tbuckley/cabot-search huggingface dataset:
Abstract 2206: Anti-tumor activity of infigratinib, a potent and selective inhibitor of FGFR1, FGFR2 and FGFR3, in FGFR fusion-positive cholangiocarcinoma and other solid tumors
Authors: Gary Li, Melanie Krook, Sameek Roychowdhury, Francesca Avogadri, Yining Ye, Susan Moran
Journal: Cancer Research (2019)

Abstract Abnormal expression and constitutive activation of receptor tyrosine kinases, such as ALK, ROS1 and TRK, as a result of gene rearrangements have been clinically validated as therapeutic targets for cancer. Recently, fusions involving the FGFR family, especially FGFR1, FGFR2 and FGFR3, have been identified in diverse solid tumors such as cholangiocarcinoma, glioblastoma, bladder, lung, breast, thyroid and prostate cancers. FGFR fusions are oncogenic drivers that ligand-independently activate the receptor kinases and their downstream signaling pathways, leading to uncontrolled cell proliferation and invasion. Infigratinib (BGJ398) is an oral and selective inhibitor of FGFR. At biochemical and cellular levels, infigratinib selectively inhibits the activity of FGFR1, FGFR2 and FGFR3 with low nM potency, while sparing FGFR4, VEGFR2 and other kinases. In FGFR fusion-positive xenograft models, including cell line-derived and patient-derived models representing diverse tumor histologies, infigratinib treatment leads to significant tumor growth inhibition and regression at clinically achievable exposure levels. The anti-tumor effect of infigratinib is accompanied by inhibition of downstream signaling pathways and induction of tumor apoptosis. Clinically, in an open-label phase II trial, infigratinib demonstrated a cORR of 39.3% in FGFR2 fusion-positive cholangiocarcinoma patients who had received one or fewer prior chemotherapy regimens. Additionally, RECIST responses were achieved in non-cholangiocarcinoma solid tumors tested positive for FGFR fusions. In conclusion, the available preclinical and clinical data demonstrate the potential of infigratinib as an effective treatment for patients with FGFR fusion-positive tumors, regardless of the fusion partners or the origin of tissue. On the basis of these data there is a clear rationale for performing tumor-agnostic clinical trials in molecularly defined cancers to maximally benefit patients with serious and life-threatening diseases. Citation Format: Gary Li, Melanie Krook, Sameek Roychowdhury, Francesca Avogadri, Yining Ye, Susan Moran. Anti-tumor activity of infigratinib, a potent and selective inhibitor of FGFR1, FGFR2 and FGFR3, in FGFR fusion-positive cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2206.
Abstract 1235: Targeting RNA-binding protein HuR to inhibit human breast cancer invasion and metastasis
Authors: Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Shuang Han, Cuncong Zhong, Ragul Gowthaman, John Karanicolas, Dan A. Dixon, Danny R. Welch, Ling Li, Min Ji, Jeffrey Aubé, Liang Xu
Journal: Cancer Research (2019)

Abstract The majority of breast cancer-related mortality is due to metastasis. Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. The RNA-binding protein Hu antigen R (HuR) is overexpressed in breast cancer. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors and cytokines that implicate major tumor hallmarks including invasion and metastasis. Knocking out HuR by CRISPR/CAS9 technology inhibits cell invasion in breast cancer cells. Therefore, HuR is an emerging target for breast cancer therapy, especially the lethal metastatic breast cancer. RNA-binding proteins had previously been considered “undruggable” due to lack of a well-defined binding pocket for target RNAs. Using high throughput screening followed by structure-based rational design and lead optimization, we have identified small molecules that inhibit HuR-mRNA interaction at nM to sub-µM potency. Our lead compound, KH-3, potently inhibits breast cancer cell growth and decreases cell invasion in vitro similar to HuR knockout, as well as increasing the expression of epithelial marker E-cadherin. In the study of mechanism of action, a transcription factor, FOXQ1, which is recently revealed to implicate in breast cancer invasion and metastasis processes, is found for the first time to be a direct mRNA target of HuR and one of the top genes that are reduced by KH-3 treatment. Exogenous introduction of FOXQ1 can rescue cell invasive capability impaired by HuR knockout and abolish the effect of KH-3 on inhibiting cell invasion in breast cancer cells. Moreover, KH-3 disrupts HuR-FOXQ1 interaction in RNP-IP, RNA pull down and FOXQ1 3′-UTR luciferase reporter assays. In vivo efficacy studies show that KH-3 not only exhibits potent antitumor efficacy in an orthotopic xenograft model of breast cancer, but also efficiently inhibits lung metastasis and improves mouse survival in an experimental metastasis model. Our data provide a proof-of-principle that HuR inhibition by KH-3 may be developed as a promising molecular therapy for inhibiting progression and metastasis of breast cancer with high HuR. Citation Format: Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Shuang Han, Cuncong Zhong, Ragul Gowthaman, John Karanicolas, Dan A. Dixon, Danny R. Welch, Ling Li, Min Ji, Jeffrey Aubé, Liang Xu. Targeting RNA-binding protein HuR to inhibit human breast cancer invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1235.
Clinical profile of multiple myeloma in Asia: An Asian Myeloma Network (AMN) study.
Authors: Jae Hoon Lee, Kihyun Kim, Jin Seok Kim, Chang Ki Min, Kazuyuki Shimizu, Takaaki Chou, Hiroshi Kosugi, Kenshi Suzuki, Hiroyuki Hata, Wenming Chen, Jian Hou, Shang-Yi Huang, Wee Joo Chng, Daryl C.L. Tan, Gerrard Teoh, James Chim, Raymond Liang, Weerasak Nawarawong, Noppadol Siritanaratkul, Brian G. Durie
Journal: Journal of Clinical Oncology (2012)

8097 Background: The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However the difference of clinical characteristics between ethnic groups is not well-defined. In Asian countries the incidence of MM has been lower compared with Western countries. However, there are growing evidences that MM is increasing very rapidly in this region. Until now, only few data of Asian patients has been reported. Asian myeloma network (AMN) decided to analyze the first multinational project to explore clinical characteristics of Asian MM patients and clinical practice performed in Asian countries. Methods: Data were collected from 21 centers from 7 countries and regions were collected retrospectively. Clinical characteristics of 2969 symptomatic MM patients at diagnosis were described. Overall survival (OS) and prognostic factors were analyzed for 2273 patients who have survival data. Results: Median OS was 54 months (95% CI 48.0-60.0). Patients who were diagnosed before 2000 were shorter survival. Transplantation was performed to 513 patients with better survival (84 vs. 45 months, p&lt;0.001). First line treatment of 2339 evaluable patients was analyzed. Overall response rate was 71% with 30%, VGPR or better. New drugs including bortezomib, thalidomide or lenalidomide were combined for 32.5% of all 2339 patients without difference in response rate or OS according to combination. Conclusions: We successfully described clinical characteristics of Asian MM patients and this project will be the base for future studies or clinical trials for Asian MM patients. Updated analyses and comparison with Western data will be presented. AMN, supported by the International Myeloma Foundation (IMF) IMWG initiative.
Histamine<sub>2</sub>-Receptor Antagonists
Authors: M Feldman, M E Burton
Journal: New England Journal of Medicine (1990)

THIS article reviews the clinical pharmacology of histamine2-receptor antagonist drugs (H2 blockers) and their usefulness in the treatment and prevention of acid-peptic disorders — namely, peptic ulcer disease, Zollinger—Ellison syndrome, gastroesophageal reflux disease, and acute stress ulcers and erosions. Erosive gastritis and erosive duodenitis are often considered acid-peptic diseases, but because they overlap with peptic ulcer disease they are not considered as separate entities in this review. Non-ulcer dyspepsia is not included as an acid-peptic disorder since it does not appear to respond to therapy with H2 blockers or antacids.1 H2 blockers are quite effective . . .
Abstract 2780: IL13RA2 is differentially regulated in papillary thyroid carcinoma versus follicular thyroid carcinoma
Authors: Siao Ting Chong, Catherine Y. Kok, Khee Ming Tan, Shou Ping Guan, Siang Hui Lai, Cindy Lim, Jiancheng Hu, Charles Sturgis, Charis Eng, Paula Y. Lam, Joanne Ngeow
Journal: Cancer Research (2019)

Abstract The interleukin-13 receptor alpha2 (IL13RA2), which is known to overexpressed in glioblastoma multiforme, plays a role in various cellular processes such as cell migration that may contribute to tumor progression. Studies have attributed IL13RA2 to invasion and metastasis in cancers of the ovary, breast, and pancreas but the pathological role of IL13RA2 in thyroid cancer is still unclear. This study aims to evaluate the expression of IL13RA2 in thyroid carcinomas and examine the role of IL13RA2 in progression of papillary thyroid cancer (PTC). We performed IL13RA2 immunochemical staining on tissue microarrays of 137 thyroid carcinomas and observed that IL13RA2 expression was significantly correlated with advanced tumor stage (pT3 / pT4; p=0.001) and regional lymph node metastasis (pN1; p&amp;lt;0.001). Moreover, the staining scores of IL13RA2 were significantly higher in PTC compared to follicular and anaplastic subtypes (p&amp;lt;0.02) and correlated with advanced tumor stage amongst PTC samples (pT3 / pT4; p=0.028). This differential profile of IL13RA2 in PTC was further validated in thyroid cancer cell lines overexpressing IL13RA2 to assay the effects on cell proliferation, cell migration and epithelial-mesenchymal transition (EMT) using CCK-8, transwell migration assay, qRT-PCR and western blot analyses. Knockdown of IL13RA2 in the PTC subtype B-CPAP cell line showed significantly reduced cell viability, cell migration and EMT markers including N-cadherin, Vimentin and Snail. Exogenous overexpression of IL13RA2 in another PTC cell line, K1 increased cell migration and EMT although cell proliferation was not affected. In summary, we demonstrated that IL13RA2 is differentially regulated in PTC and is involved in cell migration by enhancing EMT. The underlying molecular mechanisms on how IL13RA2 drives progression of thyroid cancer remains to be further investigated. Citation Format: Siao Ting Chong, Catherine Y. Kok, Khee Ming Tan, Shou Ping Guan, Siang Hui Lai, Cindy Lim, Jiancheng Hu, Charles Sturgis, Charis Eng, Paula Y. Lam, Joanne Ngeow. IL13RA2 is differentially regulated in papillary thyroid carcinoma versus follicular thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2780.
Newmouse models of melanoma metastasis and differences in brain tropism and metastatic growth pattern.
Authors: Amr M. Morsi, Avital Gazial-Sovran, Hana Baig, Robert S. Kerbel, John Golfinos, Youssef Zaim Wadghiri, Eva Hernando
Journal: Journal of Clinical Oncology (2012)

e19015 Background: 75% of patients with metastatic melanoma develop brain metastases (B-mets). Such patients show dismal prognosis with a median survival of &lt; 6 months. Scarcity of clinically relevant in vivo models has hindered melanoma B-met studies. We compared the in vivo dissemination upon ultrasound (u/s) guided intracardiac injection of B16F10 cells to 131/4-5B1 (hereafter 5B1), a WM239A subclone with enhanced brain tropism. We also implemented an ex vivo MRI protocol as a high throughput three dimensional approach for characterizing B-mets penetrance and growth. Methods: B16-F10 or 5B1 melanoma cells were injected in C57BL/6J mice (n=40) or athymic/nude mice (n=40) respectively using u/s-guided intracardiac injection. Upon weight loss, mice were euthanized, and heads prepared for ex vivo imaging. All µMRI experiments were performed with a 7T Bruker Avance II console. The protocol consisted of (110-mm) 3 isotropic T1-, T2- and T2*-weighted sequences. Results: Our ex vivo MRI recapitulates the clinical radiological T1 and T2 brightening as well as susceptibility-induced T2* darkening effect of melanoma. The B16F10 model revealed exclusive ventricular and leptomeningeal spread while the 5B1 model showed parenchymal lesions. In addition, 90% of the 5B1 mice with brain tumors showed multiple lesions (3-16) vs. 18% in the B16F10 model (1- 3). Finally, 3D volume studies revealed a higher B-met penetrance (68% vs. 18%), delayed onset of tumor detection (earliest-day 27 vs. day 15) post-injection and a slower growth rate of 5B1 brain metastases compared to B16F10 tumors. Conclusions: Our results suggest that u/s-guided intracardiac injection of melanoma cells is an optimal method to capture the cells’ spontaneous dissemination pattern (or site-specific tropism) and that the 5B1 model is a more clinically relevant model of melanoma B-met for preclinical studies.
Abstract 2205: CBT-102, an oral small molecule multi-kinase inhibitor, demonstrates favorable CSF-1R activity, offering means of controlling tumor associated macrophages
Authors: Elaine Liu, Lan Yang, Gavin Choy, Xiaoling Zhang, Tillman Pearce, Mamatha Reddy, Sanjeev Redkar, Qian Shi
Journal: Cancer Research (2019)

Abstract Background: The role of the tumor microenvironment (TME) in fostering the development of malignancies is prompting the pursuit of anticancer therapies that target its components as to opposed to the tumor itself. As part of their immune surveillance duties, immune cells form part of this microenvironment, and yet, cancer cells have devised means to downplay their tumoricidal capabilities. Colony stimulating factor 1 receptor (CSF-1R) may offer such a means of controlling tumor associated macrophages in the tumor microenvironment. Methods: The IC50 of CBT-102 against CSF1R was evaluated in both cell free system and cell based assays, where enzyme activity was evaluated with radiometric assay format, and cell growth inhibition was evaluated in the Ba/F3 hCSF1R cell line by the CellTiter-Glo (CTG) method. Further evaluation of CBT-102 IC50 was undertaken in M-NFS-60 syngeneic cell lines and human monocytes. In vivo studies of CBT-102 in combination with anti-PD1 antibody were performed in H22 and MC38 syngeneic models. Results: CBT-102 demonstrated a reproducible activity against CSF1R in a radiometric enzyme activity assay. Using engineered BaF3 hCSF1R cell lines, we demonstrated the IC50 value of CBT-102 was 0.588 µM compared to 1.333 µM of sulfatinib, a similar multi-kinase inhibitor, and 0.279 µM of GW2580, a more specific CSF1R kinase inhibitor. Similar studies conducted in M-NFS-60 cell lines and human monocyte also showed sub-micromolar activities of CBT-102. In vivo study combining CBT-102 with anti-PD1 antibody in syngeneic models demonstrated a favorable combination effect compared to each of the single agents. Conclusions: We demonstrated previously that CBT-102 effectively inhibits VEGFR and angiogenesis. The newly revealed mechanism of CBT-102, inhibiting CSF1R and macrophages, offers a promising dual mechanism of action in addition to targeting VEGFR and angiogenesis. Rational combination with check-point inhibitors (CPIs) may improve the efficacy of CBT-102 and broaden the impact of CPIs. Further studies may be needed to delineate the interplay among CBT-102’s different mechanisms and its impact in combination with CPIs. Citation Format: Elaine Liu, Lan Yang, Gavin Choy, Xiaoling Zhang, Tillman Pearce, Mamatha Reddy, Sanjeev Redkar, Qian Shi. CBT-102, an oral small molecule multi-kinase inhibitor, demonstrates favorable CSF-1R activity, offering means of controlling tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2205.
Abstract 13262: Right to Left Ventricular Interdependence at Rest and During Exercise Assessed by the Ratio Between Pulmonary Systolic to Diastolic Time in Heart Failure Reduced Ejection Fraction
Authors: Greta Generati, Francesco Bandera, Marta Pellegrino, Valentina Labate, Francesco Carbone, Eleonora Alfonzetti, Marco Guazzi
Journal: Circulation (2015)

Background: The ratio between the duration of right ventricular (RV) systole and diastole (S:D ratio) has been proposed as an index of RV performance in a pediatric population with pulmonary arterial hypertension in whom it may predict prognosis and functional capacity. In heart failure (HF) S:D may provide relevant insights in the exercise response. Aim: to analyze the correlation between rest and peak exercise S:D and functional and cardiac parameters in HFrEF. Methods: 94 HFrEF patients (mean age 66±11 y, male 70%, ischemic etiology 71%, mean LVEF 34±9%) underwent a symptom-limited cardiopulmonary exercise testing (incremental ramp protocol) combined with exercise-echo. RV S:D was assessed by echo at rest and peak exercise. Results: A good correlation was found between rest and peak S:D and CPET indexes of exercise capacity, such as peak oxygen consumption (VO2) (Sperman’s rho -0.40 and 0.38 respectively, p= 0.02 and 0.023) and maximal workload (Rho= -0.42 and -0.45, p=0.031 and 0.034). An higher S:D also correlated with more impaired ventilatory efficiency or higher VE/VCO2 slope (Rho 0.49 and 0.32, p=0.019 and 0.024). Looking at echo phenotype, interestingly S:D is associated with parameters of mitral regurgitation (MR) severity, such as effective regurgitant orifice (Rho rest 0.63, peak 0.35, p&lt;0.01) and pulmonary artery systolic pressure (PASP, rho rest 0.53, peak 0.35, p&lt;0.01) particularly at rest. S:D also correlated with right RV fractional area change at rest and peak exercise (-0.39 and -0.39, p=0.035 and 0.04). Conclusions: In HFrEF population the assessment of S:D at rest and peak exercise predicts functional status and is related to more advanced hemodynamic impairment (increased PASP and MR) as expression of more unfavorable ventricular interdependence.
Abstract 3469: CYP1B1 induces cancer progression through regulation of TRAIL pathway and uPA-uPAR system
Authors: Yeo-Jung Kwon, Young-Jin Chun
Journal: Cancer Research (2019)

Abstract Human CYP1B1 is known as a major metabolizer for estrogen and shows tumor-specific hyper-expression. To explore the role of CYP1B1 on progression of human cancer cells, we studied the effects of CYP1B1 in MCF-7, MDA-MB-231, and HeLa cells. CYP1B1 significantly induced invasion of cancer cells while strongly inhibited cancer cell apoptosis. Suppression of CYP1B1 by si/shRNA or treatment with TMS, a specific inhibitor for CYP1B1, markedly increased the protein expression level along with the level of release from cells of TNF-related apoptosis inducing ligand (TRAIL), a death ligand for cancer cells, whereas significantly decreased the expression of urokinase-type plasminogen activator receptor (uPAR) as well as uPA. We also found that CYP1B1 showed to inhibit the expression of key factors in TRAIL-induced apoptotic pathway and promote the inducers in uPA-uPAR metastasis system including integrin β1 and α5. Interestingly, uPAR overexpression only caused a significant increase of integrin β1 and α5 in protein levels, indicating protein degradation may play an important role in regulating integrin protein level. Surprisingly, CYP1B1 down-regulated p53 expression through MDM2 activation and nutlin-3a, an inhibitor for MDM2, blocked the promoting effects of CYP1B1 inducer, DMBA, on uPAR, which explains that CYP1B1 induced uPAR expression through regulation of MDM2-p53 system. Furthermore, we found that CYP1B1 suppresses TRAIL-related apoptosis through not only inhibition of TRAIL expression but also induction of DNA methylation on the promoter region of DR4, a receptor for TRAIL. Taken together, our data suggest that CYP1B1 promotes cancer cell metastasis via activating uPA-uPAR pathway which is one of the targets of p53 signaling and suppresses cancer cell apoptosis through inhibition of TRAIL-induced apoptosis by suppression of TRAIL release as well as post-translational regulation on DR4. Citation Format: Yeo-Jung Kwon, Young-Jin Chun. CYP1B1 induces cancer progression through regulation of TRAIL pathway and uPA-uPAR system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3469.
Abstract 4205: Pan-cancer molecular study of disparities among African Americans
Authors: Olivia D. Lara, Ying Wang, Wei Hu, Lin Zhang, Alejandro Rauh-Hain, Anil Sood
Journal: Cancer Research (2019)

Abstract Objective: Several factors have been proposed to contribute to racial disparities in gynecologic cancers, however there are no comprehensive studies that have investigated inherent molecular features that may be racially unique. Our objective was to perform a pan-cancer clinical and molecular analysis of African-Americans (AA) and European American (EA) patients. Methods: We performed cross-platform analyses utilizing cancer registry and molecular databases [Surveillance, Epidemiology and End Results (SEER) and The Cancer Genome Atlas (TCGA)] to evaluate differences in AA vs EA patients. To characterize genetic ancestry we utilized the recently established The Cancer Genetic Ancestry Atlas (TCGAA). We further evaluated epigenetic modifications through non-coding RNA expression in these tumors. Results: A total of 2,045,500 patients (87.5% EA, 12.5% AA) with 64 primary tumor types were evaluated using SEER to evaluate clinical outcome differences. Compared to white race, AA race had higher rate of death in 45 cancer types (HR&amp;gt;1.0, CI 1.00-5.23). 19 cancer types were then identified to have the largest differences in overall survival (HR&amp;gt;1.2). Utilizing TCGA, we analyzed molecular data of 7028 tumors (88.9% EA, 10.9% AA) having miRSeq data and genetic ancestry data. We identified differentially expressed miRNA’s in five cancer types: breast invasive (300 miRs, p&amp;lt;0.068, FDR&amp;lt;0.1), renal cell (408 miRs, p&amp;lt;0.205, FDR&amp;lt;0.1), prostate (102 miRs, p&amp;lt;2.68e-01, FDR&amp;lt;0.1), thyroid (63 miRs, p&amp;lt;1.28e-.02, FDR&amp;lt;0.1), and uterine corpus endometrial (177 miRs, p&amp;lt;8.18e-02, FDR&amp;lt;0.1) carcinomas. Differentially expressed miRs among all cancer types were associated with canonical pathways of cancer drug resistance by drug efflux, altered T- cell function, and regulation of epithelial-mesenchymal transition using Ingenuity Pathway Analysis (IPA) software. We identified miR-130, miR-180, miR-146, and miR-8 as commonly dysregulated miRs in these cancer types which may represent a molecular signature unique to African Americans. Conclusions: Our results identify molecular and genetic features unique to African Americans that may contribute to worse survival outcomes. While the cause of cancer disparities is multifactorial, a focus on molecular signatures unique to AA may identify actionable molecular abnormalities. Note: This abstract was not presented at the meeting. Citation Format: Olivia D. Lara, Ying Wang, Wei Hu, Lin Zhang, Alejandro Rauh-Hain, Anil Sood. Pan-cancer molecular study of disparities among African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4205.