bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT090: Neoadjuvant chemotherapy of FOLFIRI with or without radiotherapy in the treatment of marginally resectable recurrent rectal cancer exposed to oxaliplatin: A cohort study
Authors: Xiao Jian , Cai Zerong , Tan Yingxin , Chen Yufeng , Deng Yanhong , Zou Yifeng , Wu Xiaojian , Lan Ping 
Published: August 2018

Abstract
Background
FOLFIRI is the standard second-line chemotherapy for recurrent rectal cancer previously exposed to oxaliplatin. For resectable recurrent rectal cancer, the optimal sequence of chemotherapy and resection is still unknown. We carried out a cohort study to evaluate the efficacy and feasibility of neoadjuvant chemotherapy of FOLFIRI in this setting.
Patients and Methods
Patients aged from 18 to 80 year-old with histologically confirmed and resectable recurrent rectal adenocarcinoma previously exposed to oxaliplatin were recruited. Resectability was decided by three colorectal surgeons. Eligible patients received six preoperative and six more postoperative FOFIRI regimens (irinotecan 180mg/m2 , folinic acid 400mg/m2 and fluorouracil 2800mg/m2, repeated every 14 days). Tumor response was assessed after 3 and 6 cycles. The primary end point was R0 resection rate and the second end points were grade 3 or 4 toxicity and tumor regression grade (Ryan). All the patients signed written informed consent.
Result
65 eligible patients were enrolled in this trial. According to RECIST criteria, 22 ( 33.8%) cases had partial remission, 18 ( 27.7%) cases had stable disease, 24 ( 36.9%) cases had progression disease and 1 patient refused to evaluate and quit study. 21 ( 32.8%) patients achieved R0 resection with 5 cases of TRG 1, 11 cases of TRG 2 and 5 cases of TRG 3. 25 patients received concurrent radiotherapy. Grade 3 or 4 toxicity was seen in 4 (6%) patients. One patient had intestinal perforation and one had bowel obstruction during chemotherapy. No one died during treatment.
Conclusion
Neoadjuvant chemotherapy of FOLFIRI in resectable recurrent rectal cancer can be well tolerated. But more active regimen is still needed for this setting to accomplish better outcome.
Funding: This study was supported by 5010 Project of Clinical Research of Sun Yat-sen University (2010012)
Citation Format: Jian Xiao, Zerong Cai, Yingxin Tan, Yufeng Chen, Yanhong Deng, Yifeng Zou, Xiaojian Wu, Ping Lan. Neoadjuvant chemotherapy of FOLFIRI with or without radiotherapy in the treatment of marginally resectable recurrent rectal cancer exposed to oxaliplatin: A cohort study [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 CT090.
Abstract CT092: Effect of tumor treating fields in children with recurrent or progressive high-grade glioma and ependymoma; Pediatric Brain Tumor Consortium PBTC048
Authors: Goldman Stewart , Onar-Thomas Arzu , Dunkel Ira , Hwang Eugene 
Published: August 2018

Abstract
Background: Current treatment regimens show poor prognosis in recurrent or progressive pediatric CNS tumors. Children with high-grade gliomas (HGG) after progression cannot be cured, with reported median survival &lt;1-2 years. Overall survival (OS) of pediatric recurrent/progressive ependymoma is also poor. Tumor Treating Fields (TTFields) is an anti-mitotic cancer therapy for the treatment of recurrent (supratentorial) glioblastoma (GB). A phase 3 clinical trial in adults with newly-diagnosed GB was stopped early due to significant improvements of event-free (EFS) and OS in patients receiving TTFields in conjunction with temozolomide. A separate phase 3 trial comparing TTFields monotherapy with physician's choice chemotherapy in adults with recurrent GB demonstrated comparable OS and improved quality-of-life (QoL).
Methods: This multicenter feasibility trial [NCT03033992] will examine the feasibility and device-related toxicity of TTFields in children aged 5-21 years with supratentorial HGG and ependymoma. The secondary objectives include: response rate, event-free survival, compliance and QoL. To establish feasibility Optune device will need to be worn ≥18 hours/day for at least 23/28 days of cycle one. Patients will have a brain MRI with/without contrast performed prior to therapy, after cycles 2, 4, 6, 9, then every 3 cycles thereafter until time of progression or completion of treatment. Treatment may continue up to 26 cycles based on observed benefit and safety. A sample size of 20 patients is planned with an interim analysis after the first 11 patients. Kaplan-Meier estimates of EFS for all eligible patients will be provided separately for the HGG and ependymoma cohorts. The rates of confirmed sustained objective responses (CR+PR) observed during treatment will be estimated. All PROMIS and Neuro-QoL scores will be reported using T-score matrix (mean=50; SD=10). The projected accrual rate is 1.5-2.5 patients per month with a follow-up for 2 years. The study is currently accruing patients.
Citation Format: Stewart Goldman, Arzu Onar-Thomas, Ira Dunkel, Eugene Hwang. Effect of tumor treating fields in children with recurrent or progressive high-grade glioma and ependymoma; Pediatric Brain Tumor Consortium PBTC048 [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 CT092.
Abstract CT098: Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)
Authors: Cohen Ezra , Bishnoi Sarwan , Laux Douglas E. , Wong Deborah , Amin Asim , Nabell Lisle , Schmidt Emmett V. , Xing Biao , Leung Abraham C. , Janssen Robert 
Published: August 2018

Abstract
Background and Objectives: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembrolizumab is a PD-1 inhibitor that has demonstrated activity in HNSCC with ORR of 14%. Study DV3-MEL-01 (NCT02521870) assesses the safety and preliminary efficacy of SD-101 in combination with pembrolizumab in patients with recurrent or metastatic HNSCC.
Methods: In phase 2 expansion cohort for anti-PD-1 treatment naïve HNSCC patients, SD-101 was injected in a single tumor lesion (weekly x 4 doses then every 3 weeks x 7 doses) at 8 mg and pembrolizumab was administered intravenously at 200 mg every 3 weeks. Responses are assessed per investigator using RECIST v1.1/irRECIST.
Preliminary Data and Results: 16 anti-PD-1 treatment naïve HNSCC patients are enrolled to date: median age 65 y/o, male 94%, ECOG PS1 63%, median prior lines of therapy 1. SD-101 safety profile consists of flu-like symptoms and injection-site reactions. Grade≥3 treatment-related AEs observed to date included influenza-like symptoms, myalgia, headache, injection site pain and swelling, and fatigue with each of the toxicities occurring in 1 patient (6.7%). No increase in frequency of known pembrolizumab immune-related AEs has been observed to date. ORR in evaluable pts (n=10) was 40% (4 PRs; 1 SD, 5 PDs with 1 still on treatment). The duration of response will be characterized when follow-up data become more mature.
Conclusions: In anti-PD-1 treatment naïve HNSCC patients, SD-101 in combination with pembrolizumab showed a promising response rate and has been well tolerated. Full accrual of subjects in this cohort is ongoing.
Citation Format: Ezra Cohen, Sarwan Bishnoi, Douglas E. Laux, Deborah Wong, Asim Amin, Lisle Nabell, Emmett V. Schmidt, Biao Xing, Abraham C. Leung, Robert Janssen. Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) [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 CT098.
Abstract DDT01-05: ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor
Authors: Kati Warren 
Published: August 2018

Abstract
The BET family of proteins consists of BRD2, BRD3, BRD4 and BRDT, with each of these proteins containing two distinct bromodomains (BDI and BDII). ABBV-075, like other first generation BET family bromodomain inhibitors currently under clinical development, binds to each of the 8 bromodomains with similar affinity and inhibits the proliferation of cancer cells that represent a wide range of tumor types. We hypothesized that selectively targeting specific subsets of the BET bromodomain might abolish this broad spectrum profile such that only the tumor types that are highly addicted to the subtype specific BET bromodomain-mediated transcription would remain sensitive to these selective agents. The BDII bromdomains are highly conserved across BET family members (&gt;70% identity), suggesting that the generation of compounds that are selective for the four BDII bromodomains relative to the four BDI bromodomains might be achievable. Structure-based design targeting the Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) helped to guide the identification of structural analogs of ABBV-075 demonstrating greater than 300X selectivity for BRD4 BDII over BRD4 BDI. Further elaboration ultimately resulted in the discovery of BDII-selective compounds with improved oral bioavailability and the identification of the clinical asset ABBV-744. In striking contrast to the broad range of cell growth inhibition effected by pan BET inhibitor ABBV-075, the anti-proliferative activity for BDII-selective ABBV-744 was largely but not exclusively restricted to AML and androgen receptor (AR) positive prostate cancer cell line models, including models of Enzalutamide resistance. In vivo, doses of ABBV-744 at fractions of its MTD induced tumor growth inhibition in AML and prostate cancer xenograft models that were comparable to those observed with ABBV-075 when dosed at its MTD. Together, these in vitro and in vivo results provide proof of concept that highly selective BDII BET family bromodomain inhibitors may have improved tolerability relative to pan-BET inhibitors while maintaining tumor growth inhibition in AML and AR positive prostate cancer. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Citation Format: Warren Kati. ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor [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 DDT01-05.
Abstract LB-003: Novel multi-functional chemoprobes for the characterization of the mechanism of action of histone lysine demethylases inhibitors in cancer
Authors: Lunardi Serena , Ciceri Filippo , Crusat Cristina Mascaró , Ruiz Raquel , Carceller Elena , Ortega Alberto , Sacilotto Natalia , Dessanti Paola , Salas Jordi , Lufino Michele , Maes Tamara 
Published: August 2018

Abstract
Histone Lysine demethylases (KDMs) are emerging clinical targets in cancer. However, a characterization of the mechanism of action of KDMs small molecule inhibitors is limited by the fact that these targets act at multiple levels, having several substrates, different scaffolding roles and regulating gene expression in a cell-specific manner. We developed biotinylated chemoprobes capable of binding to the active site of different KDMs and demonstrated their versatility in target engagement and chemoproteomics analysis. First, we synthetized a biotinylated chemoprobe capable of binding selectively and irreversibly to the active form of KDM1A. By coupling the chemoprobe to an immune-based assay, we can quantify the levels of free KDM1A relative to total levels of KDM1A in a dose-dependent manner in vitro and in vivo. Using this assay, we measured the KDM1A target engagement in models for AML and SCLC. These data were used to perform quantitative pharmacological modeling of SCLC xenograft models treated with ORY-1001 (see Medhi et al, AACR 2018 submitted abstract). The technique can be readily applied to clinical samples and has been used to characterize the pharmacokinetic / pharmacodynamic relationship of KDM1A inhibitors in Phase I trials. In addition, we show that the proteomic profile of the chemoprobe pulldown mirrors the binding partners of inhibited KDM1A. Our proteomic analysis using the KDM1A specific chemoprobe in AML cells identified several ZNF transcription factors but SNAG domain proteins, known to bind to the inhibitor binding site, were not retrieved, providing insight in the interaction changes induced by a KDM1A inhibitor. The strategy was also applied to other targets such as Jumonji C (JmjC) domain-containing proteins like the KDM5 demethylase family, reported to play a role in the emergence of drug tolerance. Overall, this study offers important insights and tools for investigating the role of KDM inhibitors in cancer and their further development into the clinical setting.
Citation Format: Serena Lunardi, Filippo Ciceri, Cristina Mascaró Crusat, Raquel Ruiz, Elena Carceller, Alberto Ortega, Natalia Sacilotto, Paola Dessanti, Jordi Salas, Michele Lufino, Tamara Maes. Novel multi-functional chemoprobes for the characterization of the mechanism of action of histone lysine demethylases inhibitors in 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 LB-003.
Abstract LB-008: Intracellular delivery of SOCS3 suppresses hepatocelluar carcinoma progression
Authors: Shin Seulmee , Lee Kuysook , Hwang Yunseo , Choi Youngsil , Jo Daewoong 
Published: August 2018

Abstract
Background Practical methods to deliver proteins systemically in animals have been hampered by poor tissue penetration and inefficient cytoplasmic localization of internalized proteins. Therefore, we have developed novel cell-penetrating peptides (CPPs), named advanced macromolecule transduction domains (aMTDs), to deliver therapeutically active macromolecule including proteins systemically in vivo. The suppressor of cytokine signaling 3 (SOCS3) is negative feedback regulator of JAK/STAT signaling that plays a key role in inflammation, fibrosis and carcinogenesis in the liver. Furthermore, hypermethylation of CpG islands in the SOCS3 promoter is correlated with its transcriptional silencing in some cancers, including hepatocellular carcinoma (HCC). Objective The present study utilized aMTD sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutics against HCC. Methods Cell permeable SOCS3 proteins, with and without a 12-amino acid aMTD sequence, were expressed at high yields in E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers. Results iCP-SOCS3 fused to aMTD/SD suppressed cancer cell phenotypes (e.g., 84% inhibition of proliferation, arrested cell cycle progression, 86% inhibition of migration/invasion), apoptotic loss of cell viability (40 ~ 80% in HCC cell lines: Hep3B2.1-7, HepG2, Huh7 and SK-Hep1) and changes in apoptosis biomarker expression (e.g., Bcl-2 and cleaved caspase-3). In contrast, iCP-SOCS3 did not affect proliferation and apoptosis of non-cancer cells (Chang). In addition, iCP-SOCS3 also significantly suppressed the tumor growth (70% inhibition in Hep3B2.1-7; 67% inhibition in HepG2, respectively) in human-mouse xenograft models. The anti-tumor activity of iCP-SOCS3 was accompanied by changes in the expression of biomarkers linked to SOCS3 signaling including cyclin E, p21, Bax and VEGF. Furthermore, iCP-SOCS3 suppressed tumor growth equivalently to Cisplatin®, a well-established cytotoxic agent, but without observed toxicity or adverse effects. These results suggest that iCP-SOCS3 inhibits the growth of HCC tumor cells and tumor xenografts. Conclusions These results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of iCP-SOCS3 may provide a novel protein therapy against HCC.
Citation Format: Seulmee Shin, Kuysook Lee, Yunseo Hwang, Youngsil Choi, Daewoong Jo. Intracellular delivery of SOCS3 suppresses hepatocelluar carcinoma progression [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 LB-008.
Abstract LB-010: Intracellular delivery of SOCS3 suppresses solid tumor progression
Authors: Choi Youngsil , Jung Minyong , Shin Seulmee , Lee Kuysook , Jo Daewoong 
Published: August 2018

Abstract
Introduction Suppressor of cytokine signaling 3 (SOCS3) functions as a negative-feedback regulator of JAK/STAT signaling that suppresses JAK kinase activity and promotes degradation of the activated cytokine receptor complex. Loss of SOCS3 enhances the growth and survival of some solid tumors; therefore, methods to replenish intracellular levels of the protein may provide an effective therapy against solid tumors dependent on JAK/STAT signaling for growth or survival.
Objective The present study utilized advanced macromolecule transduction domain (aMTD) sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutic against solid tumors including gastric-, colorectal, lung-, breast-cancer and glioblastoma.
Methods Cell-permeable SOCS3 proteins, with (iCP-SOCS3) and without (Non-CP-SOCS3) a 12-amino acid aMTD sequence or containing an earlier generation of MTD based on the signal peptide of FGF4, termed membrane-translocating motif (MTM) were expressed and purified from E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers. The therapeutic potential of iCP-SOCS3 as anti-cancer agent for solid tumors was examined both in cultured cells and in human-mouse xenograft models.
Results Compared to CP-SOCS3, iCP-SOCS3 fused to aMTD exhibited higher solubility and yield (25- and 300-folds higher, respectively) that are sufficient to be developed for clinical use. Moreover, it exhibited cell-/tissue-permeability along with strong biological activity that was shown by significantly suppressed IFN-γ-induced phosphorylation of STAT1 and STAT3. In vitro study conducted with various cancer cell lines demonstrated that iCP-SOCS3 significantly suppresses cancer-associated phenotypes (e.g., &gt;80% inhibition of proliferation in lung cancer and glioblastoma, &gt;70% induction of apoptosis in gastric cancer, &gt;65% inhibition of migration/invasion in gastric cancer) and induces changes in biomarker expression (e.g., p21, cleavage caspase-3 in breast cancer). In addition, iCP-SOCS3 also significantly suppressed the tumor growth of human solid tumor xenografts (65% inhibition in gastric-, 79% in colorectal-, 69% in lung-, 63% in breast-cancer and 78% in glioblastoma CDXs, respectively).
Conclusion Taken together, these results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of SOCS3 with iCP-SOCS3 may provide novel protein therapy against solid tumors.
Citation Format: Youngsil Choi, Minyong Jung, Seulmee Shin, Kuysook Lee, Daewoong Jo. Intracellular delivery of SOCS3 suppresses solid tumor progression [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 LB-010.
Abstract LB-017: HER2 overexpression induces sensitivity to moringa isothiocyanates in breast cancer cells
Authors: OLAYANJU JULIA B. , Xia Bing 
Published: August 2018

Abstract
Isothiocyanates (ITCs) are a class of natural products with promising anti-cancer activities and chemopreventive prospects. Moringa oleifera is a plant widely cultivated in the tropics and has been popularly used for centuries by locals to treat different diseases. Moringa leaves contain four unique sugar-modified aromatic glucosinolates, which can be converted to moringa isothiocyanates (MICs) by myrosinase also present in the leaves. In this study, we tested the efficacy of MIC-1 on 9 different breast cancer cell lines and found it to be a potent anti-cancer agent against them. Interestingly, the two cells lines most sensitive to MIC-1, BT474 and HCC1954, were both positive for HER2, which is amplified in up to 30% of breast cancer and correlates with poor prognosis. The correlation between HER2 overexpression and hypersensitivity to MIC was further confirmed using pairs of MCF-7 and MDA-MB-231 cells with and without HER2 overexpression. In studies to understand why the HER2+ breast cancer cells were more sensitive to MIC than HER2- lines, we observed higher basal intracellular ROS levels in HER2+ breast cancer cell lines compared to HER2- cells. Moreover, we observed that MIC regulates the abundance of KEAP1 and NRF2 across the different cell lines used in this study. In some cases, MIC-1 upregulated both KEAP1 and NRF2 at the same time, suggesting that it may directly or indirectly inactivate KEAP1 thereby stabilizing NRF2. More efforts are underway to elucidate the precise mechanisms of action. Our work shows that MICs may open new frontiers in breast cancer prevention and therapy, particularly for those with HER2 amplification.
Citation Format: JULIA B. OLAYANJU, Bing Xia. HER2 overexpression induces sensitivity to moringa isothiocyanates in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-017.