bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B109: ASN004, a novel 5T4-targeted Dolaflexin ADC, causes complete and durable tumor regression in a variety of tumor xenograft models
Authors: Smith Roger A. , Zammit David J. , Reddy Sanjeeva P. 
Published: August 2018

Abstract
The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors, while showing very limited expression in normal adult tissues. This selective pattern of expression establishes 5T4 as an attractive therapeutic target for the Antibody-Drug Conjugate (ADC) strategy. ASN004 is an anti-5T4 ADC that incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and cytotoxic dolastatin (auristatin) analog warheads, with a drug/antibody ratio of ~15:1. ASN004 shows high affinity for the 5T4 antigen (Kd &lt; 30 pM), with selective binding and internalization to 5T4-expressing tumor cells. Potent, selective cytotoxicity has been determined for a diverse panel of tumor cell lines. ASN004 provides complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a range of 5T4 expression levels. Tumor-free survivors could be achieved in tumor models with a single dose of ASN004, as low as 1 mg/kg iv. The broad, superior activity of ASN004 was demonstrated in a head-to-head study against trastuzumab-DM1, in a low-5T4/high-HER2 expressing tumor model. Finally, efficacy of ASN004 in patient-derived tumor xenograft (PDX) models will be presented. In summary, ASN004 has been established as a promising ADC therapeutic for multiple tumor types, encompassing a wide range of 5T4-expression levels. IND-enabling studies are ongoing in preparation for advancement to clinical development.
Citation Format: Roger A. Smith, David J. Zammit, Sanjeeva P. Reddy. ASN004, a novel 5T4-targeted Dolaflexin ADC, causes complete and durable tumor regression in a variety of tumor xenograft 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 B109.
Abstract B135: The mechanism of action of BT1718, a novel small-molecule drug conjugate for the treatment of solid tumors expressing MT1-MMP
Authors: Bennett Gavin , Rigby Mike , Lutz Bob , Park Peter , Keen Nicholas 
Published: August 2018

Abstract
BT1718 is a small-molecule drug conjugate, also called Bicycle drug conjugate (BDC), comprising a constrained bicyclic peptide (Bicycle) that binds with high affinity and specificity to membrane type 1-matrix metalloprotease (MT1-MMP; MMP14; MT1) covalently linked through a hindered disulfide linker to the potent antitubulin agent DM1. MT1 is naturally involved in tissue remodeling; however, its overexpression is linked to increased tumor aggressiveness and metastasis. Overexpression of MT1 is associated with poor survival in NSCLC, TNBC, and other solid tumors. MT1 expression can also be observed in tumor-associated stromal cells. The Bicycle binder for BT1718 was identified using a proprietary phage display peptide technology consisting of highly diverse phage libraries of linear amino acid sequences constrained into two loops by a central chemical scaffold. While binding with similar affinity and specificity to that observed with monoclonal antibodies, the small size of a Bicycle (1.5-3 kDa) aids in its rapid extravasation and tumor penetration, making it an ideal format for the targeted delivery of cytotoxic payloads. BT1718 shows profound antitumor activities as a single agent when given at doses as low as 3mg/kg biw, producing complete regression of tumors in cell-line and patient-derived xenograft models. BT1718 is also able to produce rapid complete regression of very large tumors (~1000 mm3). We have evaluated the target dependence of antitumor activities of BT1718 by evaluating tumor response in a range of xenograft models with varying expression of MT1, as measured by mRNA, FACS, and IHC. We evaluated a panel of cell-line derived xenograft (CDX) and patient-derived xenograft (PDX) tumors across various indications including lung, breast, colorectal, stomach, head and neck cancer, and multiple myeloma. In both CDX and PDX models, the efficacy of BT1718 was dependent on the MT1 expression levels. Moderate and high MT1-expressing cell lines showed partial or complete regression when treated with BT1718, while low MT1-expressing lines showed limited or no effect. BT1718 is a first-in-class, cytotoxic small-molecule drug conjugate with great potential for treatment of MT1-expressing solid tumors and is about to begin clinical testing.
Citation Format: Gavin Bennett, Mike Rigby, Bob Lutz, Peter Park, Nicholas Keen. The mechanism of action of BT1718, a novel small-molecule drug conjugate for the treatment of solid tumors expressing MT1-MMP [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 B135.
Abstract 1220: Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant
Authors: Zhang Yi , Manjunath Mohith , Zhang Shilu , Chasman Deborah , Roy Sushmita , Song Jun S. 
Published: August 2018

Abstract
Genome-wide association studies (GWAS) have identified genetic variants that may significantly modulate breast cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; often, it is not even clear whether the GWAS variants are functional themselves or just genetically linked to other functional variants. We here provide an integrated method for identifying functional regulatory variants associated with breast cancer and their target genes by combining the analyses of expression quantitative trait loci (eQTL), a modified version of allele-specific expression (ASE) systematically utilizing haplotype information, transcription factor (TF) binding preference, and epigenetic information. Application of our method to the breast cancer susceptibility region in 5p12 demonstrates that the GWAS risk allele rs4415084-T is correlated with higher expression levels of the protein-coding gene MRPS30 and lncRNA RP11-53O19.1. We propose that an intergenic SNP, in linkage disequilibrium (LD) with the GWAS SNP rs4415084, is the predicted functional SNP. We provide multiple levels of evidence that the risk allele of the predicted functional SNP, in phase with the GWAS risk allele rs4415084-T, creates a GATA3 binding motif within a regulatory element, resulting in differential GATA3 binding and chromatin accessibility, which thereby promote the transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the risk SNP's role in modulating mitochondrial activities in breast cancer. Our computational framework can be extended to facilitate the rapid functional characterization of other genetic variants modulating cancer susceptibility and provides an effective way of integrating GWAS results with high-throughput genomic and epigenomic data.
Citation Format: Yi Zhang, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy, Jun S. Song. Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant [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 1220.
Abstract 1238: International comparison of cancer risks for Lynch syndrome
Authors: Jenkins Mark A. , Reece Jeanette , Lee Grant , Win Aung K. ,   International Mismatch Repair Consortium
Published: August 2018

Abstract
Aims: The International Mismatch Repair Consortium (IMRC) was formed in 2010 and comprises major worldwide consortia involved in the research and/or clinical treatment of Lynch syndrome (cancer predisposition caused by inherited mutations in mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2 and EPCAM); http://www.sphinx.org.au/imrc. The aim of this study was to determine cancer risks by geographic region.
Methods: For each cancer, we estimated the age-specific cumulative risks (penetrance) and the hazard ratios compared to the average population risk. We used a modified segregation analysis and adjusted for any ascertainment of families given this is an analysis of prospective data. We estimated penetrance by: cancer sex, mismatch repair gene, type of mutation, and geographic region.
Results: 43 investigators representing 53 different sites in 23 countries have submitted pedigree data. In total IMRC consists of 6,436 Lynch syndrome families (North America = 2,482, South America = 101, Europe = 3,307, Asia = 216, Australasia = 330). Of these, 2,214 were MLH1, 2,717 were MSH2, 1,118 were MSH6, 558 were PMS2, and 44 were EPCAM. The total number of distinct variants were 1,270 and the maximum size of families was 333 relatives. Of the distinct MMR variants submitted to the IMRC, 89% were classified as Class 4 (likely pathogenic) or 5 (pathogenic) by the InSiGHT Variant classification criteria (LOVD). Penetrance analyses were conducted only for the pathogenic or likely pathogenic variants. Preliminary analyses suggest that the risk of colorectal cancer to age 70 is highest for carriers in Australasia and North America and lowest for carriers in South America and Asia (Table 1).
Conclusion: Preliminary results suggest that cancer risks for people with Lynch syndrome differ by geographic region, which is consistent with environmental modifiers for the disease and might justify region-specific screening guidelines.
Risk (% to age 70) and hazard ratio (HR) of colorectal cancer by MMR gene and regionGeneRegionHR (95% CI)Risk MalesRisk FemalesMLH1Europe19 (14-26)50%32%MLH1Nth America32 (26-38)61%48%MLH1Australasia32 (22-46)68%55%MLH1Sth America6 (2-22)12%10%MLH1Asia7 (5-15)39%24%MSH2Europe14 (11-16)39%24%MSH2Nth America33 (28-40)61%50%MSH2Australasia36 (24-54)73%59%MSH2Sth America70 (10-490)82%75%MSH2Asia8 (5-17)21%15%
Citation Format: Mark A. Jenkins, Jeanette Reece, Grant Lee, Aung K. Win, International Mismatch Repair Consortium. International comparison of cancer risks for Lynch syndrome [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 1238.
Abstract 144: Dasatinib enhances the effects of paclitaxel on chemotherapy-resistant breast cancer through targeting breast cancer stem cells
Authors: Tian Jun , Lo Chieh , Raffa Fatmah Al , Dai Meiou , Lebrun Jean-Jacques 
Published: August 2018

Abstract
Many patients with triple negative breast cancer (TNBC) exhibit poor prognosis and are at high risk of tumor relapse and metastasis due to the resistance to conventional chemotherapy. These tumor recurrences have been attributed to the presence of breast cancer stem cells (BCSCs), a subpopulation of breast cancer cells that possesses stem-like properties and displays resistance to chemotherapy. Therefore, targeting BCSCs is a priority to overcoming chemotherapy failure in TNBCs. We generated chemotherapy-resistant TNBC cells through cyclic treatments with paclitaxel (pac). The pac-resistant cells displayed increased self-renewal potential compared to the parental TNBC cells, higher percentage BCSCs and increased phosphorylation of Src kinase at Tyr416. After performing a kinase library screening on BCSCs in chemotherapy-resistant cells, we identified dasatinib, a Src kinase family inhibitor, potently reduced BCSC self-renewal and two BCSC populations (ALDH+ and CD24lowCD44high) as well as phosphor-Src. We also demonstrated dasatinib to block pac-induced BCSC enrichment and Src activation in the parental TNBC cells. Interestingly, we found that dasatinib induced an epithelial differentiation of pac-resistant cells, resulting in their enhanced sensitivity to paclitaxel. The combination treatment of dasatinib and paclitaxel not only decreased the proportion of BCSCs and their self-renewal capacity but also synergistically reduced cell viability of pac-resistant cells. In vivo studies further demonstrated the effectiveness of dasatinib/paclitaxel combination treatment in inhibiting breast tumor growth. All these data suggest that dasatinib is a promising anti-BCSC agent and can be used in combination with paclitaxel to overcome chemotherapy resistance in TNBCs.
Citation Format: Jun Tian, Chieh Lo, Fatmah Al Raffa, Meiou Dai, Jean-Jacques Lebrun. Dasatinib enhances the effects of paclitaxel on chemotherapy-resistant breast cancer through targeting breast cancer stem 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 144.
Abstract 1586: Evaluation of AXL expression on circulating tumor cells from EGFR mutated lung cancer patients who have relapsed after the EGFR TKI treatment
Authors: Kim Young Hun , Kim Myoung Shin , Lee Jun Sup , Lee Hyun Kyung , Lee Jae Hyuk , Sohn Young Woong , Tazaki Koichi , Nakamaru Kenji , Wakita Kenichi , Jeon Byung Hee , Kim Seokhyung , Lee Se-Hoon 
Published: August 2018

Abstract
Background: The EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) has become the standard treatment in lung cancer patients with EGFR mutations. When these patients are treated with EGFR TKI, 80~90% of the patients show responses to the drug. However the tumor begins to progress again following the development of resistance about 1 year later on average. About a half of resistance mechanisms are caused by the additional mutation of the EGFR gene (T790M), and the other half of the resistance mechanisms are caused by various mechanisms, with one of them being the overexpression of the AXL protein. Confirming AXL overexpression in circulating tumor cells (CTCs) can be an alternative method for tissue biopsy, but almost no research has been conducted on this so far. Here, we evaluate the AXL expression in CTC in case resistance occurs after the EGFR inhibitor treatment.
Materials and Methods: The blood samples (10 ml) were collected from 10 EGFR TKI treated and relapsed lung cancer patients (TKI group) and 10 non-treated patients (control group). The blood samples were processed through Cytogen protocol to enrich CTCs. The enriched cells were immunofluorescent stained for CTC markers (EpCAM or Vimentin), AXL and WBC marker (CD45). The immunofluorescent stained cells were analyzed for each markers using Image Analysis program.
Result: CTCs were detected by CTC markers in all patients from TKI group (range 0-210) and control group (range 1-42). AXL positive CTCs were detected in 9 out of 10 cases from TKI group and in all cases from control group. Interestingly, the quantification of AXL staining intensity in CTCs showed that AXL overexpression (3 fold or greater than baseline) was in 50% of TKI group and 20 % of control group.
Conclusion: We have tested a new approach to evaluate the AXL overexpression in tumor cells of EGFR TKI resistant patients, and showed the feasibility of the this method. Most of lung cancer patients who undergo biopsy require hospitalization and some degree of complication due to biopsy is inevitable. Here we suggested that the blood-based method as a good alternative to the tissue biopsy in patients with tolerance.
Citation Format: Young Hun Kim, Myoung Shin Kim, Jun Sup Lee, Hyun Kyung Lee, Jae Hyuk Lee, Young Woong Sohn, Koichi Tazaki, Kenji Nakamaru, Kenichi Wakita, Byung Hee Jeon, Seokhyung Kim, Se-Hoon Lee. Evaluation of AXL expression on circulating tumor cells from EGFR mutated lung cancer patients who have relapsed after the EGFR TKI treatment [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 1586.
Abstract 1724: Evaluation of niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models
Authors: Wang Sarah , Sun Kaiming , Xiao Yonghong , Feng Bin , Mikule Keith , Ramaswamy Sridhar , Hanke Jeffrey , Wang Jing 
Published: August 2018

Abstract
Niraparib is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. PARP inhibition may enhance the immune response in tumors treated with anti-PD-1 therapy via generation of cytosolic DNA that activates T cells through the stimulator of interferon gene (STING) pathway, rendering tumors immunologically “hot” with an increase in infiltrating lymphocytes.
In this study, we explored the responses and mechanism of action of niraparib and anti-PD-1/anti-PD-L1 combination therapy in preclinical models. Out of a cohort of 14 immune-competent mouse tumor models, the combination treatment demonstrated enhanced anti-tumor activity in eight tumor models derived from BRCA-proficient and BRCA-deficient genetic backgrounds. Substantial increases compared to monotherapies in anti-tumor activity was observed in 5 models, indicative of synergy between niraparib and anti-PD-1/anti-PD-L1 therapy. The combination triggered durable responses that were coincident with induction of immune memories in a BRCA-deficient ovarian syngeneic model. Mechanistically, niraparib treatment increased the number of infiltrating CD8+ and CD4+ cells within the intratumoral region. The enhanced immune cell infiltration was accompanied by elevated interferon-stimulated gene expression. Pathway analyses using transcriptome profiling identified interferon response gene signatures as the significantly differentially-upregulated gene sets following niraparib treatment. Consistently, niraparib treatment activated the STING pathway in vitro in BRCA-deficient MDA-MB-436 human triple negative breast cancer cells. STING pathway markers including p-STING(Ser366), p-TBK1(Ser172) and p-NFκB p65 were elevated following niraparib treatment and was accompanied by an increase in IFNB mRNA expression. In summary, our data suggested that niraparib treatment in combination with anti-PD-1/anti-PD-L1 therapy enhanced immune cell infiltration, interferon-stimulated gene expression and tumor responses.
Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang. Evaluation of niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1724.
Abstract 1763A: Single-cell RNA-sequencing reveals the immune contexture of triple-negative breast cancer tumors
Authors: Qiu Si , Hong Ruoxi , Zhuang Zhenkun , Wang Shusen 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is aggressive and associated with a higher risk of early relapse. The lack of estrogen receptor, progesterone receptor, and HER2 expression precludes the use of targeted therapies, and the high level of immune cell infiltration suggests that TNBC patients may benefit from immunotherapy. The design of immunomodulatory strategies for the TNBC treatment will tremendously benefit from a comprehensive understanding of the tumor infiltrated immune cell landscape of this cancer. To this end, we performed deep single cell RNA sequencing to 7,066 immune cells collected from 8 TNBC patients using the MIRALCS platform. We identified 13 immune cell subsets according to their transcriptome features. We found that the frequency of identified T cells and macrophages varied greatly across patients. We explored the diversity of tumor-infiltrating T lymphocytes and their functional states, and described the complicated and patient specific macrophage phenotypes. We also examined the single-cell expression level of immunotherapeutic target molecules in different immune cell subgroups. Our study gives an insight into the heterogeneity of the immune cell contexture of TNBC tumors, provides a valuable resource to understand the immune ecosystem of TNBC and may accelerate immunotherapies development on this breast cancer subtype.
Citation Format: Si Qiu, Ruoxi Hong, Zhenkun Zhuang, Shusen Wang. Single-cell RNA-sequencing reveals the immune contexture of triple-negative breast cancer 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 1763A.
Abstract 1773: HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer
Authors: Lemon Bryan , Aaron Wade , Austin Richard , Baeuerle Patrick , Barath Manasi , Jones Adrie , Jones Susan D. , Kwant Kathryn , Law Che-Leung , Muchnik Anna , Sexton Kenneth , Tatalick Laurie , Wesche Holger , Yu Timothy 
Published: August 2018

Abstract
Metastatic, castrate-resistant prostate cancer (mCRPC) is diagnosed in up to 50,000 patients each year in the US alone, and roughly 27,000 patients will succumb to it every year. Once metastasized beyond regional lymph nodes, the 5-year survival rate is 30%. While novel therapeutics like abiraterone and enzalutamide have improved the treatment options for mCRPC, no curative treatment is available, and new therapies are urgently needed. HPN424 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) under development for the treatment of mCRPC. It is designed to simultaneously bind to CD3ε on T cells and to prostate specific membrane antigen (PSMA, FOLH1) on prostate cancer cells. A third domain of HPN424 binds non-covalently to serum albumin for extension of serum half-life. PSMA is expressed in &gt;90% of malignant lesions of patients, and outside the central nervous system, its expression on normal tissue is largely restricted to the prostate. HPN424 binds human PSMA with sub-nanomolar affinity. When incubated in co-cultures with resting, human T cells and prostate cancer cells, it activates T cells and induces cytokine production, proliferation and redirected target cell killing with EC50 values in the single digit picomolar range. When administered to mice bearing human prostate cancer xenografts and human T cells, HPN424 eradicates subcutaneous tumors. The affinities of HPN424 for human and cynomolgus monkey CD3 and albumin are comparable, while HPN424 binds only marginally to cynomolgus PSMA. HPN424 is very well tolerated in non-human primates, even at high doses, indicating that CD3-binding has little if any pharmacological effect in the absence of target binding. Pharmacokinetic analysis supports weekly administration in humans. Our preclinical data suggest that HPN424 will be highly efficacious, safe and convenient for the treatment of patients with mCRPC.
Citation Format: Bryan Lemon, Wade Aaron, Richard Austin, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Kathryn Kwant, Che-Leung Law, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic 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 1773.