bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4674: IL-35 regulates anti-tumor immune response in pancreatic ductal adenocarcinoma
Authors: Mirlekar Bhalchandra , Searcy Ryan , Pylayeva-Gupta Yuliya 
Published: August 2018

Abstract
Despite advances in our understanding of the mutational landscape in pancreatic ductal adenocarcinoma (PDA), this devastating disease is now the third-leading cause of U.S. cancer-related deaths. While recent successes of cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic cancer. A major barrier for immunotherapeutic approaches is marked immunosuppression within the PDA milieu. We have previously identified a novel role for IL-35 producing B regulatory cells in the pathogenesis of pancreatic cancer. However, little is known about the mechanisms behind IL-35 activity in cancer. The overarching goal of this project is to elucidate molecular and cellular mechanisms by which IL-35 facilitates the emergence of pancreatic cancer. Our results demonstrate that IL-35, but not IL-10, potentiates PDA growth. This correlates with induction of immunosuppressive T regulatory cells (Treg) and suppression of T effector cell (Teff) and cytotoxic CD8+ T cell activity, suggesting that IL-35 controls anti-tumor immune responses in PDA. Remarkably, while PDA is typically resistant to anti-PD1 immunotherapy, IL-35 deficiency converted PDA from immunologically ‘cold' to ‘hot' tumor, which allowed for a robust synergistic reduction in tumor growth in response to anti-PD-1 treatment. Insights gleaned from these and further mechanistic studies of IL-35 in PDA may be expeditiously translated into IL-35 targeted combination immunotherapy.
Citation Format: Bhalchandra Mirlekar, Ryan Searcy, Yuliya Pylayeva-Gupta. IL-35 regulates anti-tumor immune response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4674.
Abstract 4679: Rectal cancer-infiltrating T cells show clonal expansion associated with spatially restricted tolerogenic phenotypes
Authors: Penter Livius , Dietze Kerstin , Aigner Felix , Bullinger Lars , Blankenstein Thomas , Hansmann Leo 
Published: August 2018

Abstract
T cell infiltration correlates with prognosis and outcome in colorectal cancer regardless of the tumor stage. However, data on clonal expansion, phenotypes, functions, and spatial distribution of tumor-infiltrating T cells (TILs) are limited.
We hypothesized that subsets of clonally expanded rectal cancer-associated T cells are specifically recruited into the tumor and show characteristic phenotypes and functions.
Paired TILs and T cells from adjacent unaffected mucosa were isolated from five treatment-naïve rectal cancer patients. Although T cell immune phenotypes were heterogeneous, the frequencies of CD38+, PD-1+, and TIM-3+ cells were significantly higher in CD8+ TILs when compared to T cells from unaffected mucosa (p &lt; 0.05). To track clonal expansion and phenotypes at the single cell level, we combined 13-parameter FACS single cell index sorting with next generation T cell receptor (TCR) and phenotype sequencing. Paired TCRαβ sequences were obtained from 1237 TILs (on average 412 TILs per patient) and 1257 T cells infiltrating the unaffected mucosa (on average 419 T cells per patient) from three selected patients. Clonal T cell expansion was not restricted to TILs and occurred predominantly in CD8+ T cells (p &lt; 0.05). Expanded TIL clones were more frequently TIM-3+, PD-1+, and CD38+ (p &lt; 0.05) and occupied characteristic phenotype compartments when compared to T cells from unaffected mucosa with t-stochastic neighbor embedding (t-SNE) visualization. FOXP3 expression was enriched in non-expanded TILs (p &lt; 0.05).
Only 11 out of 179 TIL clones were also detectable in unaffected mucosa of the same patients and these overlapping clones were exclusively PD-1- TIM-3-.
In conclusion, rectal cancer is infiltrated by oligoclonal T cells. Selected clones were exclusively detected in TILs suggesting their expansion and recruitment driven by tumor-associated cues. Tolerance was induced i) in an antigen-specific manner by the expression of immune checkpoint molecules predominantly on clonally expanded TILs, and ii) in an antigen-independent manner by infiltrating polyclonal FOXP3+ regulatory T cells.
Citation Format: Livius Penter, Kerstin Dietze, Felix Aigner, Lars Bullinger, Thomas Blankenstein, Leo Hansmann. Rectal cancer-infiltrating T cells show clonal expansion associated with spatially restricted tolerogenic phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4679.
Abstract 4685: Phenotypic difference of CD103+ tissue-resident memory T cells in various cancers
Authors: Park Hye Seon , Kim Young-Ae , Bang Won Seon , Lee Heejae , Lee Miseon , Park In Ah , Song In Hye , Heo Sun-Hee , Lee Hyeonjin , Lee Hee Jin , Gong Gyungyub 
Published: August 2018

Abstract
Background: The presence and clinical importance of tissue-resident memory T cells (TRM) have been recently described in human lung, liver, and bladder cancer. However, the frequency and phenotypic characteristics of TRM in other tumors are largely unknown.
Methods: We analyzed single-cell populations of renal cell carcinoma (n=20), breast (n=16), colorectal (n=20), and stomach cancer (n=15) by dissociation of tumor tissue with collagenase/hyaluronidase. We investigated population of memory T cells and TRM using anti-CD45RO or anti-CD103 antibodies by flow cytometry.
Results: Colorectal cancer had higher level of CD4+ T cells (70.1%) among CD3+ T cells than other tumors (stomach cancer, 59.6%; renal cell carcinoma, 49.4%; breast cancer, 49.0%; p=0.001). In CD4+ T cells, the percentage of CD45RO+ memory T cells was higher in renal cell carcinoma (75.7%) and breast cancer (85.4%) than colorectal (36.9%) and stomach cancer (38.1%, p&lt;0.001). About 4% of CD4+ T cells in renal cell carcinoma, colorectal and stomach cancer were TRM, while 14.3% of CD4+ T cells were TRM in breast cancer (p&lt;0.001). The percentage of CD45RO+ memory T cells among CD4+ TRM was about 60% in all tumors (p=0.164). In CD8+ T cells, the percentage of CD45RO+ memory T cells was higher in renal cell carcinoma (73.5%), breast (66.4%) and stomach cancer (54.4%) than colorectal cancer (33.0%, p&lt;0.001). Stomach cancer had higher level of TRM (74.3%) among CD8+ T cells than other tumors (colorectal cancer, 19.6%; renal cell carcinoma, 20.1%; breast cancer, 30.6%; p&lt;0.001). The percentage of CD45RO+ TRM in renal cell carcinoma (89.3%) and breast cancer (89.5%) was higher than colorectal (43.0%) and stomach cancer (51.5%, p&lt;0.001).
Conclusions: The frequency and phenotypic characteristics of TRM in renal cell carcinoma, colorectal, stomach, and breast cancer were different. Further studies regarding functional difference and clinical significance of TRM in various tumors are warranted.Acknowledgement: This study was supported by Basic Science Research Programs through the National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea (NRF-2017R1D1A1B03033104).
Citation Format: Hye Seon Park, Young-Ae Kim, Won Seon Bang, Heejae Lee, Miseon Lee, In Ah Park, In Hye Song, Sun-Hee Heo, Hyeonjin Lee, Hee Jin Lee, Gyungyub Gong. Phenotypic difference of CD103+ tissue-resident memory T cells in various cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4685.
Abstract 4707: Pelareorep promotes the expression of a chemokine signature that predicts response to immunotherapy
Authors: Wilkinson Grey A. , Piar Aine , Cesarz Zoe , Tran Hue , Chakrabarty Romit , Gutierrez Andres , Coffey Matt 
Published: August 2018

Abstract
Introduction: It has been proposed that the presence of inflamed tumor phenotypes, characterized by the presence of infiltrating lymphocytes and the expression of specific chemokines and cytokines, can predict response to immunotherapy and result in better patient outcomes [1, 2]. We hypothesized that pelareorep, an immuno-oncolytic virus (IOV), may elicit predictive proinflammatory gene signatures in select cancer cell lines permissive to viral infection.
Methods: Cell lines derived from non-small cell lung cancer (NSCLC, H522), colorectal cancer (CRC, SW-620), and hepatocellular carcinoma (HCC, SNU 387) were infected at an multiplicity of infection equal to 50. We examined changes in gene expression and conducted cell viability assays at 6, 12, and 18 hours post pelareorep infection (including a non-infected control). To monitor changes in gene expression we employed a custom 780-gene Pan Cancer Immune panel developed by nanoString Technologies and specifically monitored for changes in the expression of key interferon and NF-κB signalling genes, immune checkpoint ligands, and a 12-gene chemokine signature predictive of a positive response to immunotherapy identified by Messina et al. [2].
Results: All cell lines examined were susceptible to pelareorep induced cytopathic effect. Strikingly, principal component analysis revealed that the changes in gene expression were unique and different for each cell line. Of the cell lines examined, only HCC cells infected with pelareorep promoted an inflammatory signature, similar to the one used to predict response to immunotherapy in melanoma [2].
Conclusions: This study demonstrates that pelareorep can prime or promote a predictive inflamed tumor phenotype in HCC, which correlates with the innate response recently described in HCC- animal models treated with pelareorep [3]. The role of pelareorep in the treatment of hepatocellular carcinoma deserves further investigation, particularly in combination with other immunotherapies.
References: [1] Gajewski, T.F., The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment. Semin Oncol, 2015. 42(4): p. 663-71. [2] Messina, J.L., et al., 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci Rep, 2012. 2: p. 765. [3] Samson, A., et al., Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer. Gut, 2016.
Citation Format: Grey A. Wilkinson, Aine Piar, Zoe Cesarz, Hue Tran, Romit Chakrabarty, Andres Gutierrez, Matt Coffey. Pelareorep promotes the expression of a chemokine signature that predicts response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4707.
Abstract 4738: IL-17 induces myeloid-related stimulating factors by stromal cells
Authors: Mucciolo Gianluca , Curto Roberta , Curcio Claudia , Roux Cecilia , Vannucci Luca , Novelli Francesco , Cappello Paola 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive cancer with a 5-year survival rate of ∼ 8%. An hallmark of PDA is the massive desmoplasia and the complex stromal-tumor interaction, regulated by a pletory of secreted factors. The role of IL-17 and T-helper 17 in cancer progression or anti-tumour immunity remain controversial. To assess the role of this molecule, we crossed genetically engineered mice (GEM) characterized by a spontaneous PDA development, with IL-17 knockout mice (GEM/IL-17 KO). The absence of IL-17 correlated with an increased pancreatic fibrosis, evaluated by second harmonic generation approach. The transcripts and secretome of Cancer Associated Fibroblasts (CAFs), obtained from tumors arose in both WT and IL-17 KO GEM, have been evaluated. More than 60 genes were differently modulated in the CAFs from GEM/IL-17 KO mice. Among them, GM-CSF, G-CSF, M-CSF, CXCL1 and 2 where strongly up-regulated in GEM/WT compared to GEM/IL-17 KO mice and significantly inhibited by the addition of the recombinant cytokine. The absence of those factors paralleled an increased Th1-skewed cytokine pattern released by CAF that affected T cell infiltration and response. Taken together, these results suggest that IL-17 does affect the tumor progression by promoting a CAFs-mediated release of cytokines involved in myeloid cells recruitment and suppression of an anti-tumoral immune response. This feature defines IL-17 as a potential target to shape the tumor microenvironment and favour immunotherapy success.
Citation Format: Gianluca Mucciolo, Roberta Curto, Claudia Curcio, Cecilia Roux, Luca Vannucci, Francesco Novelli, Paola Cappello. IL-17 induces myeloid-related stimulating factors by stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4738.
Abstract 4786: WSD0922: A novel, oral bioavailable, brain penetrable and reversible EGFRm+ inhibitor for the treatment of primary and metastatic brain tumors
Authors: Zhong Wei , Zhang Jinqiang , Mu Zhihua , Sun Claire 
Published: August 2018

Abstract
Epidermal growth factor receptor (EGFR) is a cell surface protein that regulates normal cellular growth in tissues of epithelial origin. Des-regulated EGFR signaling (caused by mechanisms of overexpression, mutation, autocrine activation) contributes for oncogenesis by inducing cells proliferation and resisting apoptosis. In patients with NSCLC, activating mutants (EGFRm+) occur within exon 18-21 with increased EGFR activity. About 90% of these mutations (G719x, exon 19 deletions and exon 21 mutation) are sensitizing EGFRm+. EGFR TKIs have shown good performance in clinic for systemic NSCLC anchoring EGFRm+. However, up to 65% of NSCLC patients will develop brain metastasis (BM) ultimately. Current approved EGFR TKIs are not so effective for BM due to limited brain penetration as they are substrates of P-gp or BCRP, two main efflux transporters expressed on human BBB. In patients with GBM, the most common mutation is EGFRvIII (exon2-7 deletion) with an overall frequency of 25–64%. Current EGFR TKIs are ineffective in GBM treatment probably due to resistance caused by EGFRvIII as well as limited brain penetration. One-year survival of GBM patients is approximate 43%. Herein, we report a discovery of brain penetrable EGFR inhibitor WSD0922 for NSCLC BM and GBM with IC50 against EGFRm is &lt;10nM. The ex-vivo antiproliferative GI50 in GBM tissues with EGFRvIII amplification is &lt;100nM. WSD0922 is highly selective over other kinases. In-vitro MDCKII transfected cells and Caco-2 assays showed that WSD0922 is highly permeable and not a substrate of P-gp or BCRP. Preclinical CNS PK studies confirmed good brain penetration of WSD0922 with Kp,uu,brain close to unity. Treatment of mice bearing PC-9 (exon 19 del of NSCLC) in both subcutaneous (SC) and intracranial models with WSD0922 at 1-10mpk BID via PO resulted in dose dependent tumor growth inhibition (TGI) or regression with statistically significant survival benefit. Moreover, significant TGI for mice bearing GBM PDX model was achieved by treatment with
WSD0922. No toxicity was observed in the animals during the treatment. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with BM of NSCLC or GBM harboring EGFRm+.
Citation Format: Wei Zhong, Jinqiang Zhang, Zhihua Mu, Claire Sun. WSD0922: A novel, oral bioavailable, brain penetrable and reversible EGFRm+ inhibitor for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4786.
Abstract 4787: SKLB188 inhibits the growth of head and neck cancer cell growth by suppressing EGFR signaling
Authors: Huang Shile , Barzegar Mansoureh , Ma Shuang , Yang Shengyong 
Published: August 2018

Abstract
Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. So far, only Cetuximab, an anti-EGFR monoclonal antibody, has been approved for EGFR-target therapy in HNSCC. Here we show that SKLB188, a newly synthesized small molecule compound, inhibited cell proliferation and induced apoptosis of HNSCC cells in vitro and in vivo, by targeting EGFR signaling. SKLB188 induced cell cycle arrest in G1 phase, by downregulating the expression of Cdc25A, cyclins D1/A and cyclin dependent kinases (CDK2/4), and upregulating the expression of CDK inhibitors (p21Cip1 and p27Kip1), leading to decreased phosphorylation of Rb. SKLB188 also downregulated the expression of Mcl-1 and survivin, inducing caspase-dependent apoptosis. Molecular docking predicted that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay revealed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC50 = 5 nM). Western blot analysis showed that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose-dependently inhibited FaDu xenograft growth in nude mice, and concurrently inhibited the phosphorylation of Erk1/2 and Akt in the tumors. Taken together, our results support that SKLB188 inhibits the growth of HNSCC cells in vitro and in vivo by targeting EGFR signaling.
Citation Format: Shile Huang, Mansoureh Barzegar, Shuang Ma, Shengyong Yang. SKLB188 inhibits the growth of head and neck cancer cell growth by suppressing EGFR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4787.
Abstract 4789: Clinical candidate DBPR112: A novel epidermal growth factor receptor inhibitor as a promising treatment for non-small cell lung cancer
Authors: Hsieh Hsing-Pang , Chang Jang-Yang , Kuo Ching-Chuan , Hsu John 
Published: August 2018

Abstract
Lung cancer is one of the chief causes of cancer death in the world; in addition, non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer deaths. The development of tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have shown remarkable effects in patients but some acquired resistance after treatment. Therefore, the discovery of efficacious EGFR-TKIs poses an utmost priority. Our team at IBPR has designed and synthesized a series of compounds by high throughput parallel synthesis platform. In the subsequent structure-activity relationship study (SAR) and lead optimization, approximate 150 compounds were synthesized, which concluded that the presence of an N,N-dimethyl functional group on the Michael acceptor and the S-chirality of the phenylaminoethanol side chain were both essential. Consequently, DBPR112 was identified as a potent EGFR-TKI clinical candidate showing excellent inhibitory ability on EGFRL858R/T790M and EGFR exon 20 insertion. DBPR112 was orally effective against the growth of human lung H1975 tumors subcutaneously xenografted in nude mice. A dramatic reduction in tumor size was noted with DBPR112 treatment, while displaying negligible body weight loss in all dosing groups. Furthermore, DBPR112 was more tolerable than afatinib in mice. To date, all pre-clinical studies were completed, and the IND application of DBPR112 was approved by US FDA in 2016 and the Phase I clinical trial has been initiated since July 2017 in Taiwan.
Citation Format: Hsing-Pang Hsieh, Jang-Yang Chang, Ching-Chuan Kuo, John Hsu. Clinical candidate DBPR112: A novel epidermal growth factor receptor inhibitor as a promising treatment for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4789.
Abstract 4793: WSD1227: A novel, oral bioavailable, brain penetrable and reversible VEGFR inhibitor for the treatment of primary and metastatic brain tumors
Authors: Zhang Jinqiang , Zhong Wei , Mu Zhihua , sun claire 
Published: August 2018

Abstract
Occurrence of brain metastases (BM) has been reported in ~10% cancer patients as a later manifestation of the disease with incidence depending on the type of primary tumors1: about 20~40% in NSCLC and BC2,3 and &lt;5% in CRC4,5 and ovarian cancer (OC)6. The incidence of BM is increasing in part due to the earlier diagnosis by using brain imaging techniques and the improved survival offered by systemic therapies. Patients with BM have a very poor prognosis and the overall survival is only several months after diagnosis. Surgery and radiotherapy either as single treatment or in combination are the most common options for the management of BM since many anticancer drugs cannot cross the blood-brain barrier (BBB). VEGFR2, upregulated in many cancers7,8, plays an important role in tumor angiogenesis. Anti-angiogenesis has been proved to be a good strategy to shrink tumor in many cancer treatments, such as bevacizumab in GBM, NSCLC, mBC, cediranib in OC, etc. However, those clinical validated anti-VEGF agents cannot cross BBB effectively due to either large molecule weight or being substrate of BBB efflux transporters. Herein, using our advanced medicinal chemistry with deep knowledge in CNS area, a BBB penetrable, selective and potent VEGFR2 inhibitor WSD1227 is discovered with biochemical IC50 against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFRα IC50 22.9nM, PDGFRβ IC50 19.4nM, cKit IC50 383nM, FLT3 IC50 555 nM and CSF1R IC50 1062nM. In-vitro MDCKII transfected cell assays demonstrated WSD1227 is not a substrate of P-gp or BCRP, two main efflux transporters on human BBB. Preclinical CNS PK studies confirmed good brain penetration of WSD1227 with Kp,uu,brain close to unity. WSD1227 possessed superior PK profile with sufficient free PK exposure to achieve target engagement in mice. Treatment of mice bearing SW620, a CRC xenograft in both subcutaneous (SC) and intracranial models with WSD1227 after oral dosing resulted in
significant tumor growth inhibition (TGI). Similar TGI was observed in SKOV-3 bearing mice, an OC xenograft in both SC and intracranial models. No toxicity was observed in the animals during the treatment. Moreover, predicted human PK properties are very promising to offer sufficient target engagement at a pretty low dose in clinic. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic for the treatment of patients with BM whose primary tumors have already been controlled well by systemic therapies.
Citation Format: Jinqiang Zhang, Wei Zhong, Zhihua Mu, claire sun. WSD1227: A novel, oral bioavailable, brain penetrable and reversible VEGFR inhibitor for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4793.