bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B42: The sigma-2 receptor as a target for therapeutic drug delivery in triple negative breast cancer
Authors: Makvandi Mehran , Tilahun Estifanos D. , Lieberman Brian P. , Xu Kuiying , Zeng Chenbo , Hou Catherine , Mach Robert H. 
Published: May 2016

Abstract
Introduction: Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer and typically results in poor patient prognosis. While other breast cancer subtypes benefit from targeted therapies, TNBC currently has no approved agents. The sigma-2 receptor has been validated as a proliferation marker and also a site for therapeutic drug delivery in ovarian and pancreatic cancer. In this study we evaluated the sigma-2 receptor as a target for therapeutic drug delivery in TNBC using a sigma-2 targeting vehicle conjugated to a small molecule activator of caspases(SMAC) mimetic, SW-IV-134.
Methods: Triple negative breast cancer cell lines; MDA-MB-231, HCC1937 and HCC1806 were tested for sensitivity to sigma-2 targeted compound SW-IV-134 vs. Taxol or the deconstructed conjugate subparts. 2 hr and 48 hr treatments we assessed to determine whether there was a significant in vitro targeting effect. Sigma-2 expression was quantified through radioligand saturation studies using cell homogenate tissue and the Ki value of SW-IV-134 for the sigma-2 receptor was calculated through competitive inhibition studies. Caspase 3/7 activation was assessed after 2 or 48 hr treatments.
Results: SW-IV-134 was the most potent treatment in MDA-MB-231 and HCC1937, while no difference from taxol was found in HCC1806. Sigma-2 receptor expression was found to be the highest in the MDA-MB-231 and no difference was found in HCC1937 and HCC1806. The Ki of SW-IV-134 for the sigma-2 receptor was 23 nM and is consistent with previously reported values. Caspase 3/7 activation was detected in all cell lines following treatment at 2 and 48 hr. The greatest caspase 3/7 activation was observed in the MDA-MB-231 cell line.
Conclusion: The sigma-2 receptor is expressed at different levels on the three TNBC cell lines and the receptor expression corresponds to therapeutic efficacy. SW-IV-134 was the most potent therapeutic tested in two of the three cell lines with no difference between taxol observed in HCC1806. This study shows the sigma-2 receptor is a target that can be exploited for therapeutic drug delivery in three TNBC cell lines and may provide a platform for future targeted therapy development for TNBC.
Citation Format: Mehran Makvandi, Estifanos D. Tilahun, Brian P. Lieberman, Kuiying Xu, Chenbo Zeng, Catherine Hou, Robert H. Mach. The sigma-2 receptor as a target for therapeutic drug delivery in triple negative breast cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B42.
Abstract B44: Sulfated fucan inhibits tumor interaction with endothelial cells and tumor growth: Possible contribution of an antivascular endothelial growth factor (VEGF) neutralizing activity
Authors: Mignone Viviane , Figueiredo Camila Castro , Oliveira Aline , Kozlowski Eliene , Borsig Lubor , Pavão Mauro , Mourão Paulo , Morandi Veronica 
Published: May 2016

Abstract
The primary interaction between tumor and endothelial cells is mediated by endothelial selectins and sialyl-Lewis carbohydrates found on cancer cell surface. Heparin, a sulfated polysaccharide, binds to P- and L-selectins, an effect that has been associated with attenuation of metastasis. However, due to its strong anticoagulant activity, its use in anti-tumor therapy is restricted. Sulfated fucans from sea urchins have simple, unique structures of linear chains of sulfated α-L-fucose in well-defined repetitive patterns. In this study, we tested five sulfated fucans from different species of sea urchins for their ability to interfere with the tumor-endothelium interaction and compared our findings to those obtained with heparin. Our results show that sulfated fucan from L. variegatus (FucSulf I), bearing an unique 2,4-disulfated fucose residue and low anticoagulant activity, inhibits the adhesion of tumor cells to endothelium, tumor transendothelial migration and endothelial cell tubulogenesis, both by inhibiting P-selectin mediated tumor cell adhesion, and VEGF-dependent signaling in endothelial cells. FucSulf I also inhibited proliferation of several types of tumor cell lines in vitro and tumor growth in vivo. Our results indicate this sulfated fucan is a potential antitumor agent and a possible therapeutic alternative to heparin.
Citation Format: Viviane Mignone, Camila Castro Figueiredo, Aline Oliveira, Eliene Kozlowski, Lubor Borsig, Mauro Pavão, Paulo Mourão, Veronica Morandi. Sulfated fucan inhibits tumor interaction with endothelial cells and tumor growth: Possible contribution of an antivascular endothelial growth factor (VEGF) neutralizing activity. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B44.
Abstract IA01: Immune checkpoint blockade in cancer therapy: New insights, opportunities, and prospects for cures
Authors: Allison James P. 
Published: May 2016

Abstract
The existence of multiple non-redundant inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen presenting cells. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (&gt;4 years) survival benefit in about 20% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease.
The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms.
PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25%. A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients.
Emerging data suggest that T cell responses are largely directed toward neoantigens arising as a result of mutational events associated with the carcinogenesis. While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, it is becoming clear that certain types of tumors with lower burdens of mutations (eg. prostate, breast, and kidney cancer) present special challenges for immune therapy. Strategies for effective treatment of such tumors will be discussed.
Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights, opportunities, and prospects for cures. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA01.
Abstract IA03: From the clinic to the lab: Investigating immune responses to immune checkpoint therapies
Authors: Sharma Padmanee 
Published: May 2016

Abstract
Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1 and anti-PD-L1, have led to significant clinical responses in cancer patients. To investigate immunologic changes and mechanistic pathways that are elicited by these therapies, we conducted pre-surgical clinical trials, which permit access to sufficient tumor tissues for laboratory studies. The first pre-surgical trial was conducted with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. This trial provided access to sufficient tumor-infiltrating lymphocytes to conduct phenotypic and functional studies on these cells, which indicated the ICOS/ICOSL pathway as relevant for anti-tumor immune responses in the setting of anti-CTLA-4 therapy. In addition, since standard agents that enable tumor cell death may allow for priming of a T cell immune response that can be augmented by combination with CTLA-4 blockade, we conducted a pre-surgical clinical trial with androgen deprivation (hormonal) therapy ADT+ anti-CTLA-4 (ipilimumab), in the setting of patients with regional, high-risk prostate cancer. These pre-surgical clinical trials, and other tissue-based clinical trials, led to the identification of biomarkers and additional targets. These data, which are being used to design future immunotherapy trials, will be discussed in greater details.
Citation Format: Padmanee Sharma. From the clinic to the lab: Investigating immune responses to immune checkpoint therapies. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA03.
Abstract IA17: Deciphering cancer genome evolution in heterogenous tumors
Authors: McGranahan Nicholas 
Published: May 2016

Abstract
Cancer drug resistance is almost inevitable in the majority of patients with advanced metastatic tumors. Intratumor heterogeneity, facilitating rapid tumor evolution, is one of the main causes of tumor adaptation and resistance to cancer therapies.
In this talk I will explore how cancer genome sequencing data can shed light on diversity within tumors and the processes shaping cancer genome evolution over space and time.
Harnessing both extensive multi-region and single-sequencing data we have investigated intra-tumor heterogeneity across 10 major cancer types, focusing on non-small cell lung cancer, clear cell renal cell carcinoma, and esophageal adenocarcinoma. I will discuss our findings shedding light on the extent to which mutations in known driver genes, and “actionable mutations,” linked to targeted therapies, are clonal or subclonal. Tumor phylogenies and whether patterns of tumor evolution can be deciphered in these cancer types will also be explored.
Temporal dissection of mutational signatures across cancer types will be used to reveal the dynamics of mutational processes during tumor evolution. I will explore how APOBEC mediated-mutagenesis can be linked to branched tumor evolution, and the acquisition of subclonal driver events across cancer types.
Finally, the challenges and clinical implications of intratumor heterogeneity will be discussed.
Citation Format: Nicholas McGranahan. Deciphering cancer genome evolution in heterogenous tumors. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA17.
Abstract IA25: Identifying and profiling tumor specific T cells using mass cytometry and highly multiplexed peptide-MHC tetramer staining
Authors: Newell Evan W. 
Published: May 2016

Abstract
Antigen specific T cells are critical initiators and orchestrators of the adaptive immune response. To better understand how T cells participate (appropriately or inappropriately) in the immune response to cancer, more meaningful categorizations of these cells are needed. For this purpose, a very large number of cellular parameters can be considered. Focusing on human CD8+ T cells, the utility of high dimensional mass cytometry (i.e., Cytometry by Time-Of-Flight, CyTOF) analysis will be discussed. By this approach, T cells can be probed with unprecedented detail by simultaneously evaluating surface marker expression, functional capacity and antigen-specificity. For antigen-specificity, this analysis can be performed in conjunction with a highly multiplexed method based on peptide-MHC tetramers, which allows simultaneous assessment of &gt;500 different antigen specificities in a single sample. To visualize and understand the diversity of these cells, several computational data analysis approaches are being used. Application of these approaches to identify and phenotypically profile various cancer specific T cells in humans as well as in mouse models will be described. In addition to the possibility of finding novel therapeutic targets, a long-term goal of this work is to discover more accurate biomarkers of clinical outcomes (e.g., responsiveness to immunotherapy) based on the high-dimensional characteristics of antigen-specific T cells.
Citation Format: Evan W. Newell. Identifying and profiling tumor specific T cells using mass cytometry and highly multiplexed peptide-MHC tetramer staining. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA25.
Abstract IA35: Discovery of porcupine inhibitors targeting Wnt signaling in cancer
Authors: Pan Shifeng , Liu Jun , Cheng Dai , Han Dong , Zhang Guobao , Hsieh Mindy , Ng Nicholas , Li Chun , Kasibhatla Shailaja , McNamara Peter , Seidel H. Martin , Harris Jennifer 
Published: May 2016

Abstract
Wnt signaling is tightly controlled during cellular proliferation, differentiation and embryonic morphogenesis. Aberrant activation of this pathway plays a critical role in a variety of cancers. Blockade of Wnt signaling is therefore an attractive therapeutic approach for anticancer therapy. In this presentation, we will discuss our approach to search for inhibitors of Wnt ligand secretion. We developed and performed a cellular high-throughput screen using a co-culture system. Lead structure (GNF-1331) was identified and further target elucidation revealed Porcupine, a membrane bound O-acyl transferase, as its molecular target. Further structure-activity relationship studies led to the discovery of WNT974, a potent and specific Porcupine inhibitor. Treatment of WNT974 leads to tumor regression in a Wnt dependent MMTV-Wnt1 mouse model at well tolerated doses. WNT974 is currently in Phase 1 clinical trials.
Citation Format: Shifeng Pan, Jun Liu, Dai Cheng, Dong Han, Guobao Zhang, Mindy Hsieh, Nicholas Ng, Chun Li, Shailaja Kasibhatla, Peter McNamara, H. Martin Seidel, Jennifer Harris. Discovery of porcupine inhibitors targeting Wnt signaling in cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA35.
Abstract A01: ER stress disrupts circadian rhythms via miR-211
Authors: Bu Yiwen , Diehl John Alan 
Published: May 2016

Abstract
The Endoplasmic Reticulum, ER, senses both intracellular and extracellular stimuli that perturb the folding and maturation of secretory proteins that transit the ER. In the context of neoplastic growth, oncogenes such as c-Myc, H-Ras and BRAF trigger ER stress and activate the Unfolded Protein Response (UPR), a cell adaptive signaling pathway composed of three primary signal transducers, PERK, IRE-1 and ATF6.
Bmal1 and Clock form a core heterodimeric transcription complex regulates both central and peripheral circadian rhythms. There are multiple lines of evidence suggesting that deregulation of circadian rhythms contribute to neoplastic cell growth, altered cellular metabolism and tumorigenesis. Analogously, UPR signaling contributes to tumor cell survival and tumor growth under conditions of micro-environmental and metabolic stress. However, whether UPR interactively regulates stress with the circadian clock is largely unknown.
Herein, we describe the molecular mechanisms whereby UPR signaling integrates with the circadian clock. We provide evidence that ER stress-dependent activation of PERK alters circadian oscillations via micro-RNA 211-dependent suppression of BMAL1 and Clock. We provide evidence that the mechanism of regulation of BMAL1 versus clock is distinct, reflecting novel ability of miR-211 to function in both the nucleus and cytoplasm. We provide additional support for this model through using a mouse model to interrogate the role of PERK signaling in a liver specific response to ER stress. With regard to the impact of PERK signaling and circadian clock disruption in cancer, we assessed PERK-miR-211 signaling in c-Myc and MLL-AF9 driven malignancy. Here, expression of either c-Myc or MLL-AF9 expression was directly associated with activation of PERK-miR-211 and loss of both BMAL1 and Clock expression. We also found that Myc driven human Burkitt's lymphoma has PERK hyperactivation, higher miR-211 expression, and loss of circadian oscillations. As the Bmal1 promoter is hypermethylated in multiple lymphoma cancer cell lines, we hypothesize that this is likely to reflect the action of nuclear miR-211. Consistently, anti-miR211 partially released Bmal1 repression and Inhibition PERK or suppression miR-211 rescued circadian rhythms in lymphoma cells thereby affecting their survival and proliferation. Our data suggested a model where ER stress disrupts peripheral circadian rhythms via PERK-miR211-Bmal1/Clock pathway. Targeting activated ER stress or abnormal miR-211 expression to rescue circadian rhythms could be a new potential therapy for Myc- (perhaps also other oncogenes) driven hematological malignancy.
Citation Format: Yiwen Bu, John Alan Diehl. ER stress disrupts circadian rhythms via miR-211. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A01.
Abstract A05: Retrotransposon-derived RNAs in regulating cancer-related alternative splicing
Authors: Zhou Zhihong , Wang Cheng , Hu Qidong 
Published: May 2016

Abstract
Cancer features uncontrollable growth of transformed or dedifferentiated cells. The prevalent treatment options include surgery, chemotherapy, radiation therapy, targeted therapy and transplantation. In particular, chemotherapy is designed to suppress cell growth, cause cell death and prevent cancer spread. However, the drug often kills healthy cells indiscriminately and becomes ineffective in the initially responsive patients who are then faced with an even more devastating situation. It has been suggested that there is a reciprocal feedback loop between pre-mRNA alternative splicing and chemotherapy-mediated DNA damage, hence we have investigated the potential role of pre-mRNA alternative splicing in causing resistance to chemotherapy, especially the platinum-based drug, cisplatin.
In this study, we examined the expression of SR protein-specific kinases (SRPKs) and their post-translational modification in normal and cisplatin-treated Hela and MCF7 cells. While the expression of SRPK1 and SRPK2 were initially downregulated by cisplatin, the acetylated forms of these proteins were actually enhanced dramatically. Furthermore, in the established resistant cell lines, their expression was restored. The loss-of-function experiments using the siRNA knockdown, acetylation inhibitor and HAT-deficient TIP60 suggested that the acetylated SRPKs could confer the cisplatin resistance to the cancer cells by increasing the expression of those pro-growth proteins and isoforms, such as Myc, Bcl-2, Bcl-XL and CCND1b. Remarkably, in the treated and resistant cancer cells, we observed the induced expression of Alu repeats, a large family of retrotransposons with over a million copies in the human genome. These retrotransposon-derived RNAs are associated with the downstream factors of SRPKs, SR proteins. Depletion of the Alu transcripts would re-sensitize the resistant cells to cisplatin. In particular, we observed that the induced expression of Alu RNAs was required for the generation of those pro-growth proteins, possibly through interacting and synergizing with the SR proteins. Hence, the study provides novel insights into the drug resistance mechanism and will help to develop new ways of targeting retrotransposon RNAs to overcome this haunting problem in cancer treatment.
Citation Format: Zhihong Zhou, Cheng Wang, Qidong Hu. Retrotransposon-derived RNAs in regulating cancer-related alternative splicing. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A05.
Abstract A22: Functional long noncoding RNAs in castration-resistant prostate cancer
Authors: Fei Teng , Chen Yiwen , Liu Xiaole Shirley , Brown Myles 
Published: May 2016

Abstract
Prostate cancer progression from an androgen-dependent state to an androgen-independent phase, which is also referred to castration-resistant prostate cancer (CRPC), not only results in cancer refractory to androgen deprivation therapy but also marks lethal prognosis. Androgen receptor (AR) plays central roles in both normal prostate development and prostate cancer progression. Aberrant androgen/AR signaling activity is often associated with the development of CRPC, such as increased synthesis of steroid hormone, increased expression of AR, emergence of specific AR variants etc. However, deeper understanding of detailed mechanism of CRPC development is still necessary in order to discover novel effective drug targets for the treatment of CRPC. Recent studies suggest that long non-coding RNA (lncRNA) can be extensively functional rather than just transcriptional noise and lncRNAs are also widely involved in the pathogenesis of different types of cancers including prostate cancer. To further investigate the potential role of lncRNAs during prostate cancer progression, we profiled lncRNA transcriptome using RNA-seq in prostate cancer cells in the presence or absence of androgen treatment. In combination with AR cistrome data, we identified a set of lncRNAs that are directly regulated by androgen/AR signaling. A specific lncRNA was identified as androgen/AR repressed target gene in androgen-dependent cells while showing significant higher expression in androgen-independent cells that mimics CRPC state. Interestingly, knockdown of this lncRNA specifically attenuates the growth of androgen-independent cells while has little effect on androgen-dependent cells. To understand the detailed mechanism, we identified the downstream target genes using RNA-seq upon silencing this lncRNA in either androgen-dependent or -independent cells. Moreover, this lncRNA is located in a region that is frequently amplified in CRPC and highly expressed in a subset of CRPC patients. We suggest that this lncRNA, along with other androgen/AR targets, may play a role during the development of CRPC and could serve as a potential drug target for the treatment of CRPC.
Note: This abstract was not presented at the conference.
Citation Format: Teng Fei, Yiwen Chen, Xiaole Shirley Liu, Myles Brown. Functional long noncoding RNAs in castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A22.