bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5891: ABCG2 expression contributes to CC-115 resistance
Authors: Beebe Jenny 
Published: August 2018

Abstract
Introduction: A major obstacle in the treatment of cancers is innate or acquired resistance. Multi-drug resistance proteins such as MDR1, ABCG2, MRP1, and LRP have been shown to be involved in resistance and are predictors of clinical outcomes. Expression of ABCG2, an ATP-binding cassette efflux transporter, may be responsible for observed variability of the efficacy of CC-115, a dual mTOR/DNA-PK inhibitor, currently in clinical trials. Here we evaluate the role of ABCG2 in CC-115 resistance.
Methods: Western blots, methylene blue and MTT assays, and FACS were used to determine ABCG2 expression, cell survival/viability with and without inhibitors, and accumulation of CC-115 respectively.
Results: MCF7/AdVp3000 (M3K) cells have been shown to have a significant increase in ABCG2 as compared to parental MCF7 cells. M3K cells had a 50-fold increase in IC50 to CC-115 compared to MCF7. Use of ABCG2 inhibitors FTC and C8 (1uM), decreased the IC50 of CC-115 in M3K cells by 10-fold. Accumulation studies using FACS showed that M3K cells had significantly lower accumulation of CC-115 as compared to MCF7 and addition of FTC and C8 (1uM) significantly enhanced accumulation of CC-115 to the same extent as seen in MCF7 cells. Next, HEK293/ABCG2 stable clone with overexpression of ectopic ABCG2 and its control HEK293/vec cells were used to determine ABCG2's direct impact on CC-115 resistance. HEK293/ABCG2 cells had a 10-fold increase in resistance to CC-115 with an IC50 of 2.05 uM as compared to 0.23 uM in HEK293/vec cells. Addition of FTC and C8 (1uM) decreased the IC50 by 10-fold in HEK293/ABCG2 cells. Accumulation of CC-115 in HEK293/ABCG2 cells was also significantly lower than that in HEK293/vec cells and addition of FTC and C8 (1uM) significantly increased its accumulation only in HEK293/ABCG2 cells.
Discussion: The results from this study suggest that ABCG2 contributes to and possibly is responsible for CC-115 resistance and that inhibiting ABCG2 could lead to reversal of CC-115 resistance, increased response rate, highlights the importance of personalized therapies, and has the potential to increase patient survival.
Citation Format: Jenny Beebe. ABCG2 expression contributes to CC-115 resistance [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 5891.
Abstract 59: 14-3-3zeta overexpressing breast cancer cells promote fibroblast senescence and CAF-like phenotype
Authors: Li Hongzhong , Xiao Yi , Yuan Xiangliang , Kuo Wenling , Li Ping , Yu Dihua 
Published: August 2018

Abstract
14-3-3ζ overexpression in breast cancer is associated with accelerated cancer progression and poor clinical outcome in patients. Our previous study revealed that 14-3-3ζ overexpression promotes epithelial mesenchymal transition (EMT) of breast cancer cells, which facilitates progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). However, the impact of 14-3-3ζ overexpressing breast cancer cells on tumor microenvironment (TME) and the underlying mechanisms have not been explored. We found dramatically increased cancer associated fibroblast (CAF) signatures in patients' matched IDC lesions compared to their DCIS lesions, suggesting that activated fibroblasts may be involved in DCIS to IDC transition. Global gene expression profiling uncovered increased expression of pro-inflammatory cytokines/chemokines, including IL6 and IL8, in 14-3-3ζ AND ErbB2 co-overexpressed 10A.ErbB2.1433ζ cells compared to ErbB2 overexpressed 10A.ErbB2 cells. This finding was further confirmed by ELISA and validated in other breast cancer cell lines. We tested whether increased pro-inflammatory cytokines in the conditional medium (CM) from 14-3-3ζ overexpressed cancer cells promotes CAF-like phenotype. Indeed, CM from 14-3-3ζ overexpressed cancer cells significantly increased SMA+ activated fibroblast cells compared to controls. Additionally, up-regulation of β-galactosidase and reduced cell proliferation, hallmarks of senescence cells, were detected in fibroblast cells cultured in CM from 14-3-3ζ overexpressed cancer cells. Next, we explored potential mechanism of how 14-3-3ζ overexpression in cancer cells leads to up-regulation of pro-inflammatory cytokines/chemokines. Since NF-kappaB is one of the master upstream regulator of IL-6 and IL-8, we next investigated the NF-kappaB signaling activation in 14-3-3ζ overexpressed vs control cancer cells. 14-3-3ζ overexpressing cancer cells had hyperactive canonical NF-kappaB responses, including accelerated IκBα degradation, p65 phosphorylation, as well as nuclear translocation compared to 14-3-3ζ low cancer cells. Prolonged NF-kappaB signaling activation upon pro-inflammatory cytokine stimulation was also detected in 14-3-3ζ overexpressing cancer cells. These results suggest that 14-3-3ζ overexpressing cancer cells may promote fibroblast cell senescence and CAF-like phenotype by creating by a chronic inflammatory microenvironment, which ultimately enhances DCIS to IDC transition.
Citation Format: Hongzhong Li, Yi Xiao, Xiangliang Yuan, Wenling Kuo, Ping Li, Dihua Yu. 14-3-3zeta overexpressing breast cancer cells promote fibroblast senescence and CAF-like phenotype [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 59.
Abstract 707: Circulating immune profile in childhood neuroblastoma displays an activated response with simultaneous expression of checkpoint proteins by T cells and monocytes
Authors: Oliveira Flavia B. , Magalhães Luísa M. , Passos Livia S. , Neto Joaquim C. Aguirre , Dutra Álvaro P. , Martins Patricia R. , Salles Paulo G. Oliveira , Dutra Walderez O. , Gollob Kenneth J. 
Published: August 2018

Abstract
Neuroblastoma (NB) is a rare childhood cancer typically affecting children under five and arising from neural crest sympathoadrenal linage cells. Despite its rarity, it is the most frequent solid tumor in children under five. Determination of the circulating immune response in childhood NB before treatment has begun can help in the identification of potential cells and pathways involved in disease development and suitability for immunotherapy. These studies were designed to investigate the cellular and soluble immune response (cytokines) using flow cytometry with peripheral blood samples in a group of seven NB patients and four non-NB solid tumor patients between the age of 20-42 months. These data of the systemic immune response were compared to the intensity of tumor infiltrating lymphocytes and disease outcome after 18 months of treatment. Analysis of peripheral blood cellular immune status revealed that the NB group displayed an increase in the frequency of effector memory T cells (p &lt;0.05), as well as an increase in the expression of inhibitory molecules CTLA-4 and PD-1 by CD4 + T lymphocytes (p &lt; 0.05), and CTLA-4 by CD8+ T cells (p &lt;0.06). Moreover, an increase in PD-L2 was seen on transitional (CD14+CD16+) and non-classical (CD14-CD16+) monocytes from NB (p &lt;0.05). Further studies analyzing circulating cytokines (IL-2, 4, 5, 6, 9, 10, 13, 17A, 17F, 21, 22, IFN-gamma and TNF-alpha) in the plasma of the same patients showed an overall pattern of increased cytokines from the NB group as compared to the control group with increased IL-5, IL-6, IL-9 and IL-10 (p &lt; 0.10). Lastly, the NB group showed an intense tumor infiltrating lymphocyte response in both the septa region and tumor nests, which was correlated with circulating TNF-alpha levels (R2 = 0.82, p = 0.06). Overall these findings of the systemic immune response in this rare childhood cancer indicate an active immune response with profiles consistent with both a down modulatory response and an overall activated profile based on soluble cytokines and tumor infiltrating lymphocyte intensity. These findings point to a systemic immune-modulation profile of the cellular response associated with NB disease.
Citation Format: Flavia B. Oliveira, Luísa M. Magalhães, Livia S. Passos, Joaquim C. Aguirre Neto, Álvaro P. Dutra, Patricia R. Martins, Paulo G. Oliveira Salles, Walderez O. Dutra, Kenneth J. Gollob. Circulating immune profile in childhood neuroblastoma displays an activated response with simultaneous expression of checkpoint proteins by T cells and monocytes [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 707.
Abstract 748: Non-internalizing site-specific antibody-drug conjugates based on maytansinoids display curative properties
Authors: Sala Gianluca , Capone Emily , Piccolo Enza , Ponziani Sara , Gentile Roberta , Ippoliti Rodolfo , Giansanti Francesco , Iacobelli Stefano 
Published: August 2018

Abstract
Antibody-Drug Conjugates (ADCs) are highly potent biopharmaceuticals that use the targeting ability of monoclonal antibodies to selectively bind to tumor cells where the conjugated cancer drug is released. Traditionally, the anticancer efficacy of ADCs relies on their selective internalization by cancer cells. However, it has recently been shown that non-internalizing, linkerless ADCs targeting the tumor extracellular environment can display a potent therapeutic activity. LGALS3BP (aka Mac-2 BP or 90K) represents an appealing target for non-internalizing ADC development, as the protein is largely secreted by the majority of human tumors, while being virtually undetectable in normal adult tissues except for the prostate and the colorectum. Additionally, once secreted the protein stops from spreading and clusters on the plasma membrane where it binds to some endogenous ligands. Here, we show that an engineered variant of the humanized 1959 antibody to human LGALS3BP selectively localizes around the tumor cells and once site-specifically coupled to the maytansinoid drugs DM3 or DM4 by means of disulfide linker can display a potent therapeutic activity. Both the 1959sss-DM3 and -DM4 conjugates mediated potent antitumor activity in mice bearing human tumor xenografts. Quantitative biodistribution studies confirmed a preferential accumulation of 1959sss-DM3 and -DM4 conjugates around the tumor cells. Notably, we found that both conjugates were well tolerated and cured 100% of tumor-bearing mice. Our findings offer a preclinical proof-of-concept for curative non-internalizing ADC endowed with an innovative mechanism of action.
Citation Format: Gianluca Sala, Emily Capone, Enza Piccolo, Sara Ponziani, Roberta Gentile, Rodolfo Ippoliti, Francesco Giansanti, Stefano Iacobelli. Non-internalizing site-specific antibody-drug conjugates based on maytansinoids display curative properties [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 748.
Abstract 754: Unique pharmacologic properties of Dolaflexin-based ADCs—a controlled bystander effect
Authors: Clardy Susan M. , Yurkovetskiy Alex , Yin Mao , Gumerov Dmitry , Xu Ling , Ter-Ovanesyan Elena , Bu Charlie , Johnson Alex , Protopopova Marina , Zhang Qingxiu , Bodyak Natalya , Damelin Marc , Lee David H. , Bergstrom Donald , Lowinger Timothy B. 
Published: August 2018

Abstract
Antibody-drug conjugates (ADCs) are designed to bind tumor-associated antigens and deliver conjugated cytotoxic payloads to antigen-positive cells. Some ADCs also kill neighboring cells (including antigen-negative cells) by a mechanism referred to as the bystander effect. This effect can be beneficial when the antigen has heterogeneous expression among cells in a solid tumor, but it can also increase off-target toxicity of ADCs. Herein, we report on a unique pharmacologic property of the Dolaflexin platform, which provides a controlled bystander effect that retains the benefits of the bystander effect with respect to antitumor cytotoxicity but reduces the off-target toxicity. The controlled bystander effect, termed “Dolalock,” was achieved through design of a payload, auristatin F-hydroxypropylamide (AF-HPA), that is membrane-permeable and capable of bystander killing but is further catabolized to membrane-impermeable auristatin F (AF). This catabolism of the payload “locks” the highly potent AF in the cell. Using Dolaflexin-based ADCs, we investigated the extent of intracellular AF-HPA and AF release, tumor cell retention and bystander activities in vitro and in vivo. We observed both auristatin species within cells. Co-culture assays with HER2-positive and HER2-negative cells confirmed the cell permeability and bystander-killing capabilities of AF-HPA released from a Dolaflexin-based ADC. Biodistribution studies of Dolaflexin-based ADCs revealed time-dependent concentrations of AF-HPA and AF as well as significant accumulation of AF in xenografted tumor cells, consistent with the Dolalock mechanism. An additional benefit of AF formation was seen in multidrug-resistant transporter studies, which demonstrate that AF, in contrast to AF-HPA, is not a P-glycoprotein 1 (Pgp) substrate. This property may offer additional benefit in Pgp-expressing tumors. In summary, we have shown that the novel AF-HPA payload used in the Dolaflexin platform allows for a controlled bystander effect that likely contributes to the enhanced efficacy and lack of neutropenia we have observed with Dolaflexin-based ADCs.
Citation Format: Susan M. Clardy, Alex Yurkovetskiy, Mao Yin, Dmitry Gumerov, Ling Xu, Elena Ter-Ovanesyan, Charlie Bu, Alex Johnson, Marina Protopopova, Qingxiu Zhang, Natalya Bodyak, Marc Damelin, David H. Lee, Donald Bergstrom, Timothy B. Lowinger. Unique pharmacologic properties of Dolaflexin-based ADCs—a controlled bystander effect [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 754.
Abstract 784: NCI CPTAC phase III, proteogenomic analysis of 10 cancers
Authors: Thiagarajan Mathangi 
Published: August 2018

Abstract
The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) is an international effort to accelerate the understanding of the molecular basis of cancer through the application of large-scale proteomic and genomic analysis, or proteogenomics. Leidos Biomedical Research, a prime contractor to NCI, provides a robust infrastructure for supporting the collection and sequencing of high-quality biospecimens and data, in addition to project and subcontract management for this program. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. CPTAC phase III began late 2016 to collect and analyze 200 cases of each of ten additional cancers. The cancers include sarcoma, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, uterine corpus endometrial carcinoma, clear cell renal cell carcinoma, glioblastoma multiforme, and acute myeloid leukemia. The program completed the discovery phase collection of 100 cases for 3 tumor types in the first year. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to sequencing centers and tissues to proteomics groups. Data are combined and analyzed by proteogenomic data analysis and translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons. Proteomic and proteogenomic data are made available through the Data Coordinating Center. Imaging data are made available through NCI imaging archive. We report here on progress in collection of tissues and clinical data, the preliminary analysis trends and the integration of biorepository, proteomics and genomics and analysis centers.
Citation Format: Mathangi Thiagarajan. NCI CPTAC phase III, proteogenomic analysis of 10 cancers [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 784.
Abstract 795: Isatin analog for the treatment of acute myeloid leukemia
Authors: Gowda Krishne , Annageldiyev Charyguly , Desai Dhimant , Amin Shantu , Claxton David , Sharma Arati 
Published: August 2018

Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with therapeutic modalities relying on traditional cytotoxic therapies and hematopoietic stem cell transplantation. Current first-line cytotoxic chemotherapy exhibits limited success, with 50% of younger patients and 80% of older patients succumbing to the disease. There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Our group has reported cytotoxic potential of dibromo-derivative of isatin, 5,7-dibromo-N-(p-thiocyanomethylbenzyl)isatin (KS99) against variety of solid tumors and multiple myeloma (MM) cells by inhibiting BTK, AKT and tubulin polymerization. In this study, we examined the ability of KS99, to inhibit the growth of panel of human AML cell lines and primary samples collected from AML patients. After 48h exposure, KS99 inhibited the growth of AML cell lines (IC50, 150-225nM) and primary blast samples (IC50, 600-1300nM) in a dose dependent manner. KS99 treatment also selectively reduced the clonogenicity of human acute myeloid leukemia patient cells compared to the hematopoietic stem cells. We also found that KS99 induced apoptosis by modulating expression of Mcl-1 and Bcl-2. Further studies will aim to determine the mechanism of action of KS99 and as a single agent and in combination with anti-leukemia agents and demonstrate the preclinical efficacy in AML animal models including AML patient derived xenografts. Together, these data demonstrate the therapeutic efficacy of Isatin analog and suggest that KS99 should be further developed as a novel therapeutic agent for AML.
Citation Format: Krishne Gowda, Charyguly Annageldiyev, Dhimant Desai, Shantu Amin, David Claxton, Arati Sharma. Isatin analog for the treatment of acute myeloid leukemia [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 795.
Abstract 995: Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemo-resistance and is associated with poor prognosis in pancreatic cancer
Authors: Zhang Daoxiang , Li Lin , Jiang Hongmei , Wang-Gillam Andrea , Yu Jinsheng , Head Richard , Liu Jingxia , Ruzinova Marianna B , Lim Kian-Huat 
Published: August 2018

Abstract
Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but so far success remains limited in the clinic. Furthermore, preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAFs) carries a risk of accelerating PDAC progression. These concerns underscore the need to concurrently target the key signaling mechanisms that drive the malignant attributes of both CAFs and PDAC cells. We previously reported that inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) suppresses NF-kB activity and promotes chemotherapy response in PDAC cells. In this study, we show that CAFs in PDAC tumors robustly express activated IRAK4 and NF-kb. The role of IRAK4 and NF-kB in PDAC CAFs has not been reported, and should be clarified before advancing IRAK4 inhibitors to the clinic. Using shRNAs and small molecular inhibitors, we found that IRAK4 is a key driver of NF-kB activity in CAFs. We showed that CAFs utilizes IRAK4 to drive tumor fibrosis, support PDAC cells proliferation, survival and chemo-resistance in vitro and in vivo. From cytokine array analysis of CAFs and microarray analysis of PDAC cells, we identified IL-1b as a key cytokine that activates IRAK4 in CAFs. Targeting IRAK4 or IL-1b renders PDAC tumors less fibrotic and more sensitive to gemcitabine in vivo.Moreover, high IL-1b expression by immunohistochemistry in PDAC samples is strongly associated with poor overall survival. Together, our studies established a tumor-stroma IL-1b-IRAK4 feedforward circuitry that can be therapeutically disrupted to render chemotherapy more effective in PDAC.
Citation Format: Daoxiang Zhang, Lin Li, Hongmei Jiang, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B Ruzinova, Kian-Huat Lim. Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemo-resistance and is associated with poor prognosis 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 995.