bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5008: The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation
Authors: Ferraro Gino B. , Kodack David P. , Askoxylakis Vasileios , Sheng Qing , Badeaux Mark , Goel Shom , Qi Xiaolong , Shankaraiah Ram , Cao Alexander Z. , Ramjiawan Rakesh R. , Bezwada Divya , Patel Bhushankumar , Song Youngchul , Costa Carlotta , Naxerova Kamila , Wong Christina , Kloepper Jonas , Das Rita , Tam Angela , Tanboon Jantima , Duda Dan G. , Miller Ryan C. , Siegel Marni B. , Anders Carey K. , Sanders Melinda , Estrada Valeria M. , Schlegel Robert , Arteaga Carlos L. , Brachtel Elena , Huang Alan , Fukumura Dai , Engelman Jeffrey A. , Jain Rakesh K. 
Published: July 2017

Abstract
Brain metastases represent a devastating progression of luminal breast cancer. While targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade PI3K inhibition despite efficient drug delivery. In comparison to extracranial disease, there is increased HER3 expression and phosphorylation in the brain lesions. HER3 blockade overcomes the resistance of both HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, leading to striking tumor growth delay and significant improvement of mouse survival. Collectively, these data provide a mechanistic basis underlying therapeutic resistance in the brain microenvironment and identify rapidly translatable treatment strategiesfor HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.
Citation Format: Gino B. Ferraro, David P. Kodack, Vasileios Askoxylakis, Qing Sheng, Mark Badeaux, Shom Goel, Xiaolong Qi, Ram Shankaraiah, Alexander Z. Cao, Rakesh R. Ramjiawan, Divya Bezwada, Bhushankumar Patel, Youngchul Song, Carlotta Costa, Kamila Naxerova, Christina Wong, Jonas Kloepper, Rita Das, Angela Tam, Jantima Tanboon, Dan G. Duda, Ryan C. Miller, Marni B. Siegel, Carey K. Anders, Melinda Sanders, Valeria M. Estrada, Robert Schlegel, Carlos L. Arteaga, Elena Brachtel, Alan Huang, Dai Fukumura, Jeffrey A. Engelman, Rakesh K. Jain. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation [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 5008. doi:10.1158/1538-7445.AM2017-5008
Abstract 5013: A 3D culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer
Authors: Singh Bhuminder , Li Cunxi , Graves-Deal Ramona , Ma Haiting , Starchenko Alina , Fry William H. , Lu Yuanyuan , Wang Yang , Bogatcheva Galina , Khan Mohseen P. , Milne Ginger L. , Zhao Shilin , Ayers Gregory D. , Li Nenggan , Washington Mary K. , Yeatman Timothy J. , McDonald Oliver G. , Liu Qi , Coffey Robert J. 
Published: July 2017

Abstract
We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated within type-I collagen in 3D. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent malignant properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained the parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), cetuximab strongly inhibited growth of CC, whereas SC was resistant to growth inhibition and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, to cetuximab in SC restored cetuximab sensitivity. To characterize genome-wide divergence between CC and SC, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most upregulated genes in CC was the tumor suppressor 15-PGDH/HPGD and the most upregulated gene in SC was versican (VCAN) in 3D and xenografts. Analysis of a human CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a new mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic sensitivities and disease-relevant genes for CRC.
Citation Format: Bhuminder Singh, Cunxi Li, Ramona Graves-Deal, Haiting Ma, Alina Starchenko, William H. Fry, Yuanyuan Lu, Yang Wang, Galina Bogatcheva, Mohseen P. Khan, Ginger L. Milne, Shilin Zhao, Gregory D. Ayers, Nenggan Li, Mary K. Washington, Timothy J. Yeatman, Oliver G. McDonald, Qi Liu, Robert J. Coffey. A 3D culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal 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 5013. doi:10.1158/1538-7445.AM2017-5013
Abstract 5018: Dissecting antigen-specific T-cell response in a novel mouse model of colon cancer
Authors: Beytagh Mary C. , Westcott Peter M. , Smith Olivia C. , Roper Jatin , Yilmaz Omer , Jacks Tyler E. 
Published: July 2017

Abstract
Immune checkpoint blockade therapies, which unleash the immune system’s ability to recognize and eliminate cancer cells, are currently among the most promising treatments for cancer. Antibodies that block the immune inhibitory receptors CTLA4 and PD1 have shown clinical success, with objective response rates over 20% and some durable responses exceeding 10 years. However, some cancers, such as colorectal cancer (CRC), have proven particularly refractory to immunotherapy. Although it is appreciated that the colon is an immunosuppressive environment, the mechanism and extent of immune suppression remains unclear. Studies of human CRC tumors have shown that T cell infiltration is an important predictor of clinical outcome, yet current mouse models of CRC are not particularly well suited to the mechanistic study of T cell responses against tumor-specific antigens. Syngeneic cell line transplants, by far the most widely used models to study adaptive immune response in CRC, are characterized by a highly complex tumor antigen landscape, and have not employed orthotopic transplant into the colon. In order to track highly specific T cell responses in CRC, we have employed a novel colon organoid-based system, in which transformed organoids expressing model antigens are orthotopically transplanted into the wall of the colon via colonscopy-guided injection, a method pioneered in the lab of Omer Yilmaz. Organoids were harvested from VillinCreER; Apcfl/fl mice and grown in the presence of Wnt ligand; addition of tamoxifen and removal of Wnt from the media facilitated expression of the colon-specifc Cre, deletion of Apc, and selection of transformed organoids capable of growing in the absence of Wnt. To induce expression of model antigens, organoids were infected with a lentiviral vector that, in addition to the fluorescent reporter FusionRed, expressed the T cell antigens SIYRYYGL and two antigens from ovalbumin - SIINFEKL and OVA323-339 - fused to the C-terminus of luciferase (FRLucOS), enabling us to monitor antigen expression in vivo. Organoids were then sorted and injected into the wall of the colon. Previous work by Michael DuPage, in which he expressed the LucOS construct in an autochthonous lung cancer and sarcoma mouse model, provided key insights into the dynamic nature of T cell response against cancer cells. The novel model system described here provides a powerful new tool to dissect antitumor T cell responses in the poorly understood context of CRC.
Citation Format: Mary C. Beytagh, Peter M. Westcott, Olivia C. Smith, Jatin Roper, Omer Yilmaz, Tyler E. Jacks. Dissecting antigen-specific T-cell response in a novel mouse model of colon 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 5018. doi:10.1158/1538-7445.AM2017-5018
Abstract 5029: Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial
Authors: Jamieson David , Seddon Beatrice , Kuever Katja , Dehbi Hakim-Moulay , Strauss Sandra , Beare Sandy , Veal Gareth 
Published: July 2017

Abstract
Introduction
The treatment of locally advanced or metastatic soft tissue sarcoma remains a significant clinical challenge, with overall survival rates of approximately 12 months observed with current first line palliative chemotherapy. A recently completed randomised phase III clinical trial entitled GeDDiS (ISRCTN07742377), was designed to compare first line treatment with gemcitabine in combination with docetaxel (GemDoc) versus current standard treatment with doxorubicin. A pharmacogenetic sub-study was incorporated into the trial to assess potential impact of single nucleotide polymorphisms (SNPs) in genes associated with the pharmacology of the three drugs.
Methods
A total of 240 patients were recruited to the sub-study with 119 on the doxorubicin arm and 121 on the GemDoc arm. A 4 ml blood sample was taken from each participant and genomic DNA extracted. Individual candidate SNPs were assessed by Taqman PCR in 7 genes associated with doxorubicin pharmacology, 7 genes associated with gemcitabine and 5 genes associated with the pharmacology of docetaxel. Association between the SNPs and efficacy and toxicity was assessed.
Results
SNPs within the solute transporter SLC22A16, associated with the intracellular influx of doxorubicin, were associated with worse PFS (HR = 1.72, p=0.04) and decreased frequency of grade 3/4 adverse events (71% vs 48%, p=0.04) in the doxorubicin arm of the study but not in the GemDoc arm.
Conclusions
The association of genetic variants of SLC22A16 with decreased efficacy and decreased incidence of toxicity is consistent with a loss of function in the transporter and previous observation of increased AUC in pharmacokinetic studies assuming that distribution of the drug into target and collateral tissues is restricted.
Citation Format: David Jamieson, Beatrice Seddon, Katja Kuever, Hakim-Moulay Dehbi, Sandra Strauss, Sandy Beare, Gareth Veal. Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial [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 5029. doi:10.1158/1538-7445.AM2017-5029
Abstract 5042: Defining an optimal single time point sampling strategy representative of overall capecitabine pharmacokinetics
Authors: Welch Stephen , Teft Wendy , Lenehan John , Tirona Rommel , Lumsden Karen , Winquist Eric , Kim Richard B. 
Published: July 2017

Abstract
Background: Capecitabine is an oral chemotherapy pro-drug used to treat advanced colorectal cancer. Patients may experience hand-foot syndrome and diarrhea, among other side effects, that affect quality of life and may necessitate dose modification or discontinuation. There is significant regional variation in capecitabine tolerability, related to a myriad of factors including pharmacogenomics, dietary and cultural differences. Capecitabine dose modification, when necessary, is empirical based on toxicity suggesting a personalized dosing approach might better optimize therapy. Objective: In phase I of a personalized dosing approach, our objective was to define an optimal time point for blood sampling that best represented overall exposure of capecitabine and its metabolites.
Methods: A single-arm prospective pharmacokinetic cohort study of patients with advanced or metastatic colorectal cancer prescribed capecitabine monotherapy was done. Blood samples were collected pre-dose and at timed intervals between 0 and 8 hours post-dose. Plasma concentration of capecitabine and its major metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouracil (5'-DFUR), were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).
Results: 26 patients were enrolled; 65% were male and 42.3% had metastatic disease. Mean capecitabine dose was 2854 ± 944 mg. Hand-foot symptoms (60%), fatigue (53%) and diarrhea (30%) were the most common adverse drug reactions. Dose normalized mean (SD) AUC0-8h for capecitabine, 5’-DFCR and 5’-DFUR were 6.74 (3.0), 4.19 (1.5) and 6.33 (2.8) ng/ml*h, respectively. Spearman correlation between dose normalized concentrations and AUC at each blood draw was performed. The best estimated time points for capecitabine, 5’-DFCR and 5’-DFUR were 1.5, 2 and 2 hours with r2 values of 0.6 (p &lt;0.01), 0.64 (p &lt;0.001) and 0.51 (p &lt;0.01), respectively. There was a significant correlation seen between capecitabine AUC and need for subsequent dose reduction (p&lt;0.05).
Conclusions: Blood samples obtained between 1.5 and 2 hours post-dose provide the best estimate of capecitabine exposure. Further pharmacokinetic analysis in this cohort is ongoing. This blood draw strategy will be used in a larger trial intended to develop a personalized capecitabine dosing algorithm.
Citation Format: Stephen Welch, Wendy Teft, John Lenehan, Rommel Tirona, Karen Lumsden, Eric Winquist, Richard B. Kim. Defining an optimal single time point sampling strategy representative of overall capecitabine pharmacokinetics [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 5042. doi:10.1158/1538-7445.AM2017-5042
Abstract 5081: Disruption of DNA methyltransferase (DNMT) 1 confers resistance to DNMT inhibitors in human colorectal cancer cells
Authors: Laranjeira Angelo B. , Nguyen Dat , Huang Erich , Doroshow James H. , Yang Sherry X. 
Published: July 2017

Abstract
DNA methyltransferase (DNMT) 1 is responsible for the maintenance and propagation of DNA methylation pattern, and plays an important role in cell survival and proliferation. Thus, targeting DNMT represents a promising approach for cancer treatment. However, the role of DNMT1 in treatment efficacy with DNMT inhibitors remains controversial. The aim of this study was to investigate potential alterations of DNMT inhibitor-induced cytotoxicity and cellular survival after disruption/knockout of DNMT1 in cancer cells. The human colorectal cancer cell line HCT116 and its isogenic DNMT1 knockout pair were treated with increasing concentrations of 4’-thio-5-aza-2’-deoxycytidine (aza-TdCyd), a novel DNMT inhibitor, and 5-aza-2’-deoxycytidine (aza-dCyd). Cytotoxic effects and cell survival were evaluated by MTT and clonogenic assays. Apoptosis was measured by annexin-V/propidium iodide test, and expression of DNMT1, DNMT3A and DNMT3B was detected by western blot. After 96h of drug exposure, IC50s of aza-TdCyd and aza-dCyd were 0.031µM and 0.28 µM, respectively, in HCT116 cells. In contrast, DNMT1 knockout cells were remarkably resistant to both drugs with IC50s all higher than 10 µM. The treatments resulted in a significant increase in apoptosis in the parental line versus its knockout counterpart. As for the cell survival, IC50s were ~0.12 µM for aza-TdCyd and ~4.62 µM for aza-dCyd in HCT116 cells, compared to ~43.77 µM and ~62.09 µM in DNMT1 knockout cells. As such, disruption of DNMT1 caused over 300-fold and 10-fold increase in resistance to aza-TdCyd and aza-dCyd. Moreover, we observed a G2/M arrest produced by aza-TdCyd versus aza-dCyd in the parental cells, and no apparent alteration in cell cycle phase distribution in DNMT1 knockout cells. Notably, aza-TdCyd was more potent than aza-dCyd in depleting DNMT3A and/or DNMT1 in both cell lines after 48h of treatment. Our findings demonstrate that disruption of DNMT1 leads to a significantly increased resistance to aza-TdCyd and aza-dCyd, suggesting that DNMT1 is critical to the antitumor activity of DNMT inhibitors. Aza-TdCyd is much more potent than aza-dCyd for both inhibition of DNMTs and growth of cancer cells.
Citation Format: Angelo B. Laranjeira, Dat Nguyen, Erich Huang, James H. Doroshow, Sherry X. Yang. Disruption of DNA methyltransferase (DNMT) 1 confers resistance to DNMT inhibitors in human colorectal 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 5081. doi:10.1158/1538-7445.AM2017-5081
Abstract 5088: Tumor penetrating RNA delivery for therapeutic benefit of pancreatic cancer
Authors: Hao Liangliang , Lo Justin , Bhatia Sangeeta 
Published: July 2017

Abstract
Pancreatic cancer remains a deadly disease with a median survival of less than one year, in part because we lack effective therapeutic strategies. Mutations of the oncogene KRAS and the tumor suppressor genes TP53, INK4A, and DPC4 play important roles in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC); however, these driver events have proven to be challenging targets for drug development. RNA interference through small interfering RNA (siRNA) delivery has the potential to have an impact on silencing ‘undruggable’ targets; however, siRNA delivery in tumors has been challenging in general and worsened in PDAC by the stromal barriers to drug delivery. Herein, we integrated biomedical engineering, materials science, and pre-clinical investigation to establish a novel class of tumor-penetrating nanoparticles (TPNs) to enhance delivery of siRNAs in PDAC for therapeutic benefit. Specifically, we adapted self-assembled nanoparticles comprised of siRNA complexed with tandem tumor-penetrating and membrane-translocating peptides, which enabled the specific delivery of siRNA deep into the tumor parenchyma. Specifically, to establish efficacious siRNA delivery vehicles, we characterized and selected tandem peptides that incorporate novel tumor-penetrating peptide domains known to target PDAC in mice. In parallel, we optimized the particle stability through incorporation of hydrophilic molecules, focusing on achieving desirable pharmacokinetic properties which will reduce off-target delivery and increase potency of a given siRNA dose. The resulting TPNs carry siRNA into the cytosol of monolayer cultures of tumor cells, and also exhibit penetration in pancreas organoids derived from primary mouse and human tumors. As a proof-of-concept, we used TPN in vivo to knockdown KRAS in a murine PDAC model, using subcutaneously-implanted, autochthonous KRASG12D/+p53-/- tumors. Treatment of tumor-bearing mice with systemically administrated KRAS-specific TPNs suppressed the growth of established tumors. With the delivery platform established, the ongoing goals of this project are to identify siRNA targets that synergize with the suppression of oncogenic KRAS, and to validate synthetic lethal targets by interfering with signature PDAC driver events uncovered by functional genomic efforts. Together, these studies will provide a foundation for translational studies involving new targets and delivery technology in pancreatic cancer.
Citation Format: Liangliang Hao, Justin Lo, Sangeeta Bhatia. Tumor penetrating RNA delivery for therapeutic benefit of pancreatic 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 5088. doi:10.1158/1538-7445.AM2017-5088
Abstract 5093: In vitro, in vivo and molecular effects of stromal selective targeting by uPAR retargeted oncoytic measles virus on breast cancer progression
Authors: Jing Yuqi , Chavez Valery , Acquavella Nicolas , El-Ashry Doraya , Ban Yuguang , Chen Xi , Merchan Jaime 
Published: July 2017

Abstract
The tumor microenvironment is a relevant target for novel biological therapies. While it has been demonstrated that tumor-stromal cell interactions are important in the sensitivity of the cancer cells to oncolytic virues, few studies have investigated the direct effects of an oncolytic virus on the stroma, and its implications on the virus antitumor efficacy.
MV-m-uPA and MV-h-uPA are fully retargeted, species specific, oncolytic measles viruses directed against murine or human urokinase receptor (uPAR). The effects of stromal selective targeting by uPAR retargeted MVs were investigated. In vitro infection, gene expression and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer associated fibroblasts in a species specific manner. In murine fibroblast (3T3)/human breast cancer (T47D) 3-D co-cultures, selective fibroblast targeting by MV-m-uPA inhibited breast cancer cell growth. These effects were validated in vivo, in a human breast cancer xenograft (MDA-MB-231), where intravenous administration of the murine specific MV-m-uPA led to significant tumor growth delay and improved survival compared to controls. Experiments comparing the effects of tumor (MV-h-uPA) vs. stromal (MV-m-uPA) vs. combined treatment showed that tumor and stromal targeting was associated with improved tumor control. Correlative studies demonstrated in vivo tumor targeting, increased apoptosis, and MV-m-uPA induced differential regulation of both stromal (murine) genes and cancer (human) genes associated with inflammation, angiogenesis and survival, among others, indicating viral induced modulation of tumor-stromal interactions.
Our results demonstrate for the first time the feasibility of stromal selective targeting by an oncolytic MV, viral induced modulation of the tumor microenvironment, and subsequent tumor growth delay. These findings further validate the critical role of stromal uPAR in cancer progression and the potential of oncolytic viruses as anti-stromal agents.
Citation Format: Yuqi Jing, Valery Chavez, Nicolas Acquavella, Doraya El-Ashry, Yuguang Ban, Xi Chen, Jaime Merchan. In vitro, in vivo and molecular effects of stromal selective targeting by uPAR retargeted oncoytic measles virus on breast cancer progression [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 5093. doi:10.1158/1538-7445.AM2017-5093