tbuckley/cabot-search huggingface dataset:
Abstract 2316: Elevated H-Ras suppresses death receptor-mediated apoptosis in cancer cells
Authors: Su-Ryun Kim
Journal: Cancer Research (2017)

Abstract TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis through its death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. Despite its selectivity in killing cancer cells over most normal cells, recombinant human TRAIL or its receptor agonists (monoclonal antibodies against DR4 or DR5) encountered resistance in many tumor cells while the underlying mechanisms remain partially understood. Here, we show that wild-type H-Ras GTPase is systemically upregulated in TRAIL-resistant cells compared to TRAIL-sensitive cells. The elevated H-Ras expression correlated with a deficiency of DR4 and DR5 on plasma membrane in TRAIL-resistant cell lines. Notably, knockdown of H-Ras in TRAIL-resistant cells successfully restored the surface expression of DR4 and DR5, thereby sensitizing the cells to TRAIL-induced apoptosis. Consistently, ectopic expression of H-Ras in TRAIL-sensitive cells reduced surface DR4 and DR5 which was associated with a loss of TRAIL sensitivity. By contrast, the status of K-Ras or its mutations was not casually linked to TRAIL receptor expression or TRAIL sensitivity across the panel of cancer cell lines tested. These data suggest that H-Ras may play a distinct role to negatively regulate TRAIL receptors and apoptosis. The upregulated H-Ras could be a predictor of tumor resistance to DR-targeted agents and a potential therapeutic target for combinational therapy to achieve better treatment outcomes. Citation Format: Su-Ryun Kim. Elevated H-Ras suppresses death receptor-mediated apoptosis in cancer cells [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 2316. doi:10.1158/1538-7445.AM2017-2316
Abstract 3663: An anti-CD4 depleting antibody reverses regulatory T-cell-induced suppression of dendritic cells while preventing nonspecific CD4+ T cell responses in tumor-bearing mice
Authors: Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Francis Shand, Shohei Hori, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
Journal: Cancer Research (2017)

Abstract Administration of an anti-CD4 depleting antibody induces tumor-specific CD8+ T cell responses in tumor-bearing mice, although the mechanisms underlying this phenomenon remain unclear. CD4+ Foxp3+ regulatory T cells (Treg) impair antigen presentation by DCs through CTLA4-mediated down-regulation of CD80/CD86. In the present study, we investigated the effects of an anti-CD4 depleting monoclonal antibody (mAb) on DC responses in the B16F10 and LLC subcutaneous tumor models, and compared these effects with those of Treg targeting therapy. Administration of anti-CD4 mAb up-regulated CD80/CD86 in tumor-infiltrating DCs, and in migrating-type but not resident-type DC subsets in the tumor-draining lymph node. The upregulation of CD80/CD86 on these DC populations was correlated with increased proliferation of tumor-specific CD8+ T cells in the tumor-draining lymph node. Anti-CD4 mAb-induced CD80/CD86 up-regulation and tumor-specific CD8+ T cell responses were remarkably higher than that induced by an anti-CD25 depleting mAb or an anti-CTLA4 blocking mAb, and were equivalent to that induced by diphtheria-toxin-induced selective depletion of Tregs in Foxp3-DTR mice. Importantly, the activation of CD4+ conventional T cells and B cells in the peripheral lymph nodes that was observed following Treg depletion was not observed following anti-CD4 mAb administration. In conclusion, anti-CD4 depleting antibody therapy is an effective way to evoke anti-tumor CD8+ T cell responses by reversing regulatory T cell-induced suppression of dendritic cells, and to reduce the risk of severe autoimmunity in cancer patients. Citation Format: Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Francis Shand, Shohei Hori, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima. An anti-CD4 depleting antibody reverses regulatory T-cell-induced suppression of dendritic cells while preventing nonspecific CD4+ T cell responses in tumor-bearing mice [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 3663. doi:10.1158/1538-7445.AM2017-3663
Abstract 2157: P73 isoforms regulate cellular survival and response to treatment in diffuse large B-cell lymphoma
Authors: Hesham M. Hassan, Michelle L. Varney, Pamela A. Althof, Gabriel C. Caponetti, Kai Fu, Dennis D. Weisenburger, Rakesh K. Singh, Bhavana J. Dave
Journal: Cancer Research (2017)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma (NHL) and is curable in more than 60% of the cases. Despite long-term remission achieved with current therapies, relapse occurs in almost one-third of the cases. Rearrangements of chromosome locus 1p36 with ensuing deletion or disruption of TP73, one of the most distally located putative tumor suppressor genes, is frequent in many NHL subtypes, including DLBCL, and confers inferior prognosis. Recent reports in normal B-cells and lymphoma animal models suggest an important role of p73 in B-cell lymphomas; however, the biological significance of p73 isoforms in DLBCL is not clear. TP73 is a member of the TP53 family that shares structural homology and hence is capable of transactivating p53 target genes. We investigated the relationship between rearrangements of chromosome locus 1p36 and p73 expression and examined whether differential expression of p73 isoforms (TAp73 and ΔNp73) correlate with proliferation and apoptosis in DLBCL. We utilized molecular techniques in conjunction with fluorescence in situ hybridization (FISH) in untreated histologically confirmed DLBCL patient specimens. In our data set, the 1p36 chromosomal locus was disrupted (mainly heterozygous deletion) in 35% of the cases and was significantly associated with ΔNp73 expression. Subsequent immunohistochemical analysis showed a significant positive correlation between TAp73 and cleaved caspase-3 expression and between ΔNp73 and Ki-67 expression. Additionally, we observed a negative correlation between TAp73 and the anti-apoptotic molecules Bcl-2 and Bcl-6. We then performed in vitro studies in DLBCL cells and modulated the expression of TAp73 and ΔNp73 using expression vectors and siRNA. TAp73-transfected cells were more susceptible to serum deprivation and doxorubicin treatment, conversely the ΔNp73-transfected cells were more resistant to serum deprivation and doxorubicin treatment compared to control cells. Thus, rearrangements of 1p36 consequently deregulates p73 isoform expression in DLBCL. Our data emphasizes the importance of delineating the functional aspect of genetic alterations and underscores the significant role of p73 isoforms in DLBCL pathogenesis and treatment. Citation Format: Hesham M. Hassan, Michelle L. Varney, Pamela A. Althof, Gabriel C. Caponetti, Kai Fu, Dennis D. Weisenburger, Rakesh K. Singh, Bhavana J. Dave. P73 isoforms regulate cellular survival and response to treatment in diffuse large B-cell lymphoma [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 2157. doi:10.1158/1538-7445.AM2017-2157
Abstract 4916: E3 ubiquitin ligase Cbl-b prevents tumor metastasis by maintaining the epithelial phenotype in multiple drug-resistant gastric and breast cancer cells
Authors: Ling Xu, Xiujuan Qu, Ye Zhang, Xiaofang Che, Tianshu Guo, Ying Cai, Aodi Li, Danni Li, Ce Li, Ti Wen, Yibo Fan, Kezuo Hou, Yanju Ma, Xuejun Hu, Yunpeng Liu
Journal: Cancer Research (2017)

Abstract Background: Multiple drug resistance (MDR) and metastasis are two major unfavorable factors causing failure of cancer treatment. However, the relationship between MDR and metastasis is not characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is little known. Methods: The effect of Cbl-b on tumor invasion and metastasis was analyzed in P-gp-positive gastric adenocarcinoma tissues. Transfections of Cbl-b WT and epidermal growth factor receptor (EGFR) WT plasmid were used to assess Cbl-b and EGFR involvement in epithelial-mesenchymal transition (EMT) and tumor metastasis. Results: MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and an enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. We performed immunohistochemical analysis on P-gp-positive gastric adenocarcinoma tissues and identified associations between Cbl-b expression and clinical pathological parameters. Gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion (P=0.016) and lymph node metastasis (P=0.007). Moreover, over-expression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo. Cbl-b over-expression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR- ERK/Akt-miR-200c-ZEB1 axis. However, further over-expression of EGFR on a background of Cbl-b over-expression restored both the mesenchymal phenotype and the cell migration capacity of MDR gastric and breast cancer cells. Conclusions: These results suggest that Cbl-b is an important factor for maintenance of the epithelial phenotype and inhibition of cell migration in MDR gastric and breast cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Ling Xu, Xiujuan Qu, Ye Zhang, Xiaofang Che, Tianshu Guo, Ying Cai, Aodi Li, Danni Li, Ce Li, Ti Wen, Yibo Fan, Kezuo Hou, Yanju Ma, Xuejun Hu, Yunpeng Liu. E3 ubiquitin ligase Cbl-b prevents tumor metastasis by maintaining the epithelial phenotype in multiple drug-resistant gastric and breast cancer cells [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 4916. doi:10.1158/1538-7445.AM2017-4916
Abstract 2853: Imaging tumor metabolism to guide treatment of breast cancer with drugs targeted at PI3K alpha
Authors: Susana Ros, Paula D'Santos, De-en Hu, Ankita S. Batra, Alan J. Wright, Elizabeth Mannion, Alejandra Bruna, Carlos Caldas, Kevin M. Brindle
Journal: Cancer Research (2017)

Abstract PI3KCA (which encodes the phosphoinositide-3 kinase alpha isoform) is the most frequently mutated oncogene in breast cancer. Recently, several alpha isoform-specific PI3K inhibitors have been developed and have entered into early-phase clinical trials. However, intrinsic and acquired resistance limits their utility. Non-invasive imaging methods could be used to guide treatment by not only allowing selection of the most effective drug in individual patients, but also by detecting intrinsic and acquired resistance. We have been evaluating the effectiveness of a selective PI3K alpha inhibitor, Taselisib (GDC-0032 Genentech S.A.), by monitoring the rate of [1-13C]lactate production after injection of hyperpolarized [1-13C]pyruvate in cell lines and patient-derived xenografts (PDX) models of breast cancer using 13C magnetic resonance spectroscopic imaging. Hyperpolarization of the 13C nucleus increases its sensitivity to detection in the MR experiment by 104 - 105x, thus allowing real time imaging of tumor metabolism. Preliminary data suggest that labeled lactate production can distinguish sensitive and resistant breast cancer models to Taselisib a few days after treatment. We are currently broadening the panel of PDXs analyzed and also including genetically engineered mechanistic-models of drug resistance. The present study highlights the effectiveness of hyperpolarized 13C spectroscopy/spectroscopic imaging for detecting early response or resistance to next generation PI3K inhibitors. This clinically applicable technique can provide insights into in vivo response in real-time and identify new strategies to increase the efficacy of therapy in individual patients. Citation Format: Susana Ros, Paula D'Santos, De-en Hu, Ankita S. Batra, Alan J. Wright, Elizabeth Mannion, Alejandra Bruna, Carlos Caldas, Kevin M. Brindle. Imaging tumor metabolism to guide treatment of breast cancer with drugs targeted at PI3K alpha [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 2853. doi:10.1158/1538-7445.AM2017-2853
Comparative efficacy of sunitinib administered on an intermittent or a continuous daily dosing schedule in metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumor (GIST) patients predicted using population PK approaches
Authors: Brett Houk, Carlo Bello, George Demetri, M. Michaelson, Paolo Casali, Ronald Bukowski, Darrel Cohen, Kuniaki Shirao, Bruce Redman, Gary Hudes, George Wilding, Robert Motzer
Journal: Cancer Research (2008)

5828     Background:    Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R, and RET, approved multinationally for the treatment of advanced RCC and imatinib (IM)-resistant/-intolerant GIST. We conducted meta-analyses of data from phase I-III studies in which the majority of patients received sunitinib at either 50 mg daily on an intermittent dosing schedule comprising 4 weeks on followed by 2 weeks off treatment (4/2 schedule) or 37.5 mg continuous daily dosing, with the objective of characterizing the relationship between exposure and antitumor efficacy as assessed using computed tomography scan data.    Methods:   Pharmacokinetic (PK) and efficacy data from three phase I-III clinical studies of patients with IM-resistant or -intolerant GIST were pooled (n=223 and n=57 for sunitinib- and placebo-treated patients, respectively), as were data from four phase II/III studies in cytokine-refractory (n=195) or treatment-naive (n=42) mRCC. Plasma sunitinib and SU12662 (primary active metabolite) concentrations were fitted to a two-compartment population PK model. PK parameters were then used as inputs for a PK/pharmacodymanic (PD) analysis model of tumor growth dynamics that described changes in tumor size as a function of sunitinib concentration. Clinical trial simulations were performed to estimate the efficacy of sunitinib in patients administered either 50 mg daily on a 4/2 schedule or 37.5 mg continuous daily dosing.    Results:   Tumor size decreases were similar across both dosing regimens and all individual studies (29-35% and 10-31% mean maximal individual change in RCC and GIST, respectively). Time to tumor progression and overall survival were similar with either dosing regimen in both tumor types. Greater tumor size decreases were found in patients with the highest plasma concentrations of sunitinib. The tumor growth rate was estimated to be 1.3-fold higher in RCC than GIST (0.0022 vs. 0.0017/day, respectively), although drug susceptibility was estimated to be 25-fold higher in RCC. The estimated plasma concentrations necessary to arrest tumor growth in 90% of patients were 50 ng/mL in RCC and 96 ng/mL in GIST. Clinical trial simulations suggested that patients administered either dosing regimen over a 2-year period would display similar tumor size decreases in both tumor types.         Conclusions:   PK/PD modeling indicates that increased exposure to sunitinib in both GIST and mRCC patients is associated with greater tumor size decreases and predicts that sunitinib administered continuously at 37.5 mg daily displays similar efficacy to the approved dose of 50 mg daily on a 4/2 schedule.
Abstract LB-096: SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation
Authors: Xiaofeng Wang, Ryan Lee, Burak Alver, Jeffrey Haswell, Su Wang, Emma Troisi, Bradley Bernstein, Peter Park, Charles Roberts
Journal: Cancer Research (2017)

Abstract The gene encoding SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is biallelically inactivated in nearly all rhabdoid tumors (RTs), highly aggressive and lethal cancers of early childhood. RTs are among the most genomically stable cancers, suggesting an epigenetic mechanism by which SMARCB1 loss drives cancer. Here, we show that despite having indistinguishable mutational landscapes, human RTs show distinct H3K27ac signatures at enhancers that reveal remnants of differentiation programs. In elucidating the mechanism underlying RTs, we find that SMARCB1 is not only essential for the integrity and abundance of SWI/SNF complexes, but also facilitates their targeting to appropriate enhancers. Loss of SMARCB1 alters enhancer targeting—markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers (SEs). We show that these retained SEs are essential for RT survival, including some that are shared across all RT types, such as SPRY1, and other lineage-specific SEs like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1. Citation Format: Xiaofeng Wang, Ryan Lee, Burak Alver, Jeffrey Haswell, Su Wang, Emma Troisi, Bradley Bernstein, Peter Park, Charles Roberts. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [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 LB-096. doi:10.1158/1538-7445.AM2017-LB-096
Abstract 4116: Acquired lapatinib resistant induces EMT-phenotype in breast cancer cells via Src and RUNX3
Authors: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Dong Hyeon Ha, Hyemin Jang, Yu Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im
Journal: Cancer Research (2017)

Abstract Background: Lapatinib is an effective EGFR and HER2 targeting small molecular tyrosine kinase inhibitor which is widely used for HER2 positive breast cancer patients. However, patients eventually acquire resistance, limiting its long-term use. Overexpression of heregulin, a HER3 ligand, acquired stemness were mechanism that confers resistance to the anti-HER2 lapatinib. However, still, unknown mechanisms of developing lapatinib resistant remain as a question to solve. Thus, we tried to find out there is a novel mechanism which related to lapatinib resistant, and any specified molecules were involved in this process. Methods: Acquired resistant SK-BR-3 cells were established by chronic exposure to lapatinib or trastuzumab. Lapatinib or trastuzumab sensitivity were confirmed by MTT assay. Western blotting was used to determine signal transduction molecule changes. Wound healing assay and Boyden chamber assay were conducted for verifying invasive ability. Whole exome sequencing (WES) and siRNA knock-down system were used for further analysis. Results: Lapatinib resistant (LR) cell lines showed down-regulation of p-HER2, p-Akt, and p-Erk. The activity of Src family kinase was increased in LR cells. Vimentin, famous EMT marker, is also increased in LR cells. Migration and invasion were significantly increased in LR cells. Correlated with a missense mutation of RUNX3, which identified by WES, expression of RUNX3 was decreased in LR cells. Moreover, siRNA knock-down parental cells showed more resistance to lapatinib. Conclusion: The increase of Src activation, cell migration, and invasion was observed in LR cells. RUNX3, which identified by WES, affected to lapatinib sensitivity in SK-BR-3 cells. Therefore, RUNX3 might be a specified molecule, which partially contributes resistance to lapatinib. Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Dong Hyeon Ha, Hyemin Jang, Yu Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im. Acquired lapatinib resistant induces EMT-phenotype in breast cancer cells via Src and RUNX3 [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 4116. doi:10.1158/1538-7445.AM2017-4116
Abstract 3998: Alerting the immune system by removing epigenetic silencing of Th1 chemokines
Authors: Heather M. Sonnemann, Amber J. Giles, Caitlin M. Reid, Marsha-Kay N. Hutchinson, Deric M. Park, Mark R. Gilbert
Journal: Cancer Research (2017)

Abstract BACKGROUND: Solid tumors employ multiple mechanisms to evade an immune response. However, the potential to enhance the immune response to cancer has been proven in several malignancie and is under investigation in many others, including primary CNS tumors. Brain tumors in particular lack robust T-cell infiltration. Recent studies have found that certain tumors can be induced to express T-cell attracting chemokines, CXCL9 and CXCL10, by interferon gamma (IFNg). This response is further amplified using methyltransferase inhibitors (Peng, et al. Nature 2015. Vol 527: 249-253.), resulting in increased Tcell trafficking to tumors both in vitro and in vivo. We hypothesized that T-cell trafficking to brain tumors could likewise be enhanced with DNA and histone methyltransferase inhibitors to induce CXCL9 and CXCL10 transcription. METHODS: Assays were performed on 7 human glioma brain tumor cell lines. CXCL9 and CXCL10 expression were measured by real-time PCR. Two commercially available methyltransferase inhibitors, 5-AZA-dC and GSK126, were utilized to demethylate DNA and histone H3 (K9 and K27), respectively. Histone methylation status was examined using Western blot. T-cell migration was measured using transwell migration assays. RESULTS: IFNg increased CXCL9 and CXCL10 transcription in brain tumor lines. GSK126 and 5-AZA-dC enhanced expression of CXCL9 and CXCL10 compared to IFNg alone. Migration assays confirmed T-cell trafficking towards chemokines produced by tumor cells in response to methyltransferase inhibitors. CONCLUSIONS: These studies demonstrate that brain tumors express T-cell attracting chemokines CXCL9 and CXCL10 in response to IFNg. Further, GSK126 and the combination of GSK126 and 5-AZA-dC enhanced expression of CXCL9 and CXCL10 transcription by real-time PCR and T-cell trafficking by migration assay. Together, these data provide a potential means to increase T-cell trafficking into tumors and potentially enhances the efficacy of immune therapies for brain tumors. Citation Format: Heather M. Sonnemann, Amber J. Giles, Caitlin M. Reid, Marsha-Kay N. Hutchinson, Deric M. Park, Mark R. Gilbert. Alerting the immune system by removing epigenetic silencing of Th1 chemokines [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 3998. doi:10.1158/1538-7445.AM2017-3998