bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3713: Targeting β-catenin pathway by nanoparticle-mediated delivery of norcantharidin impairs the stemness of triple negative breast cancer cells
Authors: Li Yunfei , Wang Zhishan , Xiao Yajuan , Yang Chengfeng 
Published: August 2018

Abstract
Background Norcantharidin (NCTD) is known as an inhibitor of serine/threonine protein phosphatase types 1 and 2A (PP1/PP2A) and exhibits potent anticancer efficacies. Our preliminary study identified NCTD interfering with the interaction between phospho-β-catenin and PP1/PP2A could downregulate the levels of non-phospho β-catenin in the cytoplasm in Triple Negative Breast Cancer (TNBC) cells. As β-catenin pathway plays an important role in cancer stemness, we hypothesize that NCTD could prevent β-catenin nuclear translocation, impair the stemness and reduce the metastasis of TNBC. However, the inherent features of short half-life and nephrotoxicity hinder NCTD's further in vivo application. The goal of this study was to test the therapeutic effect of targeting β-catenin pathway by nanoparticle-mediated delivery of NCTD against TNBC.
Experimental Design NCTD was loaded into an integrin α5 targeting nanoparticle (NP) (RGD-LPH) via complexing with polyethyleneimine. The targeting efficiency of RGD-LPH was tested by the in vivo imaging of RGD-LPH labeled by cyanine 7.5 (cy7.5). The effects of NP-mediated delivery NCTD on TNBC cell malignant behaviors and tumor metastasis were tested in various in vitro and in vivo models.
Results We found that RGD-LPH NP-mediated delivery of NCTD significantly reduced the active and total β-catenin levels as evidenced by Western Blot. The self-renewal capacity was remarkably blocked by RGD-LPH, as examined by sphere formation. RGD-LPH also suppressed features of cancer cells related to proliferation, as examined by MTT, clonogenic assay and soft agar colony formation. In particular, compared to free NCTD, RGD-LPH demonstrated extended-release profile and long-last effect in the
long-term experiments such as clonogenic assay and soft agar colony formation assay. In vivo, systemic delivery of RGD-LPH(cy7.5) indicated a preferential uptake in primary tumor and lung of the tumor-bearing mice. Efficacy studies indicated reduced metastasis of mice from RGD-LPH treatment.
Conclusion: Collectively, our results strongly suggest that NCTD being encapsulated in RGD-LPH, which warrants further development for preclinical and clinical studies as a novel TNBC therapeutic approach, is a robust modulator of Wnt signaling with anti-metastasis activity.
Citation Format: Yunfei Li, Zhishan Wang, Yajuan Xiao, Chengfeng Yang. Targeting β-catenin pathway by nanoparticle-mediated delivery of norcantharidin impairs the stemness of triple negative breast cancer 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 3713.
Abstract 3717: α3β1-Integrin targeted DM1 micellar prodrug for targeted therapy against ovarian cancer
Authors: Li Xiaocen , Xiao Wenwu , Wang Yayu , Chen Xiaojia , Liu Ruiwu , Lam Kit S. 
Published: August 2018

Abstract
Ovarian cancer ranks fifth in cancer deaths among women in America. The standard treatment for advanced stages ovarian cancer consists of primary debulking surgery followed by i.v. and i.p. chemotherapy. DM1, or mertansine, is a thiol-containing maytansinoid, that inhibits microtubule assembly and kills various cancer cells at low nM concentration. However, its application in the clinic has been hampered by severe toxic side effects1. Its trastuzumab conjugate (T-DM1), which was approved by the FDA in 2013, is a promising therapeutic agent for patients harboring ovarian cancers with high Her-2 expression2. However, the general limitation for antibody drug conjugates (ADCs) is low drug content, high clearance by the reticuloendothelial, and high manufacturing cost. To overcome this, we designed and synthesized a novel PEG-based, cholic acid/ DM1 hybrid telodendrimer (PEG5k-CA4-DM1) comprised of one DM1 molecule and three molecules of maleimide per telodendrimer, which self-assembled into 25nm nanomicelles for targeted therapy against ovarian cancer. To enhance the stability of this nanoparticle, PEG5k-Cys4-CA8, which contain 4 thiol groups per telodendrimer is formulated together with PEG5k-CA4-DM1 at a ratio of 2:5, to generate thiol/maleimide crosslinked DM1 micellar prodrug (DM1-nano). To further enhance its tumor-targeting ability, the surface of DM1-nano was decorated with LXY30 via a hydrophilic “stealth” linker (EK)3, using copper-free ‘Click' chemistry. LXY30 is a potent and specific ligand against α3β1 integrin which is overexpressed on the surface of many epithelial cancer cells including a panel of ovarian cancer cell lines (e.g. SKOV-3). Compared with free DM1 and non-targeted DM1-nano, LXY30-EK-DM1-nano not only prevented premature drug release, but also further enhanced tumor targeting ability, drug solubility and in vivo circulation time in blood. When loaded with a fluorescent dye (DiD), LXY30-EK-DM1-nano was found to (i) internalize inside SKOV-3 cells in vitro, (ii) significantly accumulated at the tumor site of SKOV-3 xenograft mice, and (iii) exhibit potent anti-cancer activity in vitro (IC50=26nM with SKOV-3 cells) and in vivo (SKOV-3 xenograft model). In addition, LXY30-EK-DM1-nano was found to be significantly more efficacious and less toxic than free DM1 and non-targeted DM1-nano. In conclusion, the LXY30-DM1-nano offers a promising novel nanotherapeutic agent against ovarian cancer.
Citation Format: Xiaocen Li, Wenwu Xiao, Yayu Wang, Xiaojia Chen, Ruiwu Liu, Kit S. Lam. α3β1-Integrin targeted DM1 micellar prodrug for targeted therapy against ovarian 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 3717.
Abstract 3728: α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in KC and KPC mice
Authors: Verma Raj K. , Yu Wei , Shrivastava Anju , Srivastava Rakesh K. , Shankar Sharmila 
Published: August 2018

Abstract
Activation of sonic Hedgehog (Shh) in cancer stem cell (CSC) has been demonstrated with aggressiveness of pancreatic cancer. In order to enhance the biologic activity of α-mangostin, we formulated mangostin-encapsulated PLGA nanoparticles (Mang-NPs) and examined the molecular mechanisms by which they inhibit human and KC mice (PdxCre;LSL-KrasG12D) pancreatic CSC characteristics in vitro, and pancreatic carcinogenesis in KPC (PdxCre;LSLKrasG12D;LSL-Trp53R172H) mice. Mang-NPs inhibited human and KrasG12D mice pancreatic CSC characteristics in vitro. Mang-NPs also inhibited EMT by upregulating E-cadherin and inhibiting N-cadherin and transcription factors Slug, and pluripotency maintaining factors Nanog, c-Myc, and Oct4. Furthermore, Mang-NPs inhibited the components of Shh pathway and Gli targets. In vivo, Mang-NPs inhibited the progression of pancreatic intraneoplasia to pancreatic ductal adenocarcinoma and liver metastasis in KPC mice. The inhibitory effects of Mang-NPs on carcinogenesis in KPC mice were associated with downregulation of pluripotency-maintaining factors (c-Myc, Nanog and Oct4), stem cell markers (CD24 and CD133), components of Shh pathway (Gli1, Gli2, Patched1/2, and Smoothened), Gli targets (Bcl-2, XIAP and Cyclin D1), and EMT markers and transcription factors (N-cadherin, Slug, Snail and Zeb1), and upregulation of E-cadherin. Overall, our data suggest that Mang-NPs can inhibit pancreatic cancer growth, development and metastasis by targeting Shh pathway.
Citation Format: Raj K. Verma, Wei Yu, Anju Shrivastava, Rakesh K. Srivastava, Sharmila Shankar. α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in KC and KPC mice [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 3728.
Abstract 3735: Somatostatin receptor-based imaging and treatment of murine pancreatic neuroendocrine tumors induced by MEN1-loss
Authors: Li Janet W. , Zhang Hanwen , Carlin Sean D. , Raj Nitya , Klimstra David S. , Libutti Steven K. , Weber Wolfgang A. , Reidy-Lagunes Diane , Untch Brian R. 
Published: August 2018

Abstract
Background: Somatostatin receptor ligands are used for the detection and treatment of neuroendocrine tumors. Mutations of MEN1 are frequently observed in human pancreatic neuroendocrine tumors (PanNETs). We utilized a previously described murine model of PanNET that harbors a floxed Men1 allele to study the feasibility of somatostatin receptor type 2 (SSTR2) imaging and therapy in mice. Methods: Mice with pancreatic-specific expression of Cre recombinase and floxed Men1 (Pdx1-cre, Men1f/f) were aged to 9-12 months to allow for the development of PanNETs. Mice were injected with either the SSTR2 agonist 68Ga-DOTA-TATE or antagonist 177Lu-DOTA-JR11 via tail vein. Imaging with 68Ga-DOTA-TATE was performed using PET/CT. Percent uptake of injected activity was calculated for visualized tumors. 177Lu-DOTA-JR11 binding was visualized with autoradiography. Immunofluorescence (IF) detected SSTR2 expression and a marker of DNA damage (γ-H2AX). Results: IF staining for SSTR2 showed membranous localization of the receptor limited to areas of neoplasia with high and low levels of SSTR2 expression variable by individual animal and tumor. Tumors were successfully detected in mice injected with 68Ga-DOTA-TATE using PET/CT. The mean maximum percent uptake of injected activity for visualized tumors was 2.8% +/- 0.34. Injection of 177Lu-DOTA-JR11 and subsequent autoradiography confirmed localization of radionuclide to areas of histology-confirmed neoplasia. Treatment effect (DNA damage) was observed with co-localization of γ-H2AX and SSTR2 staining in neoplastic areas as compared to hyperplastic islets and normal pancreatic parenchyma that were both SSTR2 and γ-H2AX negative. Conclusion: PanNETs from Pdx1-cre, Men1f/f mice can be successfully imaged and treated using somatostatin-based radionuclides. This genetically accurate model can be employed to study peptide receptor radionuclide therapy efficacy and toxicity either alone or in combination with other treatment strategies.
Citation Format: Janet W. Li, Hanwen Zhang, Sean D. Carlin, Nitya Raj, David S. Klimstra, Steven K. Libutti, Wolfgang A. Weber, Diane Reidy-Lagunes, Brian R. Untch. Somatostatin receptor-based imaging and treatment of murine pancreatic neuroendocrine tumors induced by MEN1-loss [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 3735.
Abstract 3741: Deciphering the regulome of androgen receptor variants in prostate cancer
Authors: Daniel Mark L. , Hickey Theresa E. , Carroll Jason S. , Tilley Wayne D. , Selth Luke A. , Dehm Scott M. 
Published: August 2018

Abstract
Prostate cancer is an androgen-dependent disease. Androgen function is controlled by the androgen receptor (AR), and treatments targeting AR are effective at preventing disease progression. Despite this, resistance and emergence of castration resistant prostate cancer (CRPC) is responsible for virtually all prostate cancer-related death. Constitutively active AR variants (AR-Vs) have been implicated as drivers of CRPC. AR-Vs consist of the unstructured AR NH2-terminal domain (NTD), and the AR DNA binding domain, but lack the ligand binding domain (LBD), which is targeted by all current therapies. While our understanding of proteins that regulate the AR LBD is mature, there is less known about the molecular regulation of the NTD. This represents a gap in knowledge given that the AR NTD is essential for AR/AR-V transcriptional activity. To address this, we used a technique termed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (RIME) with a pair of isogenic prostate cancer cell lines that were manipulated via genome engineering to express either full-length AR or AR-V. RIME identified several candidate proteins that interact with the AR NTD including BCL9, a β-catenin transcriptional coactivator. Interrogation of public databases revealed that BCL9 mRNA is overexpressed in metastatic prostate cancer compared with localized disease. Additionally, knockdown of BCL9 in cell lines expressing full-length AR inhibited expression of AR target genes as well as β-catenin target genes. Interestingly, knockdown of BCL9 did not affect these same genes in cell lines expressing AR-Vs, indicating that AR truncation could represent a mechanism of escape from BCL9 regulation. Collectively, these findings identify a new mechanism of AR regulation by BCL9 in prostate cancer.
Citation Format: Mark L. Daniel, Theresa E. Hickey, Jason S. Carroll, Wayne D. Tilley, Luke A. Selth, Scott M. Dehm. Deciphering the regulome of androgen receptor variants in prostate 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 3741.
Abstract 3750: Xenoestrogens cause estrogen receptor-dependent R-loop formation and DNA damage
Authors: Dunphy Karen A. , Majhi Prabin Dhangada , Sharma Aman , Roberts Amy L. , Daniele Elizabeth A. , Schneider Sallie S. , Jerry D Joseph 
Published: August 2018

Abstract
Background: The hormone 17β-estradiol (E2) plays an important role in breast cell proliferation and development but prolonged exposures and higher levels of E2 have been linked to genomic instability and breast cancer. Recent studies show E2 induced transactivations lead to DNA damage. A variety of environmental chemicals mimic the activities of estrogen, referred to as xenoestrogens. Thus, our hypothesis is to determine whether xenoestrogens stimulate transcriptional response and induce DNA damage similarly like E2.
Methods: The T-47D breast cancer cell line is used as a model because it expresses both estrogen receptors (ERα & ERβ) as found in normal breast tissue. Cells were exposed a physiologic range of E2 (17β-estradiol) [0.5-100nM] and the xenoestrogens, e.g., benzophenone-3 (BP-3) [0.5-50µM] and propyl paraben (PP) [0.5-10µM] with or without ER-antagonist ICI (1µM) for 24 hours. Transcriptional responses were quantified using an integrated ERE-luciferase reporter and qPCR for endogenous genes. Proliferation was monitored using the Alamar Blue assay. DNA damage was determined using γ-H2AX. R-loops were detected using the S9.6 antibody against DNA-RNA hybrids in the genome.
Results: Exposure of T-47D cells to physiologic levels of E2, PP and BP3 causes significant increase in DNA double-strand breaks (DSBs) as determined by γ-H2AX staining. We demonstrate a concomitant increase in R-loop formation with increase in γH2AX intensity. Treatment with RNaseH depletes R-loop intensity, corroborating the result. E2 and PP induce transactivation as determined by Luciferase reporter assay as well as expression of ER-response genes (PGR and AREG), whereas BP3 has modest effect on transactivation of PGR. ER transactivation as well as R-loop formation by E2, PP and BP3 were abrogated with ICI, demonstrating ER-dependency of R-loop formation. Consistent with the transcriptional response, proliferation studies determined that E2 showed highest proliferation followed by PP. However, BP3 showed no increase in proliferation.
Conclusions: Our results show that xenoestrogens have strikingly different activities in transactivation and proliferation. However, both xenoestrogens appear to stimulate R-loop accumulation that leads to DSB in an ER-dependent manner.
Citation Format: Karen A. Dunphy, Prabin Dhangada Majhi, Aman Sharma, Amy L. Roberts, Elizabeth A. Daniele, Sallie S. Schneider, D Joseph Jerry. Xenoestrogens cause estrogen receptor-dependent R-loop formation and DNA damage [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 3750.
Abstract 3764: Porcupine inhibitor RXC004 enhances immune response in pre-clinical models of cancer
Authors: Bhamra Inder , Armer Richard , Bingham Matilda , Eagle Catherine , Cook Alicia Edmenson , Phillips Caroline , Woodcock Simon 
Published: August 2018

Abstract
Background: RXC004, a potent and selective porcupine (PORCN) inhibitor, is being investigated in a safety and tolerability study in cancer patients with solid tumours (CT 2017-000720-98). In addition to the tumour targeting role of RXC004 and other Wnt pathway inhibitors, we present pre-clinical data which suggests further potential for RXC004 in modulating the immune system of the tumour microenvironment. Materials and Methods: To evaluate the potential of a novel porcupine inhibitor, RXC004, as an immunomodulatory anti-cancer agent, sub cutaneous B16F10 melanoma (C57BL/6 mice) and CT26 colorectal (BALB/c mice) murine tumour models were utilised. Mice in both models were treated with RXC004 alone or in combination with mouse anti-PD-1 antibody. Flow cytometry analysis was utilised to measure key immune cell populations in the tumour microenvironment. To probe the underlying mechanism of immune modulation in these models and to provide a link to the emerging clinical data suggesting a role for Wnt pathway activation in immune escape, human monocytic cells were isolated from PBMCs and human dendritic cells were derived in vitro. The Wnt pathway was induced in derived Dendritic cells and expression of IDO was measured. Results: In the murine CT26 model, RXC004 treatment reduced tumour size when dosed in combination with anti-PD-1 antibody, causing regression and cures in some animals. Furthermore, flow cytometry showed RXC004 in combination with anti-PD-1 antibody increased the proportion of CD8+ cytotoxic T cells as well as decreasing FoxP3+ regulatory T cells when compared to the monotherapy anti-PD-1 arm. In a syngeneic murine melanoma B16F10 model, RXC004 monotherapy at a dose of 5mg/kg QD orally significantly inhibited tumour growth, as did RXC004 combined with anti-PD-1. RXC004 had no effect on the proliferation of B16F10 cells in vitro, suggesting this was not caused by the compound directly affecting B16 cell proliferation. Flow cytometry analysis of the B16 tumours showed significant immune modulatory effects in the tumour microenvironment. In addition to mouse model data, Wnt pathway activation in human dendritic cells was shown to increase IDO expression. Conclusion: Taken together, data from murine syngeneic mouse models corroborate literature data suggesting that inhibiting the Wnt pathway may promote the immune response against human cancers.
Citation Format: Inder Bhamra, Richard Armer, Matilda Bingham, Catherine Eagle, Alicia Edmenson Cook, Caroline Phillips, Simon Woodcock. Porcupine inhibitor RXC004 enhances immune response in pre-clinical models of 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 3764.
Abstract 3771: Mechanistic and pharmacodynamic characterization of the immuno-oncological activity of RXDX-106, a novel TYRO3, AXL, and MER (TAM) inhibitor in clinical development
Authors: Albert Amanda , Lew Erin D. , Smith Kristen , Tindall Elizabeth A. , Yokoyama Yumi , Diliberto Amy , Ely Heather , Lee Jack , Nevarez Robin , Oh Joanne , Walsh Colin , Christiansen Jason , Li Gary , Shoemaker Robert 
Published: August 2018

Abstract
The TAM family of receptor tyrosine kinases (RTKs) includes TYRO3, AXL, and MER, and is a unique set of molecular targets for cancer immunotherapy. TAM RTKs play a key role in the tumor microenvironment (TME) as negative regulators of innate immune responses and contribute to the evasion of cancer cells from immunosurveillance. RXDX-106 is a novel small molecule TAM inhibitor with single-digit nanomolar kinase inhibition and slow dissociation binding kinetics resulting in potent and durable target inhibition. In preclinical studies, RXDX-106 has demonstrated immune-mediated single agent in vivo activity in multiple syngeneic tumor models and potentiated anti-tumor activity in combination with immune checkpoint inhibitors. To characterize the mechanism of action of and pharmacodynamic responses to RXDX-106 treatment, an integrated approach was employed to explore RXDX-106-mediated immune modulatory effects at the cellular, protein, and transcriptional levels. In syngeneic tumor models, RXDX-106 treatment resulted in the recruitment of both innate and adaptive immune cell subtypes to the TME. Specifically, RXDX-106 treatment resulted in increased immune cell infiltration, macrophage polarization towards an antitumor M1 phenotype, activation of T cell and NK cell function, and modulation of immune markers at both the protein and RNA level, indicative of a pro-inflammatory and anti-tumorigenic effect. Importantly, the immune modulatory effects of RXDX-106 were concordant across platforms. Immune modulation was further characterized in a dose-dependent manner, with increasing immune cell infiltration observed with escalating doses of RXDX-106. In summary, RXDX-106 has the potential to restore and enhance immune function by modulating the local immunosuppressive TME. The unique mechanism of activating both innate and adaptive immunity, and regulating cross-talk between immune cells and tumor cells, supports clinical evaluation of RXDX-106 as an immunomodulatory agent for the treatment of a variety of cancers.
Citation Format: Amanda Albert, Erin D. Lew, Kristen Smith, Elizabeth A. Tindall, Yumi Yokoyama, Amy Diliberto, Heather Ely, Jack Lee, Robin Nevarez, Joanne Oh, Colin Walsh, Jason Christiansen, Gary Li, Robert Shoemaker. Mechanistic and pharmacodynamic characterization of the immuno-oncological activity of RXDX-106, a novel TYRO3, AXL, and MER (TAM) inhibitor in clinical development [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 3771.