee, William Weiss, Carmen Rodriguez, Nadji Mehrdad, Dao Nguyen, Nagi Ayad, Priyamvada Rai, Anthony Capobianco, David Robbins
Journal: Neuro-Oncology (2018)

The classification of specific cancers into distinct subgroups, based on emerging genomic technologies, has ushered in a new era of targeted therapeutics and companion diagnostics. This promise, however, is inconsistent with a model in which the growth of solid tumors, and their resistance to various chemotherapeutics, is driven by a small number of tumor-propagating cells whose transcriptome is unlikely to be captured by these technologies. We isolated such tumor propagating cells from a mouse model for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma. Medulloblastoma sphere cultures were enriched for the medulloblastoma progenitor marker SOX2, resistant to SHH inhibitors, and formed tumors in vivo. Surprisingly, these cultures, and their ability to self-renew were WNT-dependent. We show that Trp53 loss in these sphere cultures activated canonical WNT signaling and a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup medulloblastoma in vivo, in an on-target manner, leading to increased survival. Our results suggest that the tumor propagating cells driving the growth of bulk SHH-dependent medulloblastoma are themselves WNT dependent. Further, these results suggest WNT pathway inhibition as a novel therapeutic strategy to treat TRP53 deficient SHH-subgroup medulloblastoma patients, for whom few therapeutic options exist.
LGG-26. TYPE II BRAF INHIBITOR TAK-580 SHOWS PROMISE FOR UPCOMING CLINAL TRIAL AS EVIDENCED BY SINGLE PATIENT IND STUDY
Authors: Karen D Wright, Mary Ann Zimmerman, Elizabeth Fine, Tristan Aspri, Mark W Kieran, Susan Chi
Journal: Neuro-Oncology (2018)

Abnormal signaling of the RAS/RAF pathway predominates in pediatric low-grade gliomas (PLGGs). Most (85%) non-NF1 low-grade gliomas have RAS-independent BRAF activation, either due to KIAA1549:BRAF truncated fusion duplication or V600E point mutation. We previously identified two different type II BRAF inhibitors capable of inhibiting downstream activation of pERK and tumor progression in vivo for multiple point mutations and BRAF truncated fusion forms. One compound, in particular, known as TAK-580 was active on authentic human PLGG cells ex vivo and showed excellent CNS penetration. We conducted a single patient IND study for a patient with refractory, progressive LGG. Patient was initially diagnosed at age 2 years and treated with 9 different chemotherapy regimens up until age 15 years prior to starting TAK-580. Study drug was begun orally on a QOD schedule; one cycle was comprised of 28 days. Based on both tolerance and pharmacokinetic analyses, the treatment schedule and dosing were adjusted to weekly, comparable to the adult dosing schedule. MR imaging of her tumor burden has remained stable, and patient has recently started her 33rd cycle of once weekly TAK-580. TAK-580 was well tolerated. Grade 3 and 4 likely or possibly related toxicities included acneiform rash, hyperglycemia, elevated creatinine kinase, elevated ALT and decreased phosphorus. TAK-580 posess a unique mechanism of action targeting the BRAF/MEK complex and inhibiting both BRAF point mutations and common structural abnormalities in PLGGs. These initial results support the upcoming phase I/0/II trial of TAK-580 for children with LGG and other RAS/RAF/MEK/ERK pathway activated tumors.
Vascular endothelial growth factor (VEGF) splice isoforms may hold the key to targeting tumour angiogenesis in oesophageal cancer
Authors: F. Mehedi
Journal: Annals of Oncology (2018)

Introduction: Angiogenesis is principally induced by Vascular Endothelial Growth Factor A (VEGF-A); however, the use of VEGF-A inhibitors in the treatment of oesophageal cancer (e.g. Bevacizumab) has not proven efficacious in clinical trials. It has subsequently been shown that splicing of the terminal exon of VEGF-A pre-mRNA generates two separate isoforms: pro-angiogenic VEGF165a and anti-angiogenic VEGF165b. These isoforms are balanced to regulate angiogenesis by the splicing factor SRSF1, phosphorylated by serine–arginine protein kinase 1 (SRPK1). The aim of this study was to investigate expression of VEGF-A, its isoforms, and SRPK1 in oesophageal cancer and their association with micro vessel density (MVD) and patient survival. Understanding the role of SRPK1 and VEGF-A splice isoforms in the regulation of oesophageal cancer angiogenesis may provide a new and potentially efficacious target for anti-angiogenic therapy. Angiogenesis is principally induced by Vascular Endothelial Growth Factor A (VEGF-A); however, the use of VEGF-A inhibitors in the treatment of oesophageal cancer (e.g. Bevacizumab) has not proven efficacious in clinical trials. It has subsequently been shown that splicing of the terminal exon of VEGF-A pre-mRNA generates two separate isoforms: pro-angiogenic VEGF165a and anti-angiogenic VEGF165b. These isoforms are balanced to regulate angiogenesis by the splicing factor SRSF1, phosphorylated by serine–arginine protein kinase 1 (SRPK1). The aim of this study was to investigate expression of VEGF-A, its isoforms, and SRPK1 in oesophageal cancer and their association with micro vessel density (MVD) and patient survival. Understanding the role of SRPK1 and VEGF-A splice isoforms in the regulation of oesophageal cancer angiogenesis may provide a new and potentially efficacious target for anti-angiogenic therapy. Methods: Tumour samples from 36 patients with oesophageal adenocarcinoma undergoing curative resection following neo-adjuvant chemotherapy were examined using immunohistochemistry for VEGF-A, VEGF165a, VEGF165b, CD31 (for MVD) and SRPK1. Digital droplet PCR was used to quantify SRPK1 levels at the gene level. Results: VEGF-A was not associated with MVD. There was a high (pro-angiogenic) VEGF165a/VEGF165b ratio in the majority of the oesophageal cancers examined. VEGF165a expression was positively correlated with SRPK1 expression (p = 0.01). There was a positive correlation between the pro-angiogenic (VEGF165a dominant) oesophageal cancers, MVD and poor overall survival; however, this did not reach statistical significance. Conclusion: The dominance of the pro-angiogenic VEGF splice isoform and the splicing factor SRPK1 show greater correlation with oesophageal cancer angiogenesis and disease survival than the general target of VEGF-A. Further investigation of the control and potential inhibition of this angiogenic pathway in oesophageal cancer is required.
HGG-16. SUSTAINED RESPONSE TO ERLOTINIB AND RAPAMYCIN IN A PATIENT WITH PEDIATRIC ANAPLASTIC OLIGODENDROGLIOMA
Authors: Adam Esbenshade, Bret Mobely, Devang Pastakia, Asa Brockman, Aashim Bhatia, Rob Naftel, Rebecca Ihrie
Journal: Neuro-Oncology (2018)

A 10 year old presented in 2014 with left sided weakness and numbness and was found to have a large infiltrating mass involving the right perisylvian frontal and temporal cortex and causing mass effect. It was biopsied and shown to be an anaplastic oligodendroglioma (WHO Grade III) with no LOH 1p19q. The patient underwent 60 Gy cranial radiation with temozolomide and the MRI following radiation showed the mass had progressed with increased enhancement. The patient was then started on maintenance temozolomide, bevacizumab, and irinotecan but 7 months later further progressed. The patient was switched to procarbazine, lomustine and vincristine (PCV) but after 4 months showed further progression. Patient was wheel chair bound and was made do not resuscitate. Foundation One testing was sent and revealed mutations in EGFR, a receptor tyrosine kinase, and FBXW7, a member of the SCF complex predicted to sensitize cells to rapamycin. As a consequence, the patient was started on erlotinib, an EGFR inhibitor, and rapamycin, a mTOR inhibitor. The patient showed immediate response and tumor regression and continues to remain on these medications with sustained response for 2.5 years. Immunofluorescent analyses of fixed tumor specimens indicates that EGFR-positive cells in the pre-treatment tumor frequently also exhibit high levels of p-S6, an indicator of mTOR activity, suggesting that a majority of cells within this tumor may be targeted by both inhibitors simultaneously, rather than two independent populations being present. This regimen has potential to be an effective regimen in those with similar mutations.
The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia
Authors: Carolin Rommel, Stephan Rösner, Achim Lother, Margareta Barg, Martin Schwaderer, Ralf Gilsbach, Timo Bömicke, Tilman Schnick, Sandra Mayer, Sophia Doll, Michael Hesse, Oliver Kretz, Brigitte Stiller, Franz-Josef Neumann, Matthias Mann, Markus Krane, Bernd K. Fleischmann, Ursula Ravens, Lutz Hein
Journal: Circulation Research (2018)

Rationale: Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria. Objective: Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes. Methods and Results: The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocyte-specific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cis -regulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposase-accessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis -regulatory elements containing ETV1-binding sites. Various genes involved in Ca 2+ handling or gap junction formation ( Ryr2, Jph2, Gja5 ), potassium channels ( Kcnh2, Kcnk3 ), and genes implicated in atrial fibrillation ( Tbx5 ) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation. Conclusions: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.