bluuebunny/crossref_metadata_2025 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

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

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

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

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 < 0.05). The expression of phosphorylated MEK, which is observed on a mitogen-activated protein kinase (MAPK) pathway, decreased by >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

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<.0001), biopsy Gleason score (p<.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

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

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

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 < 0.001 vs. p = 0.086). For OS, there was no significant difference among risk groups in Durie-Salmon (DS) stage (p > 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

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.
Abstract 264: Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy
Authors: Hidalgo Greta Garrido , Schrand Brett , Rabasa Ailem , Levay Agata , Berezhnoy Alexey , Modi Shrey , Bhuwan Giri Bhuwan , Dudeja Vikas , Doorduijn Elien , Hall Thorbald van , Gilboa Eli
Published: August 2018

Development of therapeutic strategies to prevent recurrence in cancer patients, or tumor progression in at risk individuals has been challenging given the long and often unpredictable time to the emergence of the malignant tumors. Neoantigens represent the most potent antigens to induce antitumor immunity, yet the ability to predict which neoantigens will be expressed in future tumors is at present not an option. We have developed a simple and broadly applicable approach to induce neoantigens in tumor cells in situ by reducing the expression of antigen processing mediators like TAP, ERAAP, or invariant chain (Ii), using siRNAs that were targeted to tumor cells by conjugation to a nucleolin-binding aptamer. Exploiting the ability to induce neoantigens in situ, we describe a novel vaccination strategy targeting potent neoantigens to control the growth of the future tumors whereby patients in remission or individuals at risk are first vaccinated against the antigen processing downregulation-induced neoantigens and when or if tumor develops the same antigens are induced in the tumor, termed prorapeutic vaccination (prophylactic + therapeutic). Mice were vaccinated against the TAP downregulation-induced neoantigens by targeting the corresponding siRNAs to dendritic cells (DC) in situ via conjugation to a short CpG oligonucleotide (ODN); the CpG ODN also activated the targeted DC to avoid induction of tolerance against the neoantigens. Vaccination with CpG ODN-TAP siRNA conjugates inhibited subsequently implanted or autochthonous tumors in several tumor models, provided the said neoantigens were also induced in the tumor by nucleolin aptamer-targeted siRNA inhibition of TAP. The CpG-siRNA and nucleolin aptamer-siRNA conjugates are simple, chemically- synthesized, off-the-shelf, and broadly applicable reagents to vaccinate against neoantigens and control the growth of future tumors irrespective of their origin.

Citation Format: Greta Garrido Hidalgo, Brett Schrand, Ailem Rabasa, Agata Levay, Alexey Berezhnoy, Shrey Modi, Giri Bhuwan Bhuwan, Vikas Dudeja, Elien Doorduijn, Thorbald van Hall, Eli Gilboa. Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy [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 264.
Abstract 2643: Increased copy number of EGFR gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy
Authors: Koudelakova Vladimira , Trojanec Radek , Potockova Jana , Drabek Jiri , Stranska Jana , Smickova Petra , Kourilova Pavla , Grygarkova Ivona , Kolek Vitezslav , Skarda Jozef , Hajduch Marian
Published: August 2018

Background: Lung cancers are the leading cause of cancer-related deaths worldwide. Surgical resection alone remains preferred treatment for early stage patients with non-small cell lung cancer (NSCLC), whereas surgery plus platinum-based adjuvant chemotherapy is recommended for stages II - IIIa. Despite wide spectrum of known genetic alterations, there is a lack of biomarkers predicting response to adjuvant therapy. The aim of our study was to determine the predictive role of selected gene alterations. Methods and patients: Formalin-fixed paraffin embedded tumor samples were obtained from 209 NSCLC patients with stage I to IIIa. Of these, 59 patients were treated by surgical resection only, the follow-up adjuvant chemotherapy was indicated in remaining 150 cases. There were 146 males and 63 females (mean age 66; range 29-82 years), tumor histology revealed 79 adenocarcinomas, 105 squamous cell carcinomas, 21 large cell carcinomas, two adenosquamous carcinomas and two sarcomatoid carcinomas. Fluorescent in situ hybridization (FISH) was used for evaluation of EGFR, CMYC, MET and FGFR1 gene copy numbers and ALK and ROS1 copy numbers and rearrangements, respectively. EGFR, KRAS and BRAF mutations were screened using Cobas EGFR Mutation Test (Roche), TheraScreen: KRAS Mutation kit (Qiagen) and BRAF p.Val600Glu kit (IntellMed). Results: In the group of 150 resectable NSCLC patients treated with platinum-based adjuvant therapy, increased copy number of EGFR gene predicted poor overall survival (OS) (p = 0.00001, hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.32-2.10) as well as disease-free survival (DFS) (p = 0.0001, HR 1.54, 95% CI 1.23-1.91) in univariate analysis. In multivariate analysis adjusted to age and stage, the EGFR copy number was independent predictor of OS (p = 0.001) as well as DFS (p = 0.0004). In the group of 59 patients treated by surgical therapy only, no correlation of tested markers with clinical-pathological data was identified. Conclusions: Increased copy number of EGFR gene was found to be an independent predictor of outcome in NSCLC patients treated by adjuvant platinum-based therapy. Acknowledgment: This work was financially supported by NPU LO1304, TE02000058 and EATRIS-CZ.

Citation Format: Vladimira Koudelakova, Radek Trojanec, Jana Potockova, Jiri Drabek, Jana Stranska, Petra Smickova, Pavla Kourilova, Ivona Grygarkova, Vitezslav Kolek, Jozef Skarda, Marian Hajduch. Increased copy number of EGFR gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy [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 2643.
Abstract 2652: Metabolomics biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women
Authors: Audet-Delage Yannick , Villeneuve Lyne , Grégoire Jean , Plante Marie , Guillemette Chantal
Published: August 2018

Endometrial cancer (EC) is the most frequent cancer of the female genital tract in developed countries. Most EC occurs after menopause and are diagnosed as endometrioid type I carcinomas that exhibit a favorable prognosis especially for grades 1 and 2. In contrast, type II non-endometrioid carcinomas such as serous tumors have a poor prognosis. The use of small molecule biomarkers may facilitate accurate diagnosis and prognostic predictions. Our goal was to identify novel blood-based markers associated with EC subtypes and recurrence after surgery in postmenopausal women. Using mass spectrometry (MS)-based metabolomics, we examined preoperative serum metabolites of healthy women (n=18), non-recurrent and recurrent cases with type I endometrioid (n=24) and type II serous (n=12) carcinomas, matched for pathological characteristics, body mass index and age. Biochemicals including complex lipids were analyzed by gas chromatography-MS and ultrahigh performance liquid chromatography-tandem MS. A total of 1592 compounds of known identity and 14 different lipid classes were assessed. When comparing EC cases to healthy women, 137 metabolites were significantly different, with spermine as the most altered biochemical, identifying this metabolite as a potential biomarker of EC. Furthermore, recurrent cases of both histological types had higher levels of the monoacylglycerol 1-oleoylglycerol than non-recurrent cases. Type I recurrent cases were also characterized by much lower levels of bile acids and elevated concentrations of phosphorylated fibrinogen cleavage peptide, whereas type II recurrent cases displayed higher levels of ceramides and their derivatives. Our findings provide a first detailed metabolomics study in EC and identify potential non-invasive biomarkers to define clinically relevant risk groups.

Citation Format: Yannick Audet-Delage, Lyne Villeneuve, Jean Grégoire, Marie Plante, Chantal Guillemette. Metabolomics biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women [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 2652.
Abstract 2658: Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature
Authors: Lokeshwar Soum D. , Jordan Andre R. , Lahorewala Sarrah S. , Lokeshwar Vinata B.
Published: August 2018

Introduction and Objective: With 10% survival at 5-years, metastatic disease presents poor prognosis for renal cell carcinoma (RCC) patients. Prognosis can be improved if biomarkers that predict disease outcome are identified and validated. Aberrantly expressed microRNAs (miRs) promote (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, consensus of a clinically significant miRNA signature has not been established. The objective of this study was to identify a miRNA signature for predicting clinical outcome in RCC patients using a four-pronged interconnected discovery and validation approach.

Methods: Differentially expressed miRs were identified and analyzed in 113 specimens (Normal kidney: 59; tumor: 54). In the discovery phase, miRNA-profiling was initially performed in matched normal and tumor specimens from 8 patients, followed by validation in 16 additional specimens. Seven miRs that were significantly aberrantly expressed in miRs in both discovery phases were analyzed by qPCR and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in a TCGA dataset of 241 RCC specimens.

Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150 and miR-155 as significantly upregulated (2-4-fold) and miR-192, miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (< 4 cm) from benign oncocytomas. miR-142-5p levels were significantly up-regulated in patients with lymph node positive disease and metastasis (P=0.0002). A 3-miR combination, miR-21+142-5p+194 significantly but negatively correlated with metastasis (P=0.0017; OR: 0.53) and disease-specific mortality (P=0.018; OR: 0.37). The signature had high sensitivity (86.7 - 93.3%) and specificity (82 - 87%) to predict metastasis and disease-specific mortality. In the TCGA dataset, the 3-miR signature significantly and negatively associated with metastasis (P=0.019; OR: 0.54) and overall survival (P=0.0919; OR: 0.37).

Conclusion: The interconnected discovery-validation approach identified a novel signature of 3 aberrantly expressed miRs as a potential prognostic indicator for disease outcome among RCC patients. Early detection of metastasis using the validated qPCR assay for the 3-miR signature may allow early intervention for improving patient prognosis.

Citation Format: Soum D. Lokeshwar, Andre R. Jordan, Sarrah S. Lahorewala, Vinata B. Lokeshwar. Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature [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 2658.
Abstract 2659: GLUT1 variants and the prognosis of patients with NSCLC after surgery
Authors: Lee Shin Yup , Do Sook Kyung , Choi Jin Eun , Neugent Michael , Goodwin Justin , Kim Jung-whan , Park Jae Yong
Published: August 2018

Background This study was conducted to investigate whether polymorphisms of glucose transporter 1 (GLUT1) gene are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection.

Methods Five single nucleotide polymorphisms (SNPs) in GLUT1 were investigated in a total of 354 patients with NSCLC who underwent curative surgery. The association of the SNPs with overall survival (OS) was analyzed.

Results Among the five SNPs investigated, two SNPs (GLUT1 rs3820589T>A and rs4658G>C) were significantly associated with OS in multivariate analyses. GLUT1 rs3820589T>A was associated with significantly better OS (adjusted hazard ratio [aHR] = 0.57, 95% confidence interval [CI] = 0.34-0.94, P = 0.03, under dominant model), and rs4658G>C was associated with significantly worse OS (aHR = 1.91, 95% CI = 1.09-3.33, P = 0.02, under recessive model). In the stratified analysis by tumor histology, the effect of these SNPs on OS was only significant in squamous cell carcinoma, but not in adenocarcinoma. When the two SNPs were combined, OS decreased as the number of bad genotypes increased (Ptrend = 4 × 10-3).

Conclusion This study suggests that genetic variation in GLUT1 may be useful in predicting survival of patients with early stage NSCLC.

Citation Format: Shin Yup Lee, Sook Kyung Do, Jin Eun Choi, Michael Neugent, Justin Goodwin, Jung-whan Kim, Jae Yong Park. GLUT1 variants and the prognosis of patients with NSCLC after surgery [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 2659.
Abstract 2665: Bioassay approach isolation and crystal structure elucidation of isoglabratephrin: A prenylated flavonoid from Tephrosia apollinea and its anticancer property
Authors: Hassan Loiy E. Ahmed , Iqbal Muhammad Adnan , Majid Aman Shah Abdul , Majid Amin M. Abdul , Zainudeen Zarina Thasneem
Published: August 2018

Cancer is characterized by uncontrolled cell division caused by dysregulation of cell proliferation. Therefore, agents that impair cancer cell proliferation could have potential therapeutic value. Higher plants are considered to be a good source of anticancer agents, and several clinically tested chemotherapeutic agents have been isolated from plants or derived from constituents of plant origin. In the present study, a prenylated flavone (isoglabratephrin) was isolated from aerial parts of Tephrosia apollinea using a bioassay-guided technique. Chemical structure of the isolated compound was elucidated using spectroscopic techniques (NMR, IR, and LC-MC) and confirmed using single crystal X-ray analysis. The antiproliferative effect of isoglabratephrin was tested using three human cancer cell lines (prostate (PC3), pancreatic (PANC-1), and colon (HCT-116) and one normal cell line (human fibroblast). Isoglabratephrin displayed selective inhibitory activity against proliferation of PC3 and PANC-1 cells with median inhibitory concentration values of 20.4 and 26.6μg/ml, respectively. Isoglabratephrin demonstrated pro-apoptotic features, as it induced chromatin dissolution, nuclear condensation, and fragmentation. It also disrupted the mitochondrial membrane potential in the treated cancer cells. Thus, isoglabratephrin could be a new lead for development of cancer chemotherapies to treat human prostate and pancreatic malignancies.

Citation Format: Loiy E. Ahmed Hassan, Muhammad Adnan Iqbal, Aman Shah Abdul Majid, Amin M. Abdul Majid, Zarina Thasneem Zainudeen. Bioassay approach isolation and crystal structure elucidation of isoglabratephrin: A prenylated flavonoid from Tephrosia apollinea and its anticancer property [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 2665.
Abstract 2667: Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma
Authors: Moll Garrick M. , Yuzbasiyan-Gurkan Vilma
Published: August 2018

Treatment success in lymphoma, the most common hematopoietic cancer seen in dogs and cats, continues to be elusive. The clinical arsenal is limited to a few conventional chemotherapeutic drug protocols that result in short-term responses. In this study, dog and cat patient-derived tumor cells were tested via high-throughput screening (HTS) against a pool of over 100 FDA-approved compounds for human cancer treatment as a means to identify potential treatment strategies that can be relatively easily adapted to the dog and cat, as well as over 500 protein kinase inhibitors as a means to identify potential oncogenic driver pathways. Cells from lymph node fine needle aspirates, pleural effusions, or peripheral blood mononuclear cells from over 20 lymphoma patients were placed in cell culture media with and without growth factors. Cells from two cases, ZS15 from a Boxer dog and MT16 from a domestic shorthair cat, have continued to expand for over 12 and 6 months, respectively. Characterization by flow cytometry for detection of CD3 and CD21 identified these patient-derived cells to be T-cell lymphocytes. HTS and follow-up dose response curve (DRC) assays were performed, identifying multiple drugs effective in inhibiting growth of MT16 and ZS15 cells at nanomolar concentrations in vitro; these included anthracenedione/anthracycline-class and actinomycin-class drugs, as well as mRNA synthesis, microtubule/spindle formation, proteasome, histone deacetylase, or insulin growth factor-1 receptor inhibitors, many of which are currently not used in veterinary species. Notably, ZS15 cell growth was inhibited by mammalian target of rapamycin (mTOR) inhibitors, corroborating previous exome sequencing data of Boxer T-cell lymphomas that identified recurrent driver mutations in the PTEN-mTOR pathway. In addition, many of these drugs showed much higher IC50s in HTS and DRC assays on primary canine and feline fibroblasts, used as surrogates for normal tissue, revealing the specificity of their action on the cancer cells. These results advocate use of HTS and DRC assays as a means for identification of oncogenic driving mechanisms and for identification of drugs novel to veterinary medicine that warrant further investigation as alternative treatments for lymphoma in companion animals, which in turn can serve as valuable and accessible models for human lymphomas.

Citation Format: Garrick M. Moll, Vilma Yuzbasiyan-Gurkan. Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma [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 2667.
Abstract 2668: Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads
Authors: Ding Ye , Li Dengfeng , Ding Chunyong , Liu Zhiqing , Wold Eric A. , Ye Na , Chen Haiying , White Mark A. , Shen Qiang , Zhou Jia
Published: August 2018

The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin.

Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads [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 2668.
Abstract 2669: Identification of a novel small-molecule inhibitor for treatment of human colon cancer patients
Authors: Park Chun-Ho , Hur Sun-Chul , Kim Joseph , Lee Dae Hee , Park Yoon Sun , Shin Jae-Sik , Hong Seung-Woo , Moon Jai-Hee , Kim Hyojin , Lee So Hee , Park Hyebin , Jung Joonyee , Kim Mi Jin , Park Sang Soo , Hong Jun Ki , Gong Ji Hee , Kim Jieun , Ku Il-Whea , Lee Hyun Ho , Jin Dong-Hoon
Published: August 2018

As the representative targeted anticancer drug for colon cancer patients, Erbitux is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild-type colon cancer patients. Even some patients with KRas wt gene did not respond to Erbitux. However, there is no treatment available for Erbitux-resistant patient group with KRAS WT gene, which is almost 50% of KRAS WT gene holders. Recently, our team identified Erbitux primary resistant related proteins named as CRG (Cetuximab-Resistant Gene) by array analysis based Erbitux responder or nonresponder colon cancer patients derived tissues and confirmed by in vitro and in vivo assay system. Based on these results, we synthesized a novel series of CRG targeted inhibitor. CRG inhibitor (CRG i;WM compound) is a lead compound for treating colon cancer patients who do not respond to Erbitux and have KRAS wild-type gene. CRG i has potent in vitro enzyme activity and high anticancer activity against various colon cancer cell lines with good selectivity in in vitro and in vivo system. Furthermore, the compound has good potent ADME/Tox. profiles for optimized lead. CRG i also displays strong anticancer effect in in vivo xenograft models and patient-derived xenograft (PDX) models. In addition, CRG i shows promising signs of overcoming Erbitux resistance in CRG knockout cells-derived xenograft model. We continue to discover improved preclinical candidates with better selectivity and ADME/Tox. profiles and validate predictive biomarker in colon cancer patients. In these efforts, we found some compounds with better profiles than CRG i. We are also trying to develop small molecules having highly potent activity against mutant CRG. In conclusion, active CRG is a promising biomarker and target for Erbitux-resistant KRAS wt colon cancer patients. Our compounds can be promising therapeutic agents for Erbitux-resistant KRAS wt colon cancer patients.

Citation Format: Chun-Ho Park, Sun-Chul Hur, Joseph Kim, Dae Hee Lee, Yoon Sun Park, Jae-Sik Shin, Seung-Woo Hong, Jai-Hee Moon, Hyojin Kim, So Hee Lee, Hyebin Park, Joonyee Jung, Mi Jin Kim, Sang Soo Park, Jun Ki Hong, Ji Hee Gong, Jieun Kim, Il-Whea Ku, Hyun Ho Lee, Dong-Hoon Jin. Identification of a novel small-molecule inhibitor for treatment of human colon 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 2669.