bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3671: Myeloid-derived suppressive cells require education from tumor-evoked Bregs to mediate metastasis
Authors: Bodogai Monica , Chang Catalina Lee , Biragyn Arya 
Published: May 2015

Abstract
Myeloid-derived suppressive cells (MDSC) are key metastasis-promoting regulatory cells. They are drastically expanded in WT BALB/c mice with highly aggressive 4T1 cancer and thought to promote metastasis by inactivating antitumor effector immune cells. Surprisingly, despite comparable expansion of MDSC, in B-cell deficient congenic mice 4T1 cancer fails to metastasize to lungs, questioning the importance of MDSC. We found that this is due to the lack of a new subset of tumor-evoked regulatory B cells (tBregs) 1,2 that induces metastasis-promoting regulatory T cells (Tregs) 3. The mechanism of this process is that cancer initiates a chain of metastasis-promoting events, such as converts normal B cells into tBregs utilizing metabolites of 5-lipooxygenase, which in turn use TGFβ to generate FoxP3+ Tregs from non-regulatory CD4+ T cells. The Tregs then inactivate effector NK and CD8+ T cells that kill the metastasizing cancer cells in the lungs. To reconcile these results with the reported importance of MDSC, we speculated that metastasis-promoting activity of MDSC requires tBregs. Here we report that tBregs educate a small subset of MDSC rendering them regulatory. As a result, the ability of 4T1 cancer to metastasize in B-cell KO mice can be restored by the adoptive transfer of the regulatory subset of MDSC from tumor-bearing WT mice. In tumor-bearing B-cell KO mice, however, tBregs are not generated and thus MDSC from these mice cannot support lung metastasis. Overall, these results further underscore the importance of tBregs by uncovering a previously unknown regulatory step that MDSC can only promote metastasis if educated by cancer-induced tBregs.
This work was supported by the National Institute on Aging, the Intramural Research Program
1 Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4 T cells to T-regulatory cells. Cancer research 71, 3505-3515, doi:10.1158/0008-5472.CAN-10-4316 (2011).
2 Bodogai, M. et al. Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L. Cancer research, doi:10.1158/0008-5472.CAN-12-4184 (2013).
3 Olkhanud, P. B. et al. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res. 69, 5996-6004 (2009).
Citation Format: Monica Bodogai, Catalina Lee Chang, Arya Biragyn. Myeloid-derived suppressive cells require education from tumor-evoked Bregs to mediate metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3671. doi:10.1158/1538-7445.AM2014-3671
Abstract 3689: Minocycline regulates hypoxia-inducible factor-1α expression through the induction of its degradation in ovarian cancer: in vitro and in vivo studies
Authors: Ataie-Kachoie Parvin , Morris David L. , Pourgholami Mohammad H. 
Published: May 2015

Abstract
Experimental data suggest therapeutic advantage from selective disruption of the hypoxia response in cancer. We recently found that minocycline decreases tumor VEGF expression in ovarian tumor xenografts in mice and herein report a companion laboratory study to test if this effect was the result of hypoxia-inducible factor (HIF) inhibition. Human ovarian carcinoma cell lines (OVCAR-3, SKOV-3 and A2780) were treated with minocycline in normoxic and hypoxic conditions and also in the presence of hypoxia-mimetic agent deferoxamine in vitro. Two different in vivo experiments investigated miocycline effects after single dose (30 mg/kg, 4 or 24 h) or longer exposure in nude mice bearing OVCAR-3 xenografts. Treatment with minocycline inhibited the accumulation of HIF-1alpha in a concentration-dependent fashion in vitro. A similar effect of minocycline was seen in vivo. Furthermore, the inhibtory effect of minocycline on HIF-1alpha was found to be associated with a significant decrease in HIF-1alpha half-life showing that minocycline enhances degradtion of HIF-1alpha. These data warrents further evaluation of minocycline in the treatment of ovarian cancer.
Citation Format: Parvin Ataie-Kachoie, David L. Morris, Mohammad H. Pourgholami. Minocycline regulates hypoxia-inducible factor-1α expression through the induction of its degradation in ovarian cancer: in vitro and in vivo studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3689. doi:10.1158/1538-7445.AM2014-3689
Abstract 369: Network-based stratification of thyroid cancer
Authors: Hofree Matan , Shen John Paul Y. , Ideker Trey 
Published: May 2015

Abstract
Many forms of cancer consist of multiple subtypes with different molecular causes and clinical outcomes. Somatic tumor genomes provide a rich new source of data for uncovering these subtypes, but have proven difficult to compare as two tumors share little in their genetic landscapes. Recently, we have introduced a method called ‘network-based stratification’ (NBS) which integrates somatic tumor genomes with gene networks. This approach allows for stratification of cancer into informative subtypes by clustering together patients who have mutations within similar network regions. Here we apply NBS to a combination of whole-exome somatic mutation data, copy number aberrations and gene fusion events in a cohort of thyroid cancer (TC) patients, an as yet unpublished part of The Cancer Genome Atlas (TCGA). Using NBS combined with the HumanNet gene interaction network we were able to discover a robust cluster assignment of thyroid patients into three subtypes. These subtypes are found to significantly associate with histological type (X2 P = 5.42x10-22) and are also found to be predictive multiple clinical variables such as predicted risk of recurrence (X2 P = 9.95x10-6, estimated based on standard (TNM) staging by AJCC Cancer Staging Manual. 7th ed.), extra-thyroidal expansion(X2 P = 4.68x10-7), lymph node status (pathological N stage, X2 P = 9.25x10-4), and pathological T stage (X2 P = 4.46x10-3). In each subtype we highlight the characteristically perturbed genes and subnetworks (Table 1) and further explore the association of mRNA and protein expression to these subtypes. The study demonstrates the utility of combining genomic profiles with interaction networks, enabling the discovery of clinically meaningful mutation based subtypes and provides genetic based subtypes with potential clinical implications.
Characteristically perturbed genes and subnetworksTypeCharacteristic histologyFrequent mutationSelected enriched terms in frequently perturbed subnetworks1FollicularCHEK2, CTNND2, DICER1, HRAS, KRAS, MUC5B, MYH13, NRAS, NTRK1, PAX8, PPARG, PTEN, SLC12A4, SLITRK3, TG, ZBTB22Ras protein signal transduction, Activation of MAPK activity2ClassicCCDC6, ETV6, MALAT1, NCOA4, NTRK3, RETProtein tyrosine kinase activity, Transmembrane receptor protein kinase activity, Regulation of blood vessel size3Classic and Tall cellBRAFStress activated MAPK cascade, Immune response-regulating signaling pathway, FGR signaling pathway, JACK-STAT cascade, activation of pro-apoptotic gene products
Citation Format: Matan Hofree, John Paul Y. Shen, Trey Ideker. Network-based stratification of thyroid cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 369. doi:10.1158/1538-7445.AM2014-369
Abstract 3690: MMP-1 and pro-MMP-10 as potential urinary pharmacodynamic biomarkers of FGFR3-targeted therapy in patients with bladder cancer
Authors: Lin Benjamin C. , Du Xiangnan , Wang Qian-Rena , Li Hao , Ingalla Ellen , Tien Janet , Rooney Isabelle , Ashkenazi Avi , Penuel Elicia , Qing Jing 
Published: May 2015

Abstract
Aberrant activation of fibroblast growth factor receptor 3 (FGFR3) via overexpression or mutation occurs frequently in bladder cancer, and experimental therapeutic agents have entered into clinical trials to evaluate the potential activity of FGFR3-targeted therapy in this disease. However, a convenient accessible biomarker indicative of targeted pathway modulation in vivo drug activity is urgently needed. Through transcriptional profiling of bladder carcinoma cells expressing inducible FGFR3 short hairpin RNAs, we identified two matrix metalloproteinases (MMPs), MMP-1 and MMP-10, as potential downstream targets of FGFR3. We found that FGFR3 signaling promotes expression and secretion of MMP-1 and pro-MMP-10 in a MEK-dependent fashion. FGFR3 inhibition by an investigational anti-FGFR3 human monoclonal antibody, R3Mab, in bladder cancer xenograft models substantially blocked tumor progression and reduced the protein levels of human MMP-1 and pro-MMP-10 in tumor tissues as well as in mouse serum. Furthermore, we detected elevated levels of both MMP-1 and pro-MMP-10 in the urine of patients with advanced bladder cancer. In a phase 1 dose-escalation trial, R3Mab administration resulted in an acute reduction of urinary MMP-1 and pro-MMP-10 levels in bladder cancer patients. Together, these findings reveal a critical role of FGFR3 in regulating MMP-1 and pro-MMP-10 expression and secretion, and identify urinary MMP-1 and pro-MMP-10 as potential pharmacodynamic biomarkers for FGFR3-targeted therapy in bladder cancer.
Citation Format: Benjamin C. Lin, Xiangnan Du, Qian-Rena Wang, Hao Li, Ellen Ingalla, Janet Tien, Isabelle Rooney, Avi Ashkenazi, Elicia Penuel, Jing Qing. MMP-1 and pro-MMP-10 as potential urinary pharmacodynamic biomarkers of FGFR3-targeted therapy in patients with bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3690. doi:10.1158/1538-7445.AM2014-3690
Abstract 3692: Preclinical studies of a mutant p53 reactivating drug in pancreatic cancer
Authors: Yu Xin , Li Zhe , Eng Oliver S. , Tsang Ashley T. , Lin Hongxia , Gounder Murugesan , Carpizo Darren R. 
Published: May 2015

Abstract
Pancreatic cancer therapy suffers from a lack of effective chemotherapy. TP53 is second only to Kras as the most commonly mutated gene in pancreatic cancer with point mutations occurring in 75% of patients. Recently, our laboratory identified NSC319726 (726) as an allele specific p53 mutant reactivating compound (Yu, et al. 2012, Cancer Cell). This compound selectively kills cancer cells that express the p53-R175H mutation by restoring wildtype structure and function to this mutant. It does not reactivate the DNA contact mutant, p53-R273H or p53-R248H. This established 726 as a lead compound for mutant p53 targeted drug development. We are currently investigating the potential of 726 as novel anti-cancer drug through pre-clinical studies in pancreatic cancer. We have investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of 726 in murine pancreatic cancer cell lines derived from the KPC mouse model expressing mutant KrasG12D and different alleles of TP53 (WT, null, p53R172H, p53R270H). Using LC/MS/MS we developed a sensitive assay for detection of 726 in mouse plasma. PK studies indicate a half-life of approximately 4 hours with an AUC of 199.78 ng/ml/h for a single 1mg/kg dose given Intravenously. Treatment of KPC cell lines with 726 indicates that the murine p53R172H protein is reactivated as indicated by loss of mutant conformation and induction of p53 target gene transcription. Cell growth inhibition assays reveal that the cell line KPCp53-R172H is sensitive to 726 while the KPCp53-R270H is not. We have developed a PD assay for 726 consisting of cleaved caspase-3 immunostaining and measurement of transcriptional levels of p53 targets PUMA, Noxa and p21. Using these assays we have tested several doses of 726 and found that we detect activity of 726 in KPCp53-R172H xenograft tumors while at the same time relatively no activity in KPCp53-R270H tumors. These same assays were also performed on KPC autochthanous tumors and again reveal activity of 726 in the KPCp53-R172H mice. Efficacy studies in the KPCp53-R172H xenografts reveal potent tumor growth inhibition at both IV (1mg/kg) and IP (5mg/kg) dosing while no evidence of growth inhibition in KPCp53-R270H. These studies confirm that 726 is an allele-specific p53 mutant reactivating compound and holds promise for future applications in pancreatic cancer.
Citation Format: Xin Yu, Zhe Li, Oliver S. Eng, Ashley T. Tsang, Hongxia Lin, Murugesan Gounder, Darren R. Carpizo. Preclinical studies of a mutant p53 reactivating drug in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3692. doi:10.1158/1538-7445.AM2014-3692
Abstract 3703: PDGFRα up-regulation mediated by Sonic Hedgehog Pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation
Authors: Sabbatino Francesco , Wang Yangyang , Wang Xinhui , Flaherty Keith T. , Pepin David , Scognamiglio Giosuè , Yu Ling , Cooper Zachary A. , Pepe Stefano , Kirkwood John M. , Frederick Dennie T. , Wargo Jennifer A. , Ferrone Soldano , Ferrone Cristina R. 
Published: May 2015

Abstract
Control of mutant BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Up-regulation of growth factor receptor such as platelet-derived growth factor receptor (PDGFR)β or insulin-like growth factor receptor (IGFR) is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that up-regulation of PDGFRα, a growth factor receptor which markedly differs in its functional properties from its family member PDGFRβ, causes BRAF-I resistance in vitro and in vivo. PDGFRα inhibition by PDGFRα-specific short hairpin RNA (shRNAs) and by clinically available PDGFRα inhibitors (sunitinib, imatinib and crenolanib) restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by the novel small molecule LDE225 restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. These effects are mediated by PDGFRα down-regulation and by inhibition of ERK and AKT activation. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors
Citation Format: Francesco Sabbatino, Yangyang Wang, Xinhui Wang, Keith T. Flaherty, David Pepin, Giosuè Scognamiglio, Ling Yu, Zachary A. Cooper, Stefano Pepe, John M. Kirkwood, Dennie T. Frederick, Jennifer A. Wargo, Soldano Ferrone, Cristina R. Ferrone. PDGFRα up-regulation mediated by Sonic Hedgehog Pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3703. doi:10.1158/1538-7445.AM2014-3703
Abstract 3704: Novel panRAF inhibitors active in melanomas that are resistant to BRAF-selective, or BRAF-selective/MEK inhibitor combinations
Authors: Girotti Maria R. , Lopes Filipa , Preece Natasha , Niculescu-Duvaz Dan , Zambon Alfonso , Davies Lawrence , Whittaker Steven , Saturno Grazia , Viros Amaya , Pedersen Malin , Suijkerbuijk Bart MJM , Menard Delphine , Mcleary Robert , Johnson Louise , Fish Laura , Ejiama Sarah , Sanchez-Laorden Berta , Carragher Neil , Macleod Kenneth , Ashton Garry , Marusiak Anna , Fusi Alberto , Brognard John , Frame Margaret , Lorigan Paul , Springer Caroline J. , Marais Richard 
Published: May 2015

Abstract
The protein kinase BRAF is mutated ∼40% of human melanomas. BRAF is a component of the RAS/RAF/MEK/ERK pathway and BRAF or MEK inhibitors increase progression-free and overall survival in melanoma patients with BRAF mutations. However, most patients relapse with acquired resistance and ∼20% of patients present intrinsic resistance and do not respond to these drugs. We describe here two novel compounds that target mutant BRAF and wild-type CRAF. Our compounds inhibited the growth of melanoma cells that were resistant to BRAF-selective inhibitors. ERK pathway reactivation is responsible for resistance to BRAF targeted therapies in ∼60% of the patients and in ∼25% of patients resistance is driven by acquisition of mutations in NRAS. We show that our compounds inhibited the growth of melanoma cells that were resistant to BRAF-selective inhibitors due to pathway reactivation mediated by different mechanisms. We show that the drugs were active against patient derived xenografts (PDXs) from patients with acquired or intrinsic resistance to BRAF-selective inhibitors and in whose tumors resistance was associated with ERK pathway reactivation. Further, our compounds are active in a PDX from a patient whose tumor developed acquired resistance to a combination of a BRAF-selective plus a MEK inhibitor and associated with acquisition of an NRAS mutation. Thus, our panRAF inhibitors can inhibit melanomas with different mechanisms of acquired or intrinsic resistance to BRAF-selective and BRAF-selective/MEK inhibitor combinations, potentially providing first-line treatment for naïve patients and second-line treatments for a range of relapsed patients.
Citation Format: Maria R. Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart MJM Suijkerbuijk, Delphine Menard, Robert Mcleary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Caroline J. Springer, Richard Marais. Novel panRAF inhibitors active in melanomas that are resistant to BRAF-selective, or BRAF-selective/MEK inhibitor combinations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3704. doi:10.1158/1538-7445.AM2014-3704
Abstract 3707: The multitargeted kinase inhibitor dasatinib induces DNA damage, Hippo pathway engagement and senescence in lung cancer cell lines that possess kinase-inactivating BRAF mutations
Authors: Sen Banibrata , Peng Shaohua , Mazumdar Tuhina , Byers Lauren A. , Kadara Humam , Johnson Faye M. 
Published: May 2015

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Therapies that target specific genetic aberrations are very effective in a subset on NSCLC. An effective approach for discovering novel therapeutic targets is to characterize responsive tumors. In this regard, we discovered a novel, kinase-inactivating BRAF mutation in the tumor of a patient with a marked and durable response to the multi-targeted kinase inhibitor dasatinib. Likewise, dasatinib induces senescence in NSCLC cells with endogenous kinase-inactivating BRAF mutations (KIBRAF). To identify the mechanism underlying this effect, we used reverse phase protein array, Western blotting and gene expression analysis on NSCLC cell lines with KIBRAF or WTBRAF incubated with dasatinib. We found that ATM, ATR, Rad 51, pH2AX, CDC6, CHEK1 (Chk1), pLATS and TAZ, were differentially regulated in mutant vs. WT cell lines. Quantitative real-time PCR analysis revealed that CHEK1, TAZ and TAZ's downstream targets were decreased following incubation with dasatinib in KIBRAF cells. Overexpression of CHEK1 or TAZ in KIBRAF NSCLC cells resulted in dasatinib resistance and decreased dasatinib-induced senescence. Given the differential effect on CHEK1 and pH2AX, we studied the effect of dasatinib on DNA damage using the COMET assay and found that dasatinib induces a significant increase in COMET-positive KIBRAF NSCLC cells. These data suggest that the inhibition of Chk1 along with inhibition of Hippo pathway results in the dasatinib sensitivity in NSCLC with KIBRAF.
Citation Format: Banibrata Sen, Shaohua Peng, Tuhina Mazumdar, Lauren A. Byers, Humam Kadara, Faye M. Johnson. The multitargeted kinase inhibitor dasatinib induces DNA damage, Hippo pathway engagement and senescence in lung cancer cell lines that possess kinase-inactivating BRAF mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3707. doi:10.1158/1538-7445.AM2014-3707