bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A143: Repurposing disulfiram as a potential novel treatment of drug-resistant metastatic colorectal cancer
Authors: Stenvang Jan , Keinicke Helle , Nielsen Signe L. , Jandu Haatisha , Bartek Jiri , Brünner Nils 
Published: August 2018

Abstract
Introduction: Drug repurposing has emerged as an attractive alternative to the classical pipeline of drug development for novel anticancer drugs. We have selected disulfiram, which was FDA approved for treatment of alcoholism already in 1951. Disulfiram has been examined in various in vitro cancer model systems and has demonstrated several different mechanistic types of anticancer effects. The consensus is that coadministration of divalent metal ions, especially copper, is required for the maximal anticancer effect of disulfiram. Disulfiram has also been investigated in a few clinical trials but with a difference in efficacy. However, there are no data on the clinical effects of disulfiram in patients with colorectal cancer, and no studies on disulfiram in colorectal cancer can be found at www.clinicaltrials.org. Methods: We have established a research platform consisting of isogenic pairs of parental (sensitive) and drug-resistant human colorectal cancer cell lines (HT-29, HCT-116, LoVo) with resistance to either oxaliplatin or SN-38 (the active metabolite of irinotecan) (Jensen et al., Mol Oncol 2015 9(6):1169-85). We have tested disulfiram ± copper in this panel. MTT assay was used to estimate cell number. Results: In all 9 cell lines it was observed that addition of copper to disulfiram resulted in increased cell cell viability inhibition. Even more importantly, when combining disulfiram and copper with oxaliplatin or SN38, an additive or synergistic viability inhibitory effect was observed with oxaliplatin in SN-38 resistant cell lines and with SN-38 in oxaliplatin resistant cell lines. Conclusions: Based on these in vitro results, we are now planning a clinical phase 2 study using Simon’s two-stage min/max design enrolling metastatic colorectal cancer patients having failed first-line treatment with either oxaliplatin- or irinotecan-containing treatment. The patients will as second-line treatment receive irinotecan- or oxaliplatin-containing treatment (depending on their first-line treatment) plus disulfiram and copper. Endpoint will be objective response rate according to RECIST version 1.1.
Citation Format: Jan Stenvang, Helle Keinicke, Signe L. Nielsen, Haatisha Jandu, Jiri Bartek, Nils Brünner. Repurposing disulfiram as a potential novel treatment of drug-resistant metastatic colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A143.
Abstract A203: Generation of human TIM3 knock-in mice for preclinical efficacy assessment of therapeutic antibodies
Authors: Zheng Lei , Huang Xuesong , Ouyang Wenyi , Chen Gang , An Annie Xiaoyu , Dong Xin , Liu Jay , Wery Jean Pierre , Shi Qian , Ouyang Davy Xuesong 
Published: August 2018

Abstract
Immune checkpoint inhibitors, i.e., PD1 and CTLA4 antibody therapeutics, have led to long-term survival in many late-stage solid tumor patients. Despite this revolutionary clinical impact, the overall response rate is still low. One major roadblock is that compensatory immune inhibitory pathways were turned on to protect tumor cells from being attacked by T cells. T cell immunoglobulin- and mucin domain-containing molecule 3 (Tim-3) is a type I transmembrane protein expressed in T cells, monocytes, macrophages, and dendritic cells. PD-1 and Tim-3 coexpression is often associated with an exhausted phenotype of tumor-infiltrating lymphocyte (TIL) in various tumor types. TIM-3 expression has been reported as a compensatory mechanism in the PD1 nonresponsive patients. Simultaneously targeting PD1 and TIM3 is now being actively tested in clinical trials. However, we still do not have an animal model that can efficiently evaluate the efficacy of therapeutic TIM3 antibodies or combinations. Here we report generation of a human TIM3 knock-in C57BL/6 mouse model, in which we replaced mouse exon 2-5 of HAVCR2 gene with human counterparts. The engineered knock-in mice express a chimeric TIM3 where its extracellular and transmembrane domains are human sequence, while the signal peptide and intracellular domain are kept intact. We confirmed that homozygous knock-in mice only express this chimeric TIM3, recognizable by human TIM3 antibody in NK cells, macrophages, and stimulated T cells. In an efficacy study, we inoculated the TIM3 knock-in mice with MC38 syngeneic tumor cells. Treating the mice with 5 mg/kg of human TIM3 antibody resulted in modest tumor growth inhibition (TGI), while in combination with anti-mouse PD1 antibody, the TGI improved to 62% following 2 weeks of treatment. We are now breeding the human PD1 and human TIM3 double knock-in mice to test the combinatory therapeutic antibodies. We have also developed human PD-L1 expressing MC38 cells, so that when inoculated in human TIM3 knock-in mice, PD-L1 and TIM3 therapeutic combination can be evaluated.
Citation Format: Lei Zheng, Xuesong Huang, Wenyi Ouyang, Gang Chen, Annie Xiaoyu An, Xin Dong, Jay Liu, Jean Pierre Wery, Qian Shi, Davy Xuesong Ouyang. Generation of human TIM3 knock-in mice for preclinical efficacy assessment of therapeutic antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A203.
Abstract B005: FPT155, a novel therapeutic CD80-Fc fusion protein with potent antitumor activity in preclinical models
Authors: Barbee Susannah D. , Sennino Barbara , De La Torre Jacqueline , Macal Monica , Walker Quinn , Jabon Marc R. , Chen Amanda , Busha David A. , Best Margaret , Pierce Kristen L. , Borges Luis , Baker Kevin P. , Brennan Thomas 
Published: August 2018

Abstract
Optimal activation of T cells requires both antigen-specific signaling and induction of costimulatory pathways. Costimulatory pathways are upregulated by foreign antigenic challenge but are not active in the normal immune state, thus maintaining peripheral tolerance to self-antigens. The absence of costimulatory signaling may likewise play a role in tolerance to cancer cells. Five Prime has developed a CD80 (B7.1) extracellular domain (ECD)-Fc fusion protein (FPT155) as a costimulatory molecule that can stimulate T-cell activation and break tumor immune tolerance. In vitro studies show that FPT155 induces T-cell activation and cytokine production via CD28. FPT155 activity requires T-cell receptor engagement, which indicates that FPT155 is not a CD28 “superagonist” that can drive T-cell activation independently of antigenic stimulation. To investigate the impact of CD80-Fc in preclinical models, we generated murine FPT155 (mFPT155), a surrogate fusion protein, composed of the mouse CD80 ECD fused with the murine Fc region of IgG2a. mFPT155 is well tolerated in mice and has potent efficacy in syngeneic tumor models, including the induction of complete tumor regression in the CT26 model. mFPT155 promotes the infiltration of T cells into the tumor core and increases the effector T:Treg ratio, thus inducing a favorable microenvironment for an effective antitumor immune response. Furthermore, combination of mFPT155 and anti-PD1 therapy leads to stronger antitumor efficacy compared to either therapy alone. Together these results indicate that mFPT155 is a potent T-cell costimulator with strong antitumor activity in mouse tumor models. We are currently performing IND-enabling studies and plan to initiate a clinical study with FPT155 in 2018.
Citation Format: Susannah D. Barbee, Barbara Sennino, Jacqueline De La Torre, Monica Macal, Quinn Walker, Marc R. Jabon, Amanda Chen, David A. Busha, Margaret Best, Kristen L. Pierce, Luis Borges, Kevin P. Baker, Thomas Brennan. FPT155, a novel therapeutic CD80-Fc fusion protein with potent antitumor activity in preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B005.
Abstract B148: Activity of the TAM kinase-targeting compound, SLC-391, is mediated by the engagement of the immune system in CT-26 syngeneic mouse model
Authors: Lai Shenshen , Li Rick , Raha Paromita , Hu Yuxiang , Yan Jun , Zhang Hong , Marotta Anthony , Zhang Zaihui 
Published: August 2018

Abstract
Overexpression of TAM family receptor tyrosine kinases such as Axl has been reported in numerous types of human cancer, and found to correlate with tumor progression and prognosis, metastasis, and drug resistance. Aside from the role in cell growth and survival, TAM kinases have long been recognized for their immunosuppressive activity as well. Hence, downregulation of their activity is expected to unleash antitumor immunity in the tumor microenvironment. As one of the several TAM-targeting small-molecule inhibitors identified, SLC-391 displays a relatively strong activity against Axl, as evidenced by the reductions of phosphotransferase activity in radiometric biochemical assay and the level of Axl Y779 phosphorylation in the cell-based assay. Contradictorily, proliferation of CT-26 murine colon carcinoma cells seemed to be unaffected by the compound in the thymidine incorporation assay with an IC50 of ~10 μM. Interestingly, SLC-391 inhibited CT-26 tumor growth by 37% in a 15-day efficacy study in which the compound was administered at 50 mg/kg p.o.. In comparison, a PD-1 antibody delayed tumor growth by 27%. Tumor-infiltrating lymphocyte phenotyping revealed increases in the number of NK cells and the ratio of M1/M2-polarized macrophages in SLC-391 treatment group, followed by the rise of CD8+ T/Treg ratio and reduction in immunosuppressive myeloid cells. This is indicative of sequential engagement and stimulation of proinflammatory innate immune response and adaptive immune response. In addition, a synergistic antitumor effect was observed when the anti-PD-1 insensitive CT-26 syngeneic model was treated with a combination of SLC-391 and an anti-PD-1 antibody and the overall survival rate of the combination group was prolonged dramatically in comparison with the vehicle control group. To summarize, the antitumor activity of SLC-391 is at least in part mediated by reversing the immunosuppressive tumor microenvironment in CT-26 colon carcinoma model.
Citation Format: Shenshen Lai, Rick Li, Paromita Raha, Yuxiang Hu, Jun Yan, Hong Zhang, Anthony Marotta, Zaihui Zhang. Activity of the TAM kinase-targeting compound, SLC-391, is mediated by the engagement of the immune system in CT-26 syngeneic mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B148.
Abstract LB-A03: Allele specific HLA loss and immune escape in lung cancer evolution
Authors: McGranahan Nicholas , Rosenthal Rachel , Hiley Crispin T. , Rowan Andrew J. , Watkins Thomas B.K. , Wilson Gareth A. , Birkbak Nicolai J. , Veeriah Selvaraju , Loo Peter Van , Herrero Javier , Swanton Charles 
Published: August 2018

Abstract
Cancer cells adopt a variety of mechanisms to evade the immune system and avoid T-cell recognition. Disruption of human leukocyte antigen (HLA), which may lead to reduced neoantigen presentation, has been proposed as an immune escape strategy in many cancers, including lung cancer. Mutations in HLA class I genes are infrequent in early stage non-small cell lung cancers (NSCLC), suggesting alternative mechanisms of HLA disruption may be common. To date, the polymorphic nature of the locus has precluded copy number analysis and exploration of HLA loss. To investigate the prevalence and importance of HLA disruption, we present LOHHLA (Loss Of Heterozygosity in Human Leukocyte Antigen), a computational tool to determine HLA allele-specific copy number from sequencing data. Building upon previous work imputing HLA haplotypes from sequencing data (Shukla, 2015; Szolek, 2014) and utilizing previously published datasets (Jamal-Hanjani, 2017; Brastianos, 2015), we endeavored to address the prevalence and timing of HLA LOH in lung cancer and its impact on tumor evolution and neoantigen presentation. Using LOHHLA, we find HLA LOH occurs in 40% of NSCLCs and is associated with a high subclonal neoantigen burden, APOBEC mediated-mutagenesis, upregulation of cytolytic activity and PD-L1 positivity. The focal nature of these alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggest that HLA LOH is an immune escape mechanism, selected later in NSCLC tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for immunotherapeutic approaches targeting neoantigens.
Citation Format: Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton. Allele specific HLA loss and immune escape in lung cancer evolution [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A03.
Abstract LB-B30: First in human, dose escalation trial of the combination of dabrafenib, trametinib, and navitoclax in patients with BRAF mutant solid tumors
Authors: Sullivan Ryan J. , Mehnert Janice , Tawbi Hussain , Lawrence Donald , Flaherty Keith , Chen Helen , Takabe Naoko , Davies Michael 
Published: August 2018

Abstract
Combined BRAF and MEK inhibitor therapy is associated with responses in patients (pts) with BRAF mutant solid tumors. Preclinically, the addition of the BH3 mimetic navitoclax improves the efficacy of BRAF inhibitor therapy to BRAF mutant cell lines. CTEP study P9466 (NCT01989585) is a clinical trial designed to test the safety of the combination of dabrafenib, trametinib, and navitoclax (DTN) in patients with BRAF mutant solid tumors.
The primary objective of this dose escalation trial was to determine the recommended phase 2 dose (RP2D) of DTN. From March 2014 to August 2017, 25 pts were enrolled, using a 3+3 design, at three dose levels (DL). A one week lead-in of navitoclax 150 mg QD was used to limit thrombocytopenia.
Dose limiting toxicities (DLTs) occurred at every dose level and included Grade 3 (Gr) alkaline phosphatase, Gr 3 Rash, Gr 4 thrombocytopenia, and Gr 3 fever. The RP2D was determined to be D 150 mg BID, T 2 mg QD, N 225 mg QD. Severe adverse events (SAEs) occurred in 10 pts. There was one Gr 5 SAE that was possibly related to study drugs (acute kidney injury). Twenty-two of 25 pts were eligible for preliminary efficacy assessment at the time of this submission. Best response, per RECIST1.1, was complete (CR) or partial (PR) response in 6 pts, stable disease (SD) in 7 pts, and disease progression (PD) in 8 pts. Of note, PD was the best response for all 5 pts with melanoma (mel) previously treated with a BRAF inhibitor. In the 6 mel pts who had not received a prior BRAF inhibitor, 5 had a PR or CR (1). Disease control (PR or SD) was seen in most colon cancer (3 of 5) and thyroid cancer (4 of 5) pts.
DTN at the RP2D was determined to be safe with preliminary efficacy in pts with BRAF mutant solid tumors. Based on this preliminary data, the randomized phase II portion of this trial of DTN compared to DT in BRAF mutant naïve patients is opening in the ETCTN in the Fall of 2017.
Citation Format: Ryan J. Sullivan, Janice Mehnert, Hussain Tawbi, Donald Lawrence, Keith Flaherty, Helen Chen, Naoko Takabe, Michael Davies. First in human, dose escalation trial of the combination of dabrafenib, trametinib, and navitoclax in patients with BRAF mutant solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B30.
Abstract 1155: The SRGTM rat: A novel SCID rat for humanization studies
Authors: Noto Fallon K. , Towobola Bisoye , Arey Angela , Narla Goutham , Chengelis Christopher , Yeshi Tseten 
Published: August 2018

Abstract
In vivo modeling of human cancer in genetically engineered rodents can provide insights into tumor kinetics, genetics and molecular biology, and allow for the testing of drug efficacy. Over the recent years, studies have demonstrated that immunodeficient mice, such as the NSG, reconstituted with functional human immune cells, such as peripheral blood mononuclear cells (PBMCs), are promising models for immuno-oncology efficacy studies. Immune humanized mice engrafted with human cancer cells show human-specific immune responses when treated with drugs that target immune pathways, such as CTLA-4 and PD-1, leading to the inhibition of tumor growth. These models provide a critical platform to study how the immune system can be engaged to drive anti-cancer efficacy.
Although the NSG and similar immunodeficient mouse strains have been beneficial for human immuno-oncology studies, there are many caveats to performing these studies in mice, including inconsistent tumor kinetics, small tumor size for downstream analyses, limited blood for PK/PD studies due to the small size of the mouse, and graft vs. host disease (GvHD) onset around 4-6 weeks post-engraftment. Humanized rat models would allow for the development of larger tumors and the ability to perform serial blood sampling on a routine basis throughout the course of treatment. We have created a Rag2 null, Il2rg null rat on the Sprague Dawley background (SRGTM) that lacks B, T, and NK cells and supports the growth of multiple human cancer cell lines, including lines that do not engraft or grow well in existing mouse models: HCT-116, H358, and VCaP. The SRGTM rat is also permissive to immune humanization with PBMCs. PBMC-engrafted SRGTM rats have a significant amount of human CD45+ lymphocytes in peripheral blood, of which the majority are T cells, comparable to immune-humanized NSG and NOG mice. Some animals also show significant levels of circulating human B cells. Interestingly, the incidence of GvHD is delayed to 12-14 weeks post-engraftment in the immune humanized SRG™ rat.
We are currently assessing functionality of the PBMC-immune humanized SRG™ rat in immuno-oncology studies as well as characterizing the ability of the SRG™ rat to support the growth of human patient derived xenografts (PDX). The generation of this novel humanized SRG™ rat model could allow for a more permissive host system to test existing and novel immunomodulatory strategies for the treatment of human disease.
Citation Format: Fallon K. Noto, Bisoye Towobola, Angela Arey, Goutham Narla, Christopher Chengelis, Tseten Yeshi. The SRGTM rat: A novel SCID rat for humanization studies [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 1155.
Abstract 1235: Repeated whole-exome sequencing for cell-free tumor DNA profiling of colon cancer patients: Searching for mechanisms of acquired chemoresistance
Authors: Vymetalkova Veronika , Pardini Barbara , Jiraskova Katerina , Urbanova Marjketa , Levy Miroslav , Veskrnova Veronika , Vodicka Pavel , Naccarati Alessio 
Published: August 2018

Abstract
Colorectal cancer (CRC) is a worldwide health burden with nearly 1.2 million new cases expected each year globally. When CRC is identified early, there is a five-year survival rate of about 90% but it drops to almost 12% once there are distant metastases. Drug resistance is a limiting factor of the efficacy of chemotherapy in CRC treatment. Significant efforts are currently being employed to discriminate patients who will benefit or not from chemotherapy. In fact, there is no current 'gold standard' to differentiate responders from non-responders. In the present work, we focused on good responders (those who benefit from the chemotherapy, not having side effects like toxicity, no relapses and having a complete response with no residual cancer) and non-/bad responders (patients with acquired chemoresistance and lack any response, or developing toxicity). The main aim was to identify markers/mutations in plasma cell-free DNA that could be associated with good/bad responders and chemoresistance. Paired plasma samples from colon cancer patients collected before and after therapy and the relative cell-free tumor DNA (ctDNA) was profiled by a whole exome sequencing approach in order to identify novel acquired mutations. Plasma ctDNA was isolated by QIAamp Circulating Nucleic Acid Kit. The SureSelectXT HS Reagent Kit was used for library preparation and libraries were sequenced by the HiSeq2500 system. Analysis was performed on nine patients (stage II and III) treated with the same 5-FU based therapy. The first sampling was collected at the time of diagnosis (i.e., active disease), and the second after 6-9 months depending on patient` s conditions (i.e., covering the tumor resection, administration of adjuvant chemotherapy). After follow up, three patients were classified as good responders and six as non/poor responders. The bioinformatics analysis is currently running. The number of total reads exceeded 990x106. Total length of all exons was 221,924,089bp. After trimming, the average read length was 113bp. Alignment to human reference genome (hg38) is &gt; 99.8%. Coverage of exons ranges from 17 to 34. Results of the study will be presented during the meeting.
Supported by grant AZV MZ 17-30920A, 15-26535A and GACR 17-16857S.
Citation Format: Veronika Vymetalkova, Barbara Pardini, Katerina Jiraskova, Marjketa Urbanova, Miroslav Levy, Veronika Veskrnova, Pavel Vodicka, Alessio Naccarati. Repeated whole-exome sequencing for cell-free tumor DNA profiling of colon cancer patients: Searching for mechanisms of acquired chemoresistance [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 1235.