bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2564: Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10
Authors: Border Ellen , Sanderson Joseph P. , Weissensteiner Thomas , Hyland Natalie , Holdich Tom , Brophy Francine , Amado Rafael , Gerry Andrew , Pumphrey Nicholas 
Published: August 2018

Abstract
Circulating T-cells, bearing T-cell receptors (TCRs) that have passed thymic selection, generally have low affinity for self-protein-derived cancer antigens and therefore have a limited ability to detect and eliminate tumor cells. Engineering TCRs to enhance and optimize their affinity, and therefore potency, for cancer targets is a promising strategy for adoptive immunotherapy in cancer patients. Modification of TCRs can potentially generate cross-reactivity to antigens expressed by normal tissue. Such cross reactivity might not be detected by in vivo animal studies, due to species differences in the antigenic repertoire. To mitigate the risk of such toxicities in clinical trials, we developed a comprehensive in vitro testing strategy. This strategy involves systematic substitution at each position of the antigenic peptide sequence using all natural amino acids to generate a profile of peptide specificity (“X-scan”). The likelihood of off-target reactivity was investigated by searching the human proteome for sequences matching this profile and testing against a panel of cell lines. Starting from a panel of parental TCRs with diverse sequences, we engineered several affinity-enhanced TCRs specific for the cancer-testis antigen MAGE-A10. The properties of two of these TCRs, which had the optimal balance of potency and specificity, could not be distinguished effectively with conventional biochemical and cellular assays. The X-scan method permitted us to select the most specific and potent candidate for further pre-clinical testing. This MAGE-A10c796 TCR is now being studied in clinical trials to treat HLA-A2+ patients with non-small cell lung cancer (NCT02592577), urothelial cancers, melanoma, or head and neck cancers (NCT02989064).
Citation Format: Ellen Border, Joseph P. Sanderson, Thomas Weissensteiner, Natalie Hyland, Tom Holdich, Francine Brophy, Rafael Amado, Andrew Gerry, Nicholas Pumphrey. Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10 [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 2564.
Abstract 2566: A TCL1-specific T-cell receptor redirects T cells against B-cell lymphomas and non-hematological tumors
Authors: Weng Jinsheng , Moriarty Kelsey E. , Pan Yong , Baio Flavio Egidio , Wang Hua , Torikai Hiroki , Maiti Sourindra N. , Chu Fuliang , Cheng Xiaoyun , Karri Swathi , Medapalli Deepshika , Cooper Laurence J. N. , Neelapu Sattva S. 
Published: August 2018

Abstract
T-cell leukemia/lymphoma Antigen1 (TCL1) is a B-cell oncoprotein that is overexpressed in multiple forms of B-cell lymphoma. In our previous study, we identified a HLA*A0201-restricted T cell epitope from TCL1 that stimulated CD8+ T cells to specifically lyse lymphoma cells. In this study, we have cloned the TCL170-79 peptide-specific T-cell receptor (TCR) gene that after lentivirus transduction into donor T cells can redirect the specificity of T cells to lyse T2 cells pulsed with TCL170-79 but not control peptide. The TCR-transduced CD8+ T cells efficiently lysed HLA-0201+, TCL1-expressing human lymphoma cell lines and primary lymphoma cells, but not normal B cells. Adoptive transfer of TCR-transduced T cells into a mantle cell lymphoma xenograft mouse model inhibited the tumor growth and significantly extended the survival of mice. In addition, we found that TCL1 is expressed in multiple solid tumors. The TCR-transduced T cells lysed colon and liver tumor cells but not normal human cells in vitro as well as in a mouse xenograft model. Collectively, our data demonstrate that TCL1-specific TCR-based immunotherapy is highly effective against human B-cell lymphomas and non-hematological tumors.
Citation Format: Jinsheng Weng, Kelsey E. Moriarty, Yong Pan, Flavio Egidio Baio, Hua Wang, Hiroki Torikai, Sourindra N. Maiti, Fuliang Chu, Xiaoyun Cheng, Swathi Karri, Deepshika Medapalli, Laurence J. N. Cooper, Sattva S. Neelapu. A TCL1-specific T-cell receptor redirects T cells against B-cell lymphomas and non-hematological tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2566.
Abstract 2572: HSD3B1 genotype and abiraterone metabolism in patients with prostate cancer
Authors: Alyamani Mohammad , Emamekhoo Hamid , Park Sunho , Taylor Jennifer , Almassi Nima , Upadhyay Sunil , Tyler Allison , Berk Michael P. , Hwang Tae Hyun , Grivas Petros , Rini Brian , Garcia Jorge , Auchus Richard J. , Sharifi Nima 
Published: August 2018

Abstract
Background The common HSD3B1 (1245C) germline variant encodes for a 3βHSD1 missense that increases enzyme activity that allows tumors to utilize extragonadal androgens and is a predictive biomarker of resistance to ADT and sensitivity to CYP17A1 inhibition by the nonsteroidal drug ketoconazole. However, 3βHSD is also the first enzyme necessary in the conversion from abiraterone, a steroidal CYP17A1 inhibitor, to 5α-abiraterone, which stimulates the androgen receptor (AR) and prostate cancer progression. The HSD3B1 (1245C) variant might therefore increase 5α-abiraterone synthesis in patients on abiraterone therapy, possibly limiting clinical benefit.
Significance This work aims to characterize the pharmacokinetics of steroidal metabolites of abiraterone and to determine the association between HSD3B1 genotype and the generation of 5α-abiraterone metabolites.
Patients and Methods Part 1: 15 healthy male volunteers received a single oral dose of 1000 mg abiraterone acetate plus 240 mg of the AR antagonist apalutamide, steroidal metabolites of abiraterone were quantitated at 12 time points from 0.5-96 hours post-dose. Part 2: 5α-abiraterone metabolites and HSD3B1 genotype was determine in 30 patients with castration-resistant prostate cancer (CRPC) on abiraterone therapy. Metabolite concentrations were normalized to the 8 hour time point of the pharmacokinetic study and the association between HSD3B1 genotype and 5α-abiraterone metabolites was determined.
Results There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. Patients who inherit 0, 1 and 2 copies of the HSD3B1 (1245C) variant have a stepwise increase in serum concentrations of 5α-abiraterone metabolites (p=0.002).
Conclusion The generation of 5α-abiraterone preferentially in patients with the HSD3B1 (1245C) variant might negate the benefits of abiraterone specifically in a patient subset that is otherwise more likely to benefit from CYP17A1 inhibition by the nonsteroidal drug ketoconazole.
Citation Format: Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Tae Hyun Hwang, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi. HSD3B1 genotype and abiraterone metabolism in patients with 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 2572.
Abstract 2576: Dclk1 can be a predictor for poor survival in patients with resected pancreatic cancer
Authors: Takemoto Yoshihiro , Nishimoto Arata , Hironaka Yukari , Suehiro Yuki , Kugimiya Naruji , Suga Atsushi , Harada Eijiro , Hamano Kimikazu 
Published: August 2018

Abstract
Background: Doublecortin-like kinase-1 (Dclk1) shows higher expression levels in human pancreatic cancer compared with human normal pancreatic tissue. Dclk1 positively regulates tumor growth, invasion, metastasis, pluripotency factors, angiogenic factors, and epithelial-mesenchymal transition (EMT)-related genes in pancreatic cancer cells. We previously reported that Dclk1 inhibition in combination with gemcitabine (GEM) treatment offers a novel approach to treat pancreatic cancer. However, few studies focusing on the role of Dclk1 in pancreatic cancer using clinical specimens have been reported. Objective: To investigate the expression of Dclk1 in resected specimens of pancreatic cancer and its prognostic significance. Methods: Tumor specimens were obtained from 26 patients with pancreatic cancer (stage 3 and 4) who underwent resection between April 2005 and March 2015 in our department. Dclk1, Ki67, and phosphorylated MEK expression levels were examined using immunohistochemical staining. The expression levels of these markers were evaluated using Histoscore (Intensity [0-3] x Extent [0-4]). In order to identify proteins phosphorylated by Dclk1, we analyzed a protein microarray using a pancreatic cancer cell line. Results: In total, 42.3% (11/26) of samples expressed high levels of Dclk1 (Histoscore≧3.3) and were classified into the high Dclk1 group. There were no significant differences between patients in the high Dclk1 group and the low Dclk1 group in terms of clinical characteristics and surgical findings. Patients in the high Dclk1 group exhibited significantly shorter survival times than those in the low Dclk1 group (P &lt; 0.05). The expression of phosphorylated MEK, which is observed on a mitogen-activated protein kinase (MAPK) pathway, decreased by &gt;50% in Dclk1-inhibited pancreatic cancer cells by protein microarray. Interestingly, the expression of pMEK and Ki67 in resected specimens tended to increase in samples in the high Dclk1 group. Therefore, Dclk1 might contribute to the progression of pancreatic cancer through the phosphorylation of MEK. Conclusion: Dclk1 may be a marker for poor prognosis in patients with resected pancreatic cancer.
Citation Format: Yoshihiro Takemoto, Arata Nishimoto, Yukari Hironaka, Yuki Suehiro, Naruji Kugimiya, Atsushi Suga, Eijiro Harada, Kimikazu Hamano. Dclk1 can be a predictor for poor survival in patients with resected pancreatic 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 2576.
Abstract 2580: A mosaic ERG oncoprotein staining pattern predicts upstaging and poor pathologic features in prostate cancer patients
Authors: Gesztes William , Dusmatova Shahnoza , Mygatt Justin , Cullen Jennifer , Yong Denise , Kuo Huai-Ching , Chen Yongmei , Hurwitz Lauren , Rosner Inger , Srivastava Shiv , Sesterhenn Isabell 
Published: August 2018

Abstract
Purpose: Building on previous work, this study examined the independent role of ERG staining pattern in the index prostate cancer (CaP) tumor, on probability of upstaging and biochemical recurrence (BCR) following radical prostatectomy (RP).
Methods: A retrospective cohort study of patients enrolled at the Walter Reed National Military Medical Center who underwent RP between 1993 and 2016 was conducted. ERG oncoprotein expression was assessed in CaP index tumors (i.e., largest and poorest grade) using immunohistochemistry (IHC) staining with 9FY monoclonal antibody of representative sections of formalin-fixed paraffin-embedded whole-mounted RP specimens. ERG status was classified as positive (ERG+), negative (ERG-) and a pattern of alternating +/- regions within the index tumor (ERG “Hybrid” or ERG-h). Kaplan Meier (KM) estimation curve analysis was used to examine BCR-free survival across ERG status. Multivariable (MV) logistic regression (LR) modeling was used to determine whether ERG status predicted upstaging (cT1-2 to pT3-4).
Results: Among 1,385 eligible patients, mean age at RP and follow up time were 58.8 and 7 years, respectively. Twenty-nine percent of patients self-classified as African-American (AA), and 18% experienced BCR. The ERG-h pattern was observed in 81 patients (5.8%). Pathologic stage T3a-T4a was observed in 51.3%, 32.2% and 30.5% of patients with ERG-h, ERG+ and ERG- tumors, respectively. In unadjusted KM analysis, 10-year BCR-free survival probabilities were 78%, 75%, and 82% for ERG-h, ERG-, and ERG+ patients, respectively (p=0.08). A trend of incrementally poorer BCR-free survival was observed for ERG-h, ERG- versus ERG positive patients. MV LR analysis revealed the greatest odds of upstaging for ERG-h vs. ERG- patients (OR=2.8, p=0.0008), controlling for age at RP (p&lt;.0001), biopsy Gleason score (p&lt;.0001), PSA at diagnosis (p=0.0054) and patient race (p=0.07).
Conclusions: In this racially diverse cohort of RP patients, a mosaic-like pattern of ERG staining predicted greater upstaging and poorer pathologic features. There may be a role for examination of this “hybrid” mosaic staining pattern in patient risk stratification during treatment decision making.
Citation Format: William Gesztes, Shahnoza Dusmatova, Justin Mygatt, Jennifer Cullen, Denise Yong, Huai-Ching Kuo, Yongmei Chen, Lauren Hurwitz, Inger Rosner, Shiv Srivastava, Isabell Sesterhenn. A mosaic ERG oncoprotein staining pattern predicts upstaging and poor pathologic features in prostate cancer patients [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 2580.
Abstract 2623: CHP-IL12 combined with surgery suppresses tumor metastasis and prolongs survival
Authors: Zhao Qingnan , Hu Jiemiao , Cutrera Jeffry J. , Mitra Abhisek , Xia Xueqing , Li Shulin 
Published: August 2018

Abstract
Interleukin 12 (IL-12) is the most promising cytokine for treating tumors by itself or arming immunogenic cells but its toxicity and moderate response limit its clinical use. To avoid or minimize the toxicity issue and boost the anti-tumor immune response, our lab has discovered a comprehensive tumor-targeting carcinoma homing peptide (CHP). Fusion of this peptide encoding DNA sequence to IL12 encoding sequence in frame yields the proprietary product—CHP-IL12 (US patent 9,657,077 B2), or tumor-targeting IL12, which increased the accumulation of IL12 in tumor environment and decreased liver toxicity compared to wild-type IL12 (wt-IL12) gene therapy. Here, we report the therapeutic efficacy of this CHP-IL12 on metastasis and to comprehend the underlying mechanism description between CHP-IL12 and wildtype (wt)-IL12 for boosting anti-tumor response, two orthotopic and spontaneous tumor metastasis models (one adult and one pediatric tumor) were utilized. CHP-IL12 gene therapy showed greater efficacy in controlling growth of established tumors compared to wt-IL12. CHP-IL12 gene therapy, in combination with surgery, reduced number of metastatic nodules in lungs, livers and bones. CHP-IL12, compared to wt-IL12, conferred a potential immunostimulatory effect involving 1) reduction of T-reg cells, myeloid-derived suppressor cells (MDSC) and tumor associated macrophages (TAM); 2) recruitment of activated CD8+ T cells to the tumor. Moreover, CHP-IL12 increased IL12, IFNγ level in tumor environment and decreased IL12, IFNγ level in serum, which is the major cause of toxicity. Furthermore, in combination with surgery, CHP-IL12 gene therapy led to long-term survival and enhanced immunological memory development of tumor bearing mice compared to wt-IL12 gene therapy.
These results collectively indicate that CHP-IL12 fusion gene therapy coupled with surgery has a powerful potency in inhibition of tumor metastasis and prolonging survival and a low potency in inducing toxicity. Therefore, CHP-IL12 fusion gene therapy in combination with surgery may translate into clinic as a promising anti-tumor strategy for both adult and pediatric tumors.
Citation Format: Qingnan Zhao, Jiemiao Hu, Jeffry J. Cutrera, Abhisek Mitra, Xueqing Xia, Shulin Li. CHP-IL12 combined with surgery suppresses tumor metastasis and prolongs survival [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 2623.
Abstract 2624: Dual PLK1 and BRD4 inhibition has synergistic therapeutic effects against high-risk rhabdomyosarcoma
Authors: Timme Natalie , Liu Shuai , Yosief Hailemichael , García Heathcliff Dorado , MacArthur Ian , Szymansky Annabell , Dohna Constantin , Seifert Georg , Hundsdörfer Patrick , Lissat Andrej , Eggert Angelika , Schulte Johannes , Zhang Wei , Henssen Anton 
Published: August 2018

Abstract
Concomitant inhibition of multiple therapeutic targets is an established strategy to improve the durability of clinical responses to targeted therapies. Rhabdomyosarcoma is the most common childhood soft tissue solid tumor and cure rates for patients with high-risk rhabdomyosarcoma remain dismal. Resistance to intensive chemotherapy is common, and few molecular therapies have been introduced clinically. High-risk rhabdomyosarcoma is driven by expression of the oncogenic fusion protein PAX3-FOXO1, which acts as a transcription factor. Recently, many efforts have been made to identify pharmacological means of inhibiting PAX3-FOXO1, given its central role in rhabdomyosarcoma cell line survival. The BET protein BRD4 has been shown to be required for transcription of PAX3-FOXO1 and its target genes and pharmacological inhibition via BET protein inhibitors exhibits anti-rhabdomyosarcoma effects. Phosphorylation of PAX3-FOXO1 by the polo like kinase 1 (PLK1) increases the stability of the oncoprotein. Based on these previous observations, we hypothesized that simultaneous inhibition of BRD4 and PLK1 could synergistically target PAX3-FOXO1 stability and activity, leading to increased anti-rhabdomyosarcoma effects. Indeed, combination treatment with PLK1 and BRD4 inhibitors exhibited synergistic effects specifically against PAX3-FOXO1-driven rhabdomyosarcoma cell lines. Dual PLK1-BRD4 inhibition suppressed proliferation and induced apoptosis in rhabdomyosarcoma cell lines at low nanomolar concentrations. Our results demonstrate a new strategy towards achieving dual synergistic targeting of BRD4 and PLK1 with a single agent which may lead to clinical translation for therapy of refractory rhabdomyosarcoma.
Citation Format: Natalie Timme, Shuai Liu, Hailemichael Yosief, Heathcliff Dorado García, Ian MacArthur, Annabell Szymansky, Constantin Dohna, Georg Seifert, Patrick Hundsdörfer, Andrej Lissat, Angelika Eggert, Johannes Schulte, Wei Zhang, Anton Henssen. Dual PLK1 and BRD4 inhibition has synergistic therapeutic effects against high-risk rhabdomyosarcoma [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 2624.
Abstract 2634: Predictive value of 18F-FDG PET/CT scanning in combination with clinical parameters in patients with newly diagnosed multiple myeloma
Authors: Tu Honglei , Zhou Fuling , Pan Yunbao , Claret Francois X 
Published: August 2018

Abstract
Objective: To evaluate the association of 18F-2`-deoxy 2`-fluorodeoxyglucose (18F-FDG) PET/CT with clinical parameters in predicting patients with newly diagnosed multiple myeloma (MM).
Methods: One hundred and twenty MM patients undergoing 18F-FDG PET/CT scanning were analyzed in a retrospective cohort study.
Results: Based on multivariate analysis, β2M, LDH, number of focal lesions (FLs) and SUVmax were significantly correlated with overall survival (OS). These 4 variables were used to construct a new staging system (NSS) based on the number of risk factors. NSS provided a better discrimination of risk between stages III and II than International staging system (ISS) (p &lt; 0.001 vs. p = 0.086). For OS, there was no significant difference among risk groups in Durie-Salmon (DS) stage (p &gt; 0.05). Based on Spearman correlation analysis, presence of lesions in appendicular skeleton, number of FLs and SUVmax appeared to indicate advanced stage of MM. ROC curves which showed the combination of β2M with Calcium got a specificity of 96.3% for the presence of lesions in appendicular skeleton, and LDH alone had 100% specificity in predicting the number of FLs, although the sensitivity was only 50%.
Conclusions: 18F-FDG PET/CT in combination with clinical parameters provided an accurate and simple method for risk stratification of patients with newly diagnosed MM.
Citation Format: Honglei Tu, Fuling Zhou, Yunbao Pan, Francois X Claret. Predictive value of 18F-FDG PET/CT scanning in combination with clinical parameters in patients with newly diagnosed multiple myeloma [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 2634.
Abstract 2637: Expression of SALL4 in prostate cancer
Authors: Alghezi Dhafer A. , Whitley Paul , Beresford Mark , Bowen Rebecca , Mitchard John , Chalmers Andrew 
Published: August 2018

Abstract
Few prognostic biomarkers for Prostate cancer have been identified and there are clinical difficulties in distinguishing between relapsing and non-relapsing disease. The aim of our study is to investigate the hypothesis that proteins that have been linked to stem cells might be potential biomarkers, that could distinguish between aggressive tumors requiring radical intervention and those that have a good prognosis. One of the potential biomarkers that are being investigated is Sall4, a zinc finger transcriptional factor which has an important role in stem cell development and oncogeneses, including a possible role in prostate cancer progression and relapse. However, its role in prostate cancer remains unclear.
Sall4 nuclear staining has been evaluated by immunohistochemistry using two sources of patient samples, a tissue microarray group and a Bath cohort. The tissue microarray group consists of 96 cases including normal prostate, adjacent normal prostate, and prostate cancer samples. The Bath cohort consists of 22 samples, including samples from patients that had recurrent disease and those who remained disease free.
Sall4 nuclear staining was found to be decreased in prostate cancer samples compared to benign tissue from the tissue microarray group. Sall4 nuclear staining was also negatively associated with poorly differentiated grades of prostate cancer in the tissue microarray group. The Bath cohort did not have enough benign tissues to confirm the relationship between cancer and benign tissues but showed a negative association with the grade. Sall4 nuclear staining in tissue from both sets of samples was not associated with prostate cancer stages. It can be seen from this preliminary data that Sall4 might play an important role in tumor formation and/or aggressiveness and warrants further investigation to understand its function and establish if it could represent a potential diagnostic biomarker for prostate cancer.
Citation Format: Dhafer A. Alghezi, Paul Whitley, Mark Beresford, Rebecca Bowen, John Mitchard, Andrew Chalmers. Expression of SALL4 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 2637.