bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4179: Potent and selective TRK inhibitor CH7057288
Authors: Tanaka Hiroshi , Sase Hitoshi , Tsukaguchi Toshiyuki , Tanimura Hiromi , Hasegawa Masami , Hasegawa Kiyoshi , Ono Yoshiyuki , Oikawa Nobuhiro , Sakamoto Hiroshi , Mio Toshiyuki 
Published: July 2017

Abstract
TRK receptor tyrosine kinases are expressed as fusion proteins encoded by various fusion genes across a wide variety of cancer types, including lung and colorectal cancer. These fusion proteins have potent oncogenic activity and are thought to be an attractive therapeutic target. In a kinase inhibitor screening we identified CH7057288, a potent and selective TRK inhibitor belonging to a novel chemical class. Our inhibitor showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. In subcutaneously implanted xenograft models of TRK fusion-positive cells, strong tumor growth inhibition was observed. Furthermore, CH7057288 induced regression of intracranial tumors and greatly improved event-free survival in an intracranial implantation model mimicking brain metastasis. Recently, resistant mutations in TRK have been reported in patients showing disease progression after treatment with a TRK inhibitor under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against some of the resistant mutants as it did to wild-type TRK. In summary, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer.
Citation Format: Hiroshi Tanaka, Hitoshi Sase, Toshiyuki Tsukaguchi, Hiromi Tanimura, Masami Hasegawa, Kiyoshi Hasegawa, Yoshiyuki Ono, Nobuhiro Oikawa, Hiroshi Sakamoto, Toshiyuki Mio. Potent and selective TRK inhibitor CH7057288 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4179. doi:10.1158/1538-7445.AM2017-4179
Abstract 4193: A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor scaffold
Authors: Shi Yihui , Park Jaehyeon , Lagisetti Chandraiah , Zhou Wei , Sambucetti Lidia C. , Webb Thomas R. 
Published: July 2017

Abstract
The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors. We found that these compounds, and their analogs, show significant cdc2-like kinase (CLK) inhibition and clear structure-activity relationships (SAR) at CLKs. We prepared a set of analogs and were able to ‘dial out’ the CDK activity and simultaneously developed CLK inhibitors with low nanomolar activity. Thus, we have demonstrated the utility of our exon-skipping assay and identified new molecules that exhibit potency and selectivity for CLK, as well as some structurally related dual CLK/CDK inhibitors.
Citation Format: Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C. Sambucetti, Thomas R. Webb. A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor scaffold [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4193. doi:10.1158/1538-7445.AM2017-4193
Abstract 4203: Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion
Authors: Thatte Jayant , Talaoc Elvira C. , Scott Colleen , Ren Ken , Broudy Thomas 
Published: July 2017

Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct primary hepatic malignancy that has conventionally been considered to be a histologic variant of hepatocellular carcinoma. However, it has more recently been recognized as a distinct clinical entity with respect to its epidemiology and prognosis. The etiology of FL-HCC is unclear and there is no clinical or histological evidence for association with chronic liver disease. Recent genetic studies have identified the fusion gene DNAJB1-PRKACA as a recurrent genetic lesion in the disease. Molecular pathogenesis of FL-HCC; however, is not well understood and has been reported to occur in association with focal nodular hyperplasia. Overexpression of genes in PIK3, MAPK and RAS pathways is observed in FL-HCC and in contrast to viral-associated HCC, epigenetic instability is rare in FL-HCC.
Here we describe development of a novel FL-HCC Patient Derived Xenograft (PDX) model LI5132. RNASeq analysis revealed presence of DNAJB1-PRKACA gene fusion on chromosome 19, a molecular signature of FL-HCC. Clinical diagnosis as HCC of fibrolamellar type was confirmed by H&E staining in the PDX tumor. The PDX tumor had a distinctive intratumoral fibrosis with a lamellar pattern. PDX model was established by inoculating patient tumor cells subcutaneously in NOD-SCID mice. Robust tumor growth was observed with a 100% take rate in NOD-SCID mice.
To evaluate the translational relevance of this model toward therapeutic development, the efficacy of a novel multi-target Aurora kinase A and angiokinase inhibitor, ENMD-2076, was evaluated in a therapeutic mode in this model. ENMD-2076 showed significant efficacy in suppressing tumor growth in NOD-SCID mice, at the 200 mg/kg dose evaluated in this study. Weight loss observed during the treatment period could not be attributed to ENMD-2076 as it was similar to weight loss observed with vehicle treatment. ENMD-2076 has now progressed in to phase II trials in the clinic for treatment of FL-HCC. This demonstrates the translational utility of this FL-HCC model in development of anti-cancer therapeutic agents.
Citation Format: Jayant Thatte, Elvira C. Talaoc, Colleen Scott, Ken Ren, Thomas Broudy. Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2017-4203
Abstract 4204: ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models
Authors: Reddy Sanjeeva P. , Rao Niranjan , Zammit David , Thompson Scott K. , Smith Roger A. , Denis Louis 
Published: July 2017

Abstract
Spleen tyrosine kinase (SYK) and Janus kinase (JAK) play important roles in the pathogenesis of various types of lymphomas, solid tumors, and myeloproliferative and inflammation disorders. Inhibition of both SYK and JAK kinases has been shown to suppress tumor growth in various preclinical and/or clinical studies. ASN002 is a novel and potent dual inhibitor of SYK and JAK kinases with IC50 values of 4-46 nM in biochemical assays. In mechanistic cell-based studies, ASN002 strongly suppressed the SYK and JAK family kinase signaling pathways as measured in pLAT and pSTAT assays, respectively. When profiled in a panel of 178 cell lines, the compound showed strong anti-proliferative activity in many lymphoid/leukemia cell lines, including SU-DHL-6, SU-DHL-4, OCI-LY10, H929 and Pfeiffer. The proliferation of many solid tumor cell lines representing bladder, lung and colorectal cancer tumor types was also potently inhibited. Importantly, it also strongly inhibited the growth of ibrutinib and idelalisib resistant cell lines. ASN002 was highly efficacious in inhibiting the tumor growth in several tumor xenograft models which include Pfeiffer (diffuse large B-cell lymphoma, DLBCL), SU-DHL-6 (DLBCL), H929 (myeloma), HEL (erythroleukemia), and RT112 (bladder). ASN002 shows little to no inhibition of CYP450 isozymes suggesting low potential for drug-drug interactions. ASN002 is currently being evaluated in a Phase I/II clinical study in patients with lymphomas (DLBCL, mantle cell lymphoma and follicular lymphoma) and solid tumors.
Citation Format: Sanjeeva P. Reddy, Niranjan Rao, David Zammit, Scott K. Thompson, Roger A. Smith, Louis Denis. ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4204. doi:10.1158/1538-7445.AM2017-4204
Abstract 4209: Inhibitory activity of lichen secondary metabolite, physciosporin, against lung cancer cell motility
Authors: Yang Yi , Yu Young Hyun , Ha Hyung-Ho , Lee Kyung-Hwa , Moon Kyung-Sub , Kim Kyung Keun , Kim Hangun 
Published: July 2017

Abstract
Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3'-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action.
Citation Format: Yi Yang, Young Hyun Yu, Hyung-Ho Ha, Kyung-Hwa Lee, Kyung-Sub Moon, Kyung Keun Kim, Hangun Kim. Inhibitory activity of lichen secondary metabolite, physciosporin, against lung cancer cell motility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4209. doi:10.1158/1538-7445.AM2017-4209
Abstract 4218: Racial similarities in the effects of depression on hospital cost of breast cancer
Authors: Husaini Baqar A. , Miller Oscar , Novotny Meggan , Levine Robert 
Published: July 2017

Abstract
Objective: Breast cancer (BC) incidence is reported to have declined in the nation. However, the role of depression on hospital costs for BC by race remains unknown. In this presentation, we examine two issues: (i) prevalence of BC with comorbid depression among discharged hospital patients; (ii) racial variation in the effect of co-morbid depression on hospital costs of BC patients.
Methods: We extracted data on depression and breast cancer from the 2008 Tennessee Hospital Discharge Data System (HDDS). The BC sample (n=2,523) patients were mostly white (86%) with an average age of 63 years. We computed age-adjusted BC prevalence rates per CDC methodology, and compared the hospital costs for BC patients with vs. without depression.
Results: Age adjusted BC rates (per 100,000) were higher among white than black patients (92.2 vs. 43.3, p&lt;.000). Nearly one-fourth (23%) of BC patients had depression (no racial differences: (25% white vs. 24% black BC patients). Hospital costs for BC patients were 17% higher compared to non-BC patients, and cost was 55% higher among BC patients with co-morbid depression compared to non-depressed BC patients ($64,439 vs. $41,344). The higher cost for depressed BC patients was similar across both white and black BC females.
Conclusion: BC is higher among white females compared to black females. BC patients cost with depression tended to be significantly higher compared to non-depressed patients regardless of race. Since nearly one-fourth of BC patients were depressed with higher hospital cost, these results point to possible significant costs savings by treating depression before the need for hospitalization among BC patients.
Citation Format: Baqar A. Husaini, Oscar Miller, Meggan Novotny, Robert Levine. Racial similarities in the effects of depression on hospital cost of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4218. doi:10.1158/1538-7445.AM2017-4218
Abstract 4225: Disparities in cervical cancer screening participation: a comparison of Russian, Somali and Kurdish immigrants with the Finnish general population
Authors: Idehen Esther E. , Koponen Päivikki , Harkanen Tommi , Korhonen Tellervo 
Published: July 2017

Abstract
Background: Cervical cancer screening through Pap test has been shown as an effective preventive measure for early detection of precancerous in the cervix. Finland offers mass Pap test screening to all eligible women. Knowledge about disparities in the screening participation among immigrants compared with the Finnish general population is limited.
Objectives: (1) To compare Pap test screening participation in the past five years among Russian, Somali and Kurdish immigrants living in Finland with the Finnish general female population; (2) to examine if the observed disparities remain similar when adjusted for socio- demographic and health-related confounding factors.
Methods: Data from the Finnish Migrant Health and Well-being Study and Finnish Health 2011 Survey were used. Random samples of persons living in six cities in Finland were drawn from the national population registry. Data of self-reported cervical screening participation (Pap test) among women aged 29-60 were available from the women of Russian (n=257), Somali (n=113), Kurdish (n=167) origin and the general population (n= 436). Logistic regression was used for statistical analysis.
Results: The age-adjusted Pap test participation rates were 79% among the Russian, 41% among the Kurdish, and 64% among the Somali, compared to 94% among the Finnish general population. After adjusting for age, socio - demographic, and health-related confounders, the immigrants had significantly lower likelihood for screening compared with the Finnish reference group (Russian Odds Ratio[OR] 0.33, 95% confidence interval [CI] 0.19-0.58; Somali [OR]0.08, [CI] 0.03-0.19; Kurdish [OR] 0.17 [CI]0.08-0.34).
Conclusions: Initial results demonstrate significantly lower likelihood for Pap test screening among the immigrant groups compared with the Finnish general population.
Note: This abstract was not presented at the meeting.
Citation Format: Esther E. Idehen, Päivikki Koponen, Tommi Harkanen, Tellervo Korhonen. Disparities in cervical cancer screening participation: a comparison of Russian, Somali and Kurdish immigrants with the Finnish general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4225. doi:10.1158/1538-7445.AM2017-4225
Abstract 4229: Metabolically active macrophages: A novel link between obesity and TNBC
Authors: Tiwari Payal , Schoenfelt Kelly , Blank Ariane , Cui Chang , Rosner Marsha Rich , Becker Lev 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC) patients have an extremely poor prognosis due to their high metastatic potential and lack of targeted drug therapies. Emerging epidemiological data suggest that obesity is strongly linked to the incidence and severity of TNBC. However, mechanisms by which obesity potentiates TNBC progression are unclear. Adipose tissue macrophages (ATMs) are an attractive mechanistic link between obesity and TNBC because they are the predominant type of macrophage in the breast during early tumorigenesis and obesity causes accumulation of ATMs. However, during obesity, the macrophage phenotype was reported to switch from an apparent pro-tumorigenic M2-like phenotype to an apparent anti-tumorigenic M1-like phenotype. This result raises a paradox: how does obesity promote tumor progression if it activates an anti-tumorigenic macrophage phenotype? Here we show that metabolic dysfunction promotes a mechanistically distinct pro-inflammatory phenotype (metabolic activation; MMe) in breast adipose tissue macrophages isolated from obese women. These ATMs express cell surface markers of MMe (CD36, ABCA1) but not M1 (CD38, CD319, CD274) macrophages. We further demonstrate that pretreating TNBC cells with conditioned media derived from MMe but not M1 macrophages promotes mammosphere formation as well as invasion in vitro, and intravasation of cancer cells into the blood in vivo. Moreover, pre-treated cancer cells showed a two-fold increase in the expression of stem-like cell markers (OCT4, SOX2 and NANOG). Remarkably, we saw the same effect on ‘stemness’ of tumor cells in a spontaneous TNBC mouse model when fed a 60% high fat diet and a significant increase in tumor incidence in obese mice compared to lean mice in a syngeneic mouse model. We further show that blocking inflammatory cytokines expression in MMe(s) using genetic knockouts inhibits the ability of MMe(s) to promote both mammosphere formation and invasion. These findings suggest that obesity-induced changes to mammary adipose tissue reprogram macrophages to an MMe phenotype that potentiates TNBC initiation and metastasis via inflammatory cytokines. A comprehensive understanding of the signaling mechanism(s) involved in metabolic activation of mammary ATMs would enable development of directed therapies towards this specific pro-tumorigenic macrophage phenotype, thereby leaving the immune system of cancer patients intact.
Citation Format: Payal Tiwari, Kelly Schoenfelt, Ariane Blank, Chang Cui, Marsha Rich Rosner, Lev Becker. Metabolically active macrophages: A novel link between obesity and TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4229. doi:10.1158/1538-7445.AM2017-4229
Abstract 424: Landscape of somatic mutations in drug-resistant acute myeloid leukemia
Authors: Eldfors Samuli , Kontro Mika , Akimov Yevhen , Kallioniemi Olli , Porkka Kimmo , Heckman Caroline 
Published: July 2017

Abstract
Introduction: Most patients with acute myeloid leukemia (AML) initially respond to cytarabine-anthracycline induction chemotherapy. However, in many patients, the disease recurs in a lethal drug-resistant form. Somatic mutations underlying the pathogenesis of AML have been extensively characterized by sequencing of newly diagnosed AMLs. However, the mutations driving therapy resistance and disease progression at relapse have not been well characterized. In this study, we have exome sequenced a cohort of relapsed and refractory AMLs and compared the landscape of somatic mutations at relapse to diagnosis phase AMLs to identify mutations that contribute to therapy resistance and disease progression.
Materials and Methods: We performed exome sequencing of diagnosis phase AMLs (n=70) and relapsed or primary refractory AMLs (n=54). Patients with AML M3 subtype were excluded from the study. Paired diagnosis and relapse samples were available from 27 patients. A skin biopsy was used as the germline control. Nine patients had received an allogeneic hematopoietic stem cell transplant before relapse. Somatic mutations were called using varscan2 and copy number aberrations using copyCat. Since the identification of large insertions from next-generation sequencing data remains challenging using existing algorithms, FLT3 internal tandem duplications (FLT3-ITDs) were identified using a novel custom algorithm optimized for FLT3-ITD detection. Population variants were filtered out to remove donor-derived germline variants in chimeric post-transplant relapse samples.
Results: Comparison of somatic mutation frequencies in diagnosis and relapse and refractory samples showed that on average relapsed tumors have a higher number of driver mutations than tumors at diagnosis. WT1, TP53, CBL, IDH1 and PTPN11 were mutated at a higher frequency in relapsed samples than at diagnosis, with 13 %, 11 %, 11 %, 9 % and 9 % of relapsed or refractory samples and 4 %, 6 %, 3 %, 4 % and 7 % of diagnosis mutated respectively. Analysis of paired diagnosis-relapse samples showed that in patients with WT1, CBL or PTPN11 mutation at diagnosis the second allele is frequently mutated or lost due to uniparental disomy occurring at relapse.
Conclusions: On average relapsed AMLs have a higher number of driver mutations than diagnosis phase AMLs indicating that acquisition of additional driver mutations contributes to relapse. AMLs frequently acquire additional mutations in the same genes and pathways that already harbored mutations at diagnosis.
Citation Format: Samuli Eldfors, Mika Kontro, Yevhen Akimov, Olli Kallioniemi, Kimmo Porkka, Caroline Heckman. Landscape of somatic mutations in drug-resistant acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 424. doi:10.1158/1538-7445.AM2017-424