bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 697: Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer
Authors: Lee Miseon , Lee Hee Jin , Song In Hye , Park In Ah , Heo Sun-Hee , Kim Young-Ae , Bang Won Seon , Lee AReum , Lee Hyeonjin , Lee Heejae , Gong Gyungyub 
Published: August 2018

Abstract
Background: The level of tumor-infiltrating lymphocytes (TILs) and the presence of tertiary lymphoid structures (TLSs) are significant prognostic and predictive factors in primary breast cancer. However, understanding about the differences of TILs and TLSs among different metastatic sites or between primary breast tumors and metastatic sites is limited.
Methods: A total of 337 cases of metastatic breast cancer with available hematoxylin and eosin slides of metastatic sites (biopsy, n=185; operation, n=152) were included. We analyzed the percentage of TILs (defined as the percentage of invasive carcinoma stroma infiltrated by lymphocytes in 10% increments; if less than 10% of stroma was infiltrated by TILs, 1% or 5% criteria were used; all available full sections were evaluated) and the presence of TLSs (defined as the lymphoid aggregation with high endothelial venules) in primary and metastatic sites.
Results: The mean percentage of TILs in the lung (19.5%) was significantly higher than those in the liver (4.2%), brain (8.3%), and ovary (3.4%, p&lt;0.001). The level of TILs in metastatic tumors of the lung was higher than those in primary tumors (Wilcoxon signed-rank test, p&lt;0.001), while metastatic tumors of the liver (p=0.024) and brain (p=0.095) showed lower level of TILs than in primary tumors. TLSs were found only in the lung (27%) and liver (13%). Patients with lung metastasis (p&lt;0.001), higher level of TILs (p=0.001), and presence of TLS (p=0.002) showed better overall survival. In patients with lung metastasis, who showed best clinical outcome, those with 10% or more of TIL had better overall survival than those with less than 10% (p=0.008).
Conclusion:. Metastatic breast tumors in the lung had more TILs than other sites and matched primary tumors. Underlying mechanism of differences of TILs among metastatic sites should be investigated.
Citation Format: Miseon Lee, Hee Jin Lee, In Hye Song, In Ah Park, Sun-Hee Heo, Young-Ae Kim, Won Seon Bang, AReum Lee, Hyeonjin Lee, Heejae Lee, Gyungyub Gong. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast 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 697.
Abstract 742: Nonclinical safety evaluation of STRO-001, a site-specific anti-CD74 antibody-drug conjugate for the potential treatment of B-cell malignancies
Authors: Solis Willy , Almeida Venita De , Yu Abigail , Bruhns Maureen , Zawada James , Galan Adam , Matheny Shannon , Molina Arturo , Hallam Trevor , Lupher Mark 
Published: August 2018

Abstract
Antibody-drug conjugates (ADCs) constitute an expanding class of therapeutic molecules in preclinical and clinical development for multiple oncology indications. These antibody-based therapeutics are designed to selectively deliver cytotoxic payloads to tumor targets to improve efficacy and minimize toxicity. Cluster of differentiation 74 (CD74), a membrane-bound glycoprotein, is an antigen amenable ADC targeting because of its low expression in normal tissues and over expression in B-cell malignancies (multiple myeloma and non-Hodgkin's Lymphoma). STRO-001, a well-defined, homogenous, and site-specific ADC, is comprised of maytansinoid cytotoxic drugs conjugated to an anti-CD74 aglycosylated antibody (SP7219) through a noncleavable linker at two engineered non-natural amino acids. In an in vitro immunological activation assay, STRO-001 did not elicit cytokine production when incubated with human PBMCs for 48 hours, suggesting a low risk for immunological response in cancer patients. In a tissue cross-reactivity study with human tissues, STRO-001-specific membranous staining was detected primarily in lymphoid organs and lymphocytic infiltrates in multiple non-lymphoid tissues. In an exploratory nonclinical safety study in cynomolgus monkeys, a pharmacologically relevant model for toxicity testing, STRO-001 was tolerated at 1, 3, and 10 mg/kg, but not at 30 mg/kg, when intravenously administered on days 1 and 15 followed by a 4-week observation period. Dose-dependent and transient decreases in B-cells and monocytes were observed at tolerated doses (on-target pharmacology), with no effects on NK/T-cells. At tolerated doses, the main findings included reversible toxicities to hematopoietic and lymphoid tissues that correlated with cytopenias. Hematopoietic toxicity is considered antigen-independent, clinically manageable, and consistent with that of other ADCs with similar payloads. Toxicokinetic analysis confirmed drug exposures (total antibody, ADC, and a prominent linker-maytansine catabolite) with evidence of non-linearity suggesting target-dependent clearance. In summary, STRO-001 ADC has a favorable nonclinical safety profile and Phase I study of STRO-001 in patients with B-cell malignancies is planned.
Citation Format: Willy Solis, Venita De Almeida, Abigail Yu, Maureen Bruhns, James Zawada, Adam Galan, Shannon Matheny, Arturo Molina, Trevor Hallam, Mark Lupher. Nonclinical safety evaluation of STRO-001, a site-specific anti-CD74 antibody-drug conjugate for the potential treatment of B-cell malignancies [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 742.
Abstract 764: GSTP1 knockdown and inhibition impairs pancreatic ductal adenocarcinoma (PDAC) growth
Authors: Singh Rahul Raj , Reindl Katie M. 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related mortalities in the Western world and continues to be a major unresolvable health problem at the start of the 21st century. Resistance to the currently available treatment options has led to development of new approaches, such as personalized medicine and immunotherapy. However, new therapeutic strategies based on the unique molecular biology and physiology of pancreatic cancer hold the greatest promise. Glutathione S-transferase pi 1 (GSTP1) is a key detoxification enzyme which metabolizes xenobiotic compounds and byproducts of cellular metabolism. GSTP1 is overexpressed in many tumors, particularly ovarian, non-small cell lung, breast, colon, and pancreas. Moreover, GSTP1 is overexpressed in drug-resistant cancer cell lines. The reasons for increased expression ratios compared to normal tissues or wild-type cell lines are not well understood.
To investigate the role of GSTP1 in PDAC pathogenicity, we generated two knockdown lines of GSTP1 in metabolically diverse PDAC cells. We showed that GSTP1 knockdown impairs the growth and proliferation of PDAC cells. Additionally, GSTP1 knockdown cells exhibit elevated reactive oxygen species (ROS) levels and a prolonged G0/G1 phase of the cell cycle. Intrigued by these results, we next examined whether pharmacological inhibition with a selective GSTP1 inhibitor, Ezatiostat (TLK199), also impaired PDAC pathogenicity. Ezatiostat is a small molecule drug and is novel glutathione analog, which selectively binds and inhibits GSTP1. Ezatiostat treatment in PDAC cells recapitulated the proliferation impairments observed with genetic inactivation of GSTP1 and elevated ROS levels. Orthotopic implantation of GSTP1 knockdown cells in athymic nude mice resulted in reduced tumor weight and volume compared to the control. The growth trajectory of the tumors was monitored via Vevo-3100 ultrasound imaging system. Our preliminary data indicate enhanced sensitivity of glycolytic cancer cells towards an ROS-inducing agent and a GSTP1 inhibitor, piperlongumine (PL). Interestingly, we have found PL is less cytotoxic to cells with reduced GSTP1 levels, indicating that PL primarily works by inhibiting GSTP1 activity. Together, these data suggest that GSTP1 knockdown and inhibition impairs the growth and survival of phenotypically diverse PDAC cells in vitro and in vivo. Moreover, GSTP1 knockdown results in elevated ROS levels and an extended G0/G1 phase of the cell cycle. With these data, we propose that GSTP1 is a novel therapeutic target for PDAC.
Citation Format: Rahul Raj Singh, Katie M. Reindl. GSTP1 knockdown and inhibition impairs pancreatic ductal adenocarcinoma (PDAC) growth [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 764.
Abstract 767: Identification of cell surface proteins expressed exclusively on mutant KRas-dependent cancer cells
Authors: Agrawal Vijayendra , Fang Bin , Welsh Eric A. , Koomen John , Sebti Said M. 
Published: August 2018

Abstract
Mutant KRas is a major contributor to human oncogenesis and confers resistance to therapy. Identification of cell surface proteins that are expressed exclusively in mutant KRas-driven tumors could lead to novel approaches for diagnosing and treating mutant KRas-dependent tumors. To this end, we used a biotinylation/mass spectrometry approach to capture cell surface proteins from mutant KRas-dependent and -independent human cancer cells. KRas was depleted from both mutant KRas-dependent and -independent cells, and the cells were subjected to cell surface protein biotinylation using EZ-Link Sulfo-NHS-SS-Biotin reagent and captured via neutravidin column. The efficiency of cell surface protein capture was confirmed by the presence of membrane proteins EGFR, IGF1R and absence of cytosolic proteins RhoGDIa in biotin-pull down fractions (western blot analysis). Mass spectrometric and proteomics analyses of biotinylated proteins yielded 20 highly probable hits with very high expression in mutant KRas-dependent cells and very low expression in mutant KRas-independent cells. Upon KRas depletion, the level of these proteins was significantly reduced in mutant KRas-dependent cells (up to 25 fold) but not in mutant KRas-independent cells. Currently, we are analyzing these 20 hits to determine if any of these are required for the survival of mutant KRas-dependent cells. Results from these studies have the potential to lead to novel approaches for diagnosing and treating mutant KRas-driven cancers.
Citation Format: Vijayendra Agrawal, Bin Fang, Eric A. Welsh, John Koomen, Said M. Sebti. Identification of cell surface proteins expressed exclusively on mutant KRas-dependent 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 767.
Abstract 792: A novel covalent reversible BTK inhibitor for B cell malignancies with enhanced selectivity and in vivo efficacy
Authors: Chen Xi , Huang Shaoqiang , Hu Fred , Xian Jun , Yang Jian , Qiang Jing , Le Meijie , Wu Yuchuan 
Published: August 2018

Abstract
Bruton's tyrosine kinase (BTK), a member of Tec family kinase, plays a pivotal role in the regulation of BCR signaling, which is important for B cell development and function. Ibrutinib, which has been approved by FDA, is an effective treatment option for multiple types of B cell neoplasms. However, the treatment associated adverse events (AEs) are one of the major concerns due to its poor kinase selectivity . Here, we present a novel covalent, but reversible BTK inhibitor, XNW-1011, which demonstrated enhanced potency, better selectivity, improved drug-like properties and superior in vivo efficacy with a favorable safety profile. XNW-1011 was developed structurally and biochemically differently from current BTK inhibitors, being more potent and highly selective. In the in vitro assay, unlike Ibrutinib, it did not inhibit EGFR, ITK, JAK3, LYN and SRC. It completely suppressed the cell proliferation of a panel of lymphoma cell lines such as TMD-8 and Rec-1. Besides, XNW-1011 inhibited cellular phosphorylation of BTK and calcium efflux, confirming the inhibition of activation of BTK in vitro. We have shown that XNW-1011 formed covalent bond with cysteine in a cysteine reactivity assay. In addition, a washout assay by Western Blot confirmed the reversibility of inhibition of XNW-1011 to BTK. XNW-1011 has a good prolife of ADME, which translated into improved in vivo PK properties over Ibrutinib (low clearance and prolonged half-life). XNW-1011 was further evaluated in several animal models such as REC-1 and TMD-8 tumor xenografts. XNW-1011 inhibited tumor growth with as low as 3.125 mpk by BID and resulted in tumor regression with 12.5 mpk by BID. Interestingly, XNW-1011 completely inhibited the tumor growth of a patient derived xenograft (PDX) with Myd88 mutation. The dose proportionality was confirmed through determination of the plasma concentration and in vivo BTK occupancy in the last day of treatment. In summary, XNW-1011 is a potent, selective, covalent reversible BTK inhibitor with improved ADME prolife and in vivo efficacy, which makes it suitable for further evaluation in clinical setting.
Citation Format: Xi Chen, Shaoqiang Huang, Fred Hu, Jun Xian, Jian Yang, Jing Qiang, Meijie Le, Yuchuan Wu. A novel covalent reversible BTK inhibitor for B cell malignancies with enhanced selectivity and in vivo efficacy [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 792.
Abstract 812: New c-KIT mutations in GISTs: Bad for good
Authors: Laurini Erik , Aulic Suzana , Marson Domenico , Fermeglia Maurizio , Riboni Roberta , Lucioni Marco , Dellera Elena , Alessiani Mario , Perfetti Vittorio , Pricl Sabrina 
Published: August 2018

Abstract
Gastrointestinal stromal tumors are mesenchymal tumors arising in the stomach and small bowel and more rarely in the rectum, esophagus, peritoneum and retroperitoneum. These tumors are characterized by KIT or PDGFRA mutations. KIT mutations are all in frame and lead to constitutive tyrosine kinase domain activation without ligand binding. Mutations concern four exons (9, 11, 13 and 17) but mainly exon 11.
In this work we report a case of a GIST patient with wild-type PDGFRA but bearing two mutations in KIT exon 9, i.e., the insertion mutation Y503_F504insAY and the missense mutation K509N.
The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well.
Accordingly, in silico experiments were performed to disclose the effects exerted by these new mutations on the protein structure, its thermodynamic stability, and the ability to promote/interfere with Imatinib binding.
Direct drug binding thermodynamics and kinetics of the mutant KIT were measured using isothermal titration calorimetry. FInally, in vitro kinase assays were performed to monitor the phosphorylation status of this new mutant KIT.
The prototypical KIT mutations Δ559 and T670I were also analyzed in parallel for comparison.
To our knowledge, only AY 502-503 duplication/insertion and K509I substitution have been previously reported.
Citation Format: Erik Laurini, Suzana Aulic, Domenico Marson, Maurizio Fermeglia, Roberta Riboni, Marco Lucioni, Elena Dellera, Mario Alessiani, Vittorio Perfetti, Sabrina Pricl. New c-KIT mutations in GISTs: Bad for good [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 812.
Abstract 816: Antibody-drug conjugate targeting glypican-1 shows potent antitumor effect in pancreatic cancer
Authors: Serada Satoshi , Nishigaki Takahiko , Sugase Takahito , Saito Yurina , Takahashi Tsuyoshi , Hiramatsu Kosuke , Fujimoto Minoru , Mori Masaki , Doki Yuichiro , Naka Tetsuji 
Published: August 2018

Abstract
Pancreatic cancer is the most lethal malignancy; thus developing new treatment options is urgently required. We confirmed that enhanced expression of glypican-1 (GPC1) was observed in pancreatic cancer. In this study, we aimed to develop novel antibody-drug conjugate (ADC) targeting GPC1 as a new therapy for pancreatic cancer. By the immunohistochemical analysis, enhanced expression of GPC1 was observed in pancreatic cancer. Among pancreatic cancer cell lines, BxPC3 and T3M4 cells expressed high expression of GPC1 compared to SUIT2 cells. We developed new anti-GPC1 monoclonal antibody (mAb) and selected a clone having highly internalizing activity. The anti-GPC1 mAb was conjugated with cytotoxic agent monomethyl auristatin F (MMAF). Compared with the control ADC, this GPC1-ADC showed potent antitumor effect toward BxPC3 and T3M4, while little activity in SUIT2 cells. In BxPC3 xenograft model, GPC1-ADC had significant and potent tumor growth inhibition in a dose dependent manner. In addition, using patient derived tumor xenograft (PDX) model with GPC1-positive pancreatic cancer, GPC1-ADC also showed significant tumor growth inhibition. In the tumor tissue, GPC1-ADC-mediated G2/M phase cell cycle arrest was detected in GPC1-ADC treated mice compared to control-ADC treated mice. In summary, our newly developed GPC1-ADC showed significant tumor growth inhibition against not only GPC1-positive pancreatic cell line but also patient derived GPC1-positive pancreatic cancer. Our preclinical data demonstrated that targeting GPC1 by ADC is a promising therapy for patients with GPC1-positive pancreatic cancer.
Citation Format: Satoshi Serada, Takahiko Nishigaki, Takahito Sugase, Yurina Saito, Tsuyoshi Takahashi, Kosuke Hiramatsu, Minoru Fujimoto, Masaki Mori, Yuichiro Doki, Tetsuji Naka. Antibody-drug conjugate targeting glypican-1 shows potent antitumor effect in 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 816.
Abstract 817: Overcoming FGFRs-mediated drug resistance by inhibiting myristoylation of FRS2α
Authors: Cai Houjian , Li Qianjin 
Published: August 2018

Abstract
Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling facilitates tumor initiation and progression. Although there are currently approved inhibitors and agents in clinical trials targeting FGFR kinase activity that show therapeutic benefit, over-expression and/or mutations of FGFRs eventually confer drug-resistance and bypass the mechanisms of kinase inhibitors in a variety of cancer types. We hypothesize that a compound blocks the myristoylation of FRS2α, thus suppressing its interaction with FGFRs or FGFRs drug resistant mutants (FGFRsDRM) and downstream proteins. As a result, it inhibits oncogenic signaling and tumor progression mediated by FGF/FGFRs or FGFRsDRM. The goal of this study is to investigate if the novel lead compound inhibits FGF/FGFRs oncogenic signaling and overcomes FGFRsDRM mediated drug resistance. We used CRISPR/Cas9 mediated gene knockout to demonstrate that FRS2α is essential for FGF/FGFR signaling. The myristoylation of FRS2α was detected by Click chemistry. Additionally, inhibition of cell proliferation, migration, invasion assays and cell cycle analysis were analyzed in numerous cancer cells. Prostate regeneration assay and xenograft tumor models were applied for in vivo studies. We demonstrate that loss of myristoylation of FRS2α, a scaffold protein key in FGFRs signaling, inhibits FGF/FGFRs-mediated oncogenic signaling and FGF10-induced tumorigenesis. Additionally, a previously synthesized myristoyl-CoA analog, B13, which targets the activity of N-myristoyltransferases, suppresses FRS2α myristoylation, and modulates the phosphorylation and localization of FRS2α at the cytoplasmic membrane. B13 exhibited an inhibitory effect on oncogenic signaling induced by wild type FGFRs and their drug resistant mutants (FGFRsDRM). The single agent or in collaboration with an FGFR inhibitor suppressed FGF induced wild type FGFR or FGFRDRM initiated PI3K and/or MAPK signaling, subsequently inhibiting cell proliferation and migration in a variety of cancer cell types by inducing cell cycle arrest. Finally, B13 significantly inhibited growth of xenograft tumors without pathological toxicity to the liver, kidney, or lung in vivo. Our study demonstrates that B13, a myristoyl-CoA analog, inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. This study provides a novel therapeutic approach for inhibiting cancer progression mediated by FGF/FGFRs and their drug resistant mutants.
Citation Format: Houjian Cai, Qianjin Li. Overcoming FGFRs-mediated drug resistance by inhibiting myristoylation of FRS2α [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 817.
Abstract 823: Anti-melanoma effects of novel Cripto-1 CFC small peptide mimetics
Authors: Iaccarino Emanuela , Untiveros Gustavo , Sandomenico Annamaria , Caporale Andrea , Calvanese Luisa , Falcigno Lucia , D'Auria Gabriella , Ruvo Menotti , Strizzi Luigi 
Published: August 2018

Abstract
The diagnosis of melanoma is increasing and current therapies for advanced disease remain unsuccessful. Thus, research aimed at developing novel targeting approaches is needed. Cripto-1 (CR-1), an epidermal growth factor (EGF)-like developmental morphogen, functions as a co-receptor for the tumor growth factor (TGF)-beta related molecule, Nodal. CR-1/Nodal signaling pathways can induce cell survival, proliferation and migration of cancer cells. Studies have shown that Nodal is expressed at high levels in advanced melanoma. CR-1 has also been shown to be expressed in melanoma but limited to a small subpopulation of melanoma cells with more stem cell-like characteristics. Recent work has demonstrated that targeting Nodal in melanoma is associated with reduction of a significant population of melanoma cells. However, a residual population continues to persist. We hypothesize that interference with CR-1/Nodal receptor binding dynamics will negatively affect downstream Nodal-dependent signaling events important for cancer growth and further reduce the number of surviving melanoma cells. To test this hypothesis, we have developed small peptides that mimic CR-1 CFC binding domain and prevent CR-1 from binding to the ALK4 receptor necessary for proper CR-1 co-receptor function for Nodal. We show that in vitro treatment of human melanoma cells with our prototype CFC mimetic B3 reduced melanoma cell viability and negatively affected melanoma cell cycle progression. We also show that treatment with B3 resulted in reduction of active Smad2/3 and ERK1/2, known to be involved in downstream Nodal signaling, as a result of B3 interference with CR-1 co-receptor function. These preliminary data provide the scientific rationale for the development of anti-CR-1 and Nodal therapeutics that can synergize with or complement current treatment approaches in melanoma.
Citation Format: Emanuela Iaccarino, Gustavo Untiveros, Annamaria Sandomenico, Andrea Caporale, Luisa Calvanese, Lucia Falcigno, Gabriella D'Auria, Menotti Ruvo, Luigi Strizzi. Anti-melanoma effects of novel Cripto-1 CFC small peptide mimetics [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 823.