bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3679: PD-L1 driven excluded phenotype in melanoma
Authors: Morrison Carl , Conroy Jeffrey , Nesline Mary , Glenn Sean , Burgher Blake , Qin Maochun , Andreas Jonathan , Giamo Vincent , Lenzo Felicia L. , Omilian Angela , Bshara Wiam , Papanicolau-Sengos Antonios , Wang Yirong , Ernstoff Marc , Gardner Mark , Pabla Sarabjot 
Published: August 2018

Abstract
Background: The excluded phenotype has been previously described by the presence of abundant immune cells that do not penetrate the parenchyma of these tumors but instead are retained in the stroma that surrounds nests of tumor cells. These features support a pre-existing anti-tumor immune-related response, but the details of this mechanism are not well elucidated.
Methods: 300 formalin-fixed, paraffin-embedded (FFPE) metastatic cutaneous melanoma samples were evaluated by the RNA-seq component of a comprehensive immune profile panel to measure transcript levels of immune-related genes. Resultant data was QC filtered, normalized and ranked based on an assorted reference population of various tumor types. The expression of PD-L1 on the surface of tumor cells was assessed in tumor samples by means of an automated IHC assay (28-8, Dako). A tumor was considered PD-L1 positive if ≥1% of viable tumor cells exhibited complete circumferential or partial linear plasma membrane staining at any intensity. Excluded pattern of T-cell infiltration was defined by CD8 immunohistochemistry by the following definition: Restriction of more than 95% of all CD8+ T-cells present in a tumor to the periphery or interstitial stromal areas and not actively invading nest or groups of neoplastic cells.
Results: The excluded phenotype was identified in 34 of 300 (11%). PD-L1 by IHC was positive (≥1%) in the neoplastic cases in 16 of 34 (47%) cases. Membranous staining in immune cells was identified in only 3 of 34 (9%) cases, but was present in &gt;90% of all cases in a non-membranous pattern. In more than one-half of all cases the non-membranous pattern of PD-L1 IHC staining was restricted to the excluded TILs. Higher expression of PD-L1 by RNA-seq was associated with this excluded PD-L1 pattern of staining.
Conclusion: In 300 metastatic cutaneous melanoma cases we demonstrated that the excluded phenotype is frequent and represents ~10% of all cases. Moreover, in a significant number of excluded cases expression of PD-L1 by IHC was distinctly limited to the excluded TILs. This finding would support a unique mechanism of PD-L1 anti-tumor immune-related response that needs further investigation.
Citation Format: Carl Morrison, Jeffrey Conroy, Mary Nesline, Sean Glenn, Blake Burgher, Maochun Qin, Jonathan Andreas, Vincent Giamo, Felicia L. Lenzo, Angela Omilian, Wiam Bshara, Antonios Papanicolau-Sengos, Yirong Wang, Marc Ernstoff, Mark Gardner, Sarabjot Pabla. PD-L1 driven excluded phenotype in melanoma [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 3679.
Abstract 3702: A novel nanoparticle-based theranostic agent targeting low-density lipoprotein receptor-related protein-1 enhances the efficacy of neoadjuvant radiotherapy in colorectal cancer
Authors: Lee Kyoung Jin , Park Serk In , Jeong Seong-Yun , Choi Eun Kyung 
Published: August 2018

Abstract
Neoadjuvant radiotherapy is becoming an important therapeutic option for colorectal cancer (CRC) patients, although complete tumor response is observed only in 20 to 30% patients. However, precise biologic mechanisms underlying resistance to radiotherapy remain to be elucidated. In this study, we established a radiotherapy-resistant CRC patient-derived xenograft (PDX) mouse model, and we discovered that low-density lipoprotein receptor-related protein-1 (LRP-1) is increased in radiotherapy-resistant tumors compared with radiotherapy-sensitive tumors. Immunohistochemistry, mRNA and protein expression analyses of radiotherapy-sensitive vs. -refractory CRC patient samples confirmed a statistically significant association between LRP-1 levels and radiotherapy resistance of CRC. We also found that LRP-1 expression is significantly associated with the prognosis of CRC patients by analyzing gene expression data of CRC patients in Gene Expression Omnibus public database. Subsequently, aiming to develop radio-sensitizing nanoparticles targeting LRP-1 for chemotherapeutic drug delivery and in vivo imaging, we screened and identified an LRP-1-binding peptide in a radiotherapy-resistant CRC PDX mouse model using M13 phage display. We next engineered human serum albumin nanoparticles (HSA NPs) containing the LRP-1-binding peptide (for tumor localization), 5-FU (for cytotoxic chemotherapy) and Cy7 fluorophore (for in vivo imaging). When administered in CRC PDX-bearing mice, the LRP-1-targeting HSA NPs accumulated specifically in the CRC tumor tissue and dramatically increased the efficacy of radiotherapy. In addition, whole-body fluorescence imaging of PDX CRC-bearing mice showed that the HSA-NP accumulated only in radiation-treated tumors with high ROI values. In summary, we identified that LRP-1 is a novel signature protein of radiotherapy-resistant CRC, and validated that LRP-1 is closely associated with the progression of CRC. We developed a novel HSA nanoparticle-based theranostic agent loaded with LRP-1-binding peptide, 5-FU and a fluorophore that is applicable to both diagnostic imaging and radio-sensitizing neoadjuvant therapy of CRC. This approach is clinically applicable to improve the effectiveness of neoadjuvant radiotherapy and increase the ratio of complete tumor response in radio-resistant CRC.
Citation Format: Kyoung Jin Lee, Serk In Park, Seong-Yun Jeong, Eun Kyung Choi. A novel nanoparticle-based theranostic agent targeting low-density lipoprotein receptor-related protein-1 enhances the efficacy of neoadjuvant radiotherapy in colorectal 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 3702.
Abstract 3709: Characterization, in vitro and in vivo efficacy studies of docetaxel trastuzumab stealth immunoliposome in human breast cancer models
Authors: Rodallec Anne , Brunel Jean Michel , Robert Stephane , Giacometti Sarah , Savina Ariel , Bouquet Fanny , Lacarelle Bruno , Ciccolini Joseph , Fanciullino Raphaelle 
Published: August 2018

Abstract
In HER2-positive breast cancer, the Trastuzumab + Docetaxel doublet has a significant efficacy but is hampered by frequent toxicities that could be addressed with nanoparticles. We have developed an Antibody-Nano Conjugate (ANC), combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab. This entity is expected to improve the efficacy/toxicity balance of this doublet, by improving trafficking and delivery to the tumors. ANCs were synthesized using thin-film method and trastuzumab was grafted via sulfydryl groups on maleimide polyethylene glycol. Two compositions (ANC-1 and ANC-2) were tested and compared (i.e., size, morphology, encapsulation rate, engrafting rate, and stability). Antiproliferative activity was tested on a panel of human breast cancer models ranging fromHER2-negative (MDA-MB-231) to HER2-positive (MDA-MB-453) or -overexpressing (SKBR3), both on 2D and spheroid models. Biodistribution, efficacy and survival were tested in MDAMB-231 and MDA-MB-453 bearing nude mice. ANC-1 presented a greater size (140 ± 3 nm), docetaxel encapsulation rate (73 ± 6 %) and stability as compared with ANC-2. In vitro, both ANCs were found to be more efficient than standard docetaxel + trastuzumab, with a better performance for ANC-1. In vivo, ANC-1 accumulated better in tumors, resulting in a higher reduction in tumor growth (i.e. &gt;+36%) and prolonged survival (i.e. &gt;+33%) as compared with standard treatment. Both in vitro and in vivo results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models. Of note, although modest, even Her2- model (i.e., MDA231) was found to benefit from the nanoparticle.
Citation Format: Anne Rodallec, Jean Michel Brunel, Stephane Robert, Sarah Giacometti, Ariel Savina, Fanny Bouquet, Bruno Lacarelle, Joseph Ciccolini, Raphaelle Fanciullino. Characterization, in vitro and in vivo efficacy studies of docetaxel trastuzumab stealth immunoliposome in human breast cancer models [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 3709.
Abstract 3738: Three-dimensional treatment-resistant breast cancer spheroids as a predictive model of in vivo response to endocrine therapy
Authors: Rosales Carlo I. , Zhao Jiong , Gutgesell Lauren M. , Xiong Rui , Tonetti Debra A. , Thatcher Gregory R. 
Published: August 2018

Abstract
1 out of every 8 U.S. women will develop invasive breast cancer during her lifetime, making it the second most common form of cancer affecting women. Breast cancer is also a leading cause of cancer related deaths for women in the U.S., second only to lung cancer. Activation of estrogen receptor alpha (ERα) is the primary proliferative mechanism of breast cancer cells, making it a logical target for therapy. ER ligands with antiestrogenic activity, such as the selective estrogen receptor modulator (SERM), tamoxifen, and selective estrogen receptor degrader (SERD), fulvestrant, have proven clinically successful as treatments for breast cancer; however, resistance in up to 50% of patients provides a therapeutic challenge. Once resistant, breast cancer cells become endocrine-independent, because of this, there is an urgent need for both novel therapy and improved models of resistant breast cancer. Our lab has created a panel of various endocrine-independent cell lines to mimic SERM and SERD resistance. Along with traditional 2D cell culturing, 3D spheroids have also been utilized to gain a better understanding of resistance. Importantly, the response to therapeutic agents, of cell lines in 2D versus 3D cultures is not identical. We observe that 3D cultures better replicate observations in mouse xenograft models, demonstrating that elements of the spheroid microenvironment, such as cell-cell interactions and the presence of extracellular matrix (EM), mimic aspects of the tumor microenvironment in vivo. Cells cultured as spheroids are therefore a suitable in vitro model for drug discovery, predictive of response in preclinical animal models, in contrast to 2D monolayer cell cultures.
Citation Format: Carlo I. Rosales, Jiong Zhao, Lauren M. Gutgesell, Rui Xiong, Debra A. Tonetti, Gregory R. Thatcher. Three-dimensional treatment-resistant breast cancer spheroids as a predictive model of in vivo response to endocrine therapy [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 3738.
Abstract 3744: Multiple endocrine-resistant breast cancer cell lines retain ER and sensitivity to endocrine therapy
Authors: Gutgesell Lauren M. , Xiong Rui , Zhao Jiong , Zhao Huiping , Tonetti Debra A. , Thatcher Gregory R. 
Published: August 2018

Abstract
Endocrine therapy is the standard of care for breast cancer expressing estrogen receptor (ER),
which occurs in 70% of patients. Unfortunately, acquired or de novo resistance to endocrine
therapy is observed in up to 50% of patients, leaving a significant portion of patients with
insufficient treatment options. Endocrine-resistance, usually defined as resistance to tamoxifen
and aromatase inhibitor (AI) therapy, can also include resistance to selective estrogen receptor
degraders (SERDs), since these also target ER. Since multiple mechanisms contribute to
resistance, development of multiple resistant cell lines is needed for drug discovery and to identify
characteristics that may suggest susceptibility to alternative and combination therapies. We have
developed 5 stable, endocrine-resistant cell lines from a parent MCF-7 cell line, which all retain
ER: one of these cell lines, MCF-7:CFR is resistant to the SERD fulvestrant. Clinical metastatic
breast cancers that have gained endocrine resistance are overwhelmingly ER+. In addition to ER,
progesterone receptor (PR) and glucocorticoid receptor (GR) status of these lines was assessed,
and correlated with the response of these cells in culture to four classes of endocrine therapeutics:
SERDs, selective ER modulators (SERMs), and selective human ER partial agonists (ShERPAs).
Growth of all 5 cell lines was endocrine independent, indicating resistance to AI therapy. Two of
the ER+, PR- cell lines were most resistant to the spectrum of endocrine therapies, but these cell
lines both showed sensitivity to ShERPAs, especially in combination with non-endocrine targeted
therapies, such as the PI3K inhibitor, alpelisib. Paradoxically, all endocrine-resistant cell lines
responded to at least one of the endocrine therapies tested, demonstrating that if ER is not lost
in the metastatic state, it remains a vulnerability suitable for therapeutic targeting.
Citation Format: Lauren M. Gutgesell, Rui Xiong, Jiong Zhao, Huiping Zhao, Debra A. Tonetti, Gregory R. Thatcher. Multiple endocrine-resistant breast cancer cell lines retain ER and sensitivity to endocrine therapy [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 3744.
Abstract 3746: Targeting adrenal androgen to treat prostate cancer
Authors: Wu Yue , Wang Jianmin , Tang Li , Pop Elena , Stocking John J. , Attwood Kristopher M. , Smith Gary J. 
Published: August 2018

Abstract
Background: Adrenal androgens are the most abundant androgens in humans, with dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) being the major adrenal androgens in circulation. Significantly, adrenal androgens may serve as substrates for intratumoral (intracrine) production of testosterone (T) and/or dihydrotestosterone (DHT), the ligands for androgen receptor (AR). However, adrenal androgens also have functions that are independent of AR. The present study addressed the capability of prostate cancer tissue to use adrenal androgens for T/DHT production, delineated signaling pathways activated by adrenal androgens, and determined whether adrenal androgens sustained tumor growth after androgen-deprivation therapy (ADT).
Experimental Procedures: Metabolism of adrenal androgen was evaluated ex vivo using fresh clinical prostate tissue specimens. The production of DHT or DHEA was determined using ELISA. Human prostate cancer cells lines were used for in vitro experiments. The effects of adrenal androgens on tumor growth were evaluated in vivo using xenografts of the human prostate cancer cell line VCaP in castrated or intact mice.
Results: 1) Human prostate tissue was able to produce DHT using DHEA-S at a physiologic concentration (3.5 μM). The production of DHT from DHEA-S was absolutely dependent on the activity of steroid sulfatase (STS). DHEA at a physiologic concentration (10 nM) was not a suitable substrate for DHT production, but was used by prostate tissue when available at a supra-physiologic concentration (3.5 μM) to produce DHT. 2) DHEA-S was able to stimulate growth of prostate cancer cells in vitro. The growth stimulatory effect of DHEA-S was mediated by AR-dependent and AR-independent signaling pathways. A subset of the genes modulated specifically by DHEA-S were distinctive from the T-modulated genes. 3) DHEA sustained tumor growth after castration. DHEA-stimulated growth was attributed to activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway.
Conclusions: Prostate tissue can use adrenal androgens for DHT production. Adrenal androgens may stimulate prostate cancer growth using AR-dependent pathways that are mediated via intratumoral T/DHT production, or using AR-independent signaling pathways such as the IGF1R signaling pathway. Identification of targets and therapeutics to block the adrenal androgen-stimulated pathways may help develop novel strategies to treat prostate cancer.
Citation Format: Yue Wu, Jianmin Wang, Li Tang, Elena Pop, John J. Stocking, Kristopher M. Attwood, Gary J. Smith. Targeting adrenal androgen to treat 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 3746.
Abstract 3761: Histone deacetylase inhibitor, Entinostat enhances the tumor specific immune response by generating T-cell central memory in the TME
Authors: Gaur Pankaj , Verma Vivek , Nandre Rahul , Vir Pooja , Wang Hua , Kang Baolin , Ordentlich Peter , Wang Lei , Gupta Seema , Khleif Samir N. 
Published: August 2018

Abstract
The epigenetic deregulation of T-cells and enhanced numbers of immunosuppressive cells in the tumor microenvironment (TME) are associated with decreased anti-tumor effects. Hence, targeting the epigenetic modifications using modulators such as histone deacetylase inhibitors (HDACi) provides the basis for a potential role for these agents in cancer-immunotherapy. In this context, Entinostat, an oral HDACi has been shown to reprogram the TME by impacting the numbers and activity of the immunosuppressive cell populations resulting in enhanced anti-tumor activity when combined with immune checkpoint blockade. However, the effect of this inhibitor on anti-tumor activity of effector T-cells is not well understood. Here, using animal tumor-models that require antigen-vaccine for T cell priming, we showed that Entinostat significantly synergized with tumor antigen-specific vaccine in delaying the tumor growth and prolonging mice survival. Further, we found that administering Entinostat in combination with antigen-priming resulted in sustainable long-term anti-tumor effects. Immunologically, Entinostat significantly enhanced the total CD8+, antigen-specific CD8+, granzyme B+ (GB+) CD8+, and antigen-specific GB+CD8+ T-cells in the TME when combined with the vaccine. Interestingly, we found that Entinostat led to a significant increase in the number of central memory T-cells (TCM; CD62L+CD44+) and decrease in the effector memory cells (TEM; CD62L-CD44+) in the TME. Notably, we did not find significant immune modulation in the periphery following the combination treatment indicating that the immune modulatory effects of Entinostat were localized to TME and hence may be associated with less systemic toxicity. Taken together these results highlight the ability of Entinostat to significantly enhance anti-tumor responses partly through the generation of central-memory which may translate to durable responses. These data provide further support on the potential of utilizing Entinostat in combinatorial immunotherapeutic strategies.
Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Peter Ordentlich, Lei Wang, Seema Gupta, Samir N. Khleif. Histone deacetylase inhibitor, Entinostat enhances the tumor specific immune response by generating T-cell central memory in the TME [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 3761.
Abstract 3762: Novel RORγt agonist induces antitumor immune effect through enhancement of tumor antigen-specific CD8+ T-cell infiltration into the TME
Authors: Gaur Pankaj , Verma Vivek , Nandre Rahul , Vir Pooja , Wang Hua , Kang Baolin , Carter Laura , Hu Xiao , Liu Xikui , Gupta Seema , Khleif Samir 
Published: August 2018

Abstract
RORγt is a master transcription factor, which regulates the proliferation and functionality of Type 17 T-cells (TH17 and Tc17). Recent nonclinical studies have shown that in addition to promoting effector differentiation, stemness and plasticity, RORγt also inhibits Treg differentiation, an important component of suppressive tumor microenvironment (TME). Therefore, stimulation of RORγt by synthetic, small-molecule agonists holds promise as an immunotherapy. We tested the effects of a RORγ agonist (LYC-54143; 100 mg/kg BID given continuously till the end of study) on the tumor growth and survival in mice in combination with a tumor antigen-specific vaccine (3 doses, one week apart), which is required for proper priming in this model. We found that the RORγ agonist resulted in a highly significant enhancement of the antitumor effect delaying the tumor growth (p≤0.001 at day 21 compared to vaccine alone treatment) and prolonging survival. At day 36 after tumor implantation, 80% of mice survived in the RORγ agonist + vaccine treatment group compared to 0% survival following RORγ agonist or vaccine alone treatments. Immunologically, we found that RORγ agonist treatment led to a significant decrease in the numbers of Tregs and a significant increase in IL-17+ IFNγ+ T cells in the TME. Moreover, RORγ agonist treatment led to a significant increase in the numbers of T cells including increased antigen-specific CD8+ T-cells in the TME. Interestingly, scheduling RORγ agonist before or with the vaccine demonstrated comparable antitumor activity, suggesting that the scheduling of RORγ agonist treatment does not affect the therapeutic outcomes. These results show that an RORγ agonist can enhance the antitumor immune response by enhancing effector functions and by decreasing immune suppression in the TME by increasing cytokine production and switching the differentiation of immune-suppressive Tregs to effector Th17 cells and support that RORγ agonists are promising immune-modulatory agents in cancer.
Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. Novel RORγt agonist induces antitumor immune effect through enhancement of tumor antigen-specific CD8+ T-cell infiltration into the TME [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 3762.