tbuckley/cabot-search huggingface dataset:
Abstract 2186: Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity <i>in vivo</i>
Authors: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari
Journal: Cancer Research (2017)

Abstract Antibodies targeting surface antigens on cancer cells typically have progressively lower access to tumor cells that are further removed from blood vessels. Also, the antibody will not bind to cells in the tumor mass that do not express antigen, including stromal cells of the tumor, many of which reportedly aid in the survival or metastasis of cancer cells. ADCs can bind to antigen positive cancer cells, after which they are internalized and catabolized to release one or more cytotoxic metabolite(s) that can kill the targeted cell. Metabolites that are membrane permeable may also diffuse into and kill neighboring cells, often called bystander cells, that would normally be less accessible. The goal of this work was to design ADCs that would have increased bystander activity, which could result in greater killing of cancer cells and stromal cells in the tumor environment. We have prepared a new type of peptide-cleavable immolative ADC (PCI-ADC) that efficiently releases membrane permeable cytotoxic maytansinoid metabolites upon cleavage of the peptide linker, followed by immolation. Several PCI-ADCs were prepared that release metabolites having different degrees of hydrophobicity. As the hydrophobicity of the metabolite increased, the PCI-ADCs’ bystander activity also increased. The lead PCI-ADC generally displayed a similar degree of in vitro cytotoxicity as maytansinoid ADCs that utilize disulfide linkers, however the PCI-ADC induced significantly more bystander killing. In mice bearing large tumor xenografts (250 mm3) or tumor xenografts that express the target antigen heterogeneously, PCI-ADCs were found to be more efficacious than maytansinoid ADCs that use disulfide linkers, as well as our recently reported peptide-para-anilino maytansinoid ADCs. The nature of the amino acid residues in the peptide linker of the PCI-ADC was also altered so that the tolerability of the ADCs in mice could be increased without impeding efficacy. In conclusion, we have developed a promising new type of maytansinoid ADC, one that provides a high degree of bystander killing, improved activity in homogeneous and heterogeneous tumor models in vivo, and has a different mechanism of metabolite release than current maytansinoid based ADCs. Citation Format: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari. Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2017-2186
Abstract 5736: Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer
Authors: Takahiro Tsuji, Hiroaki Ozasa, Yuichi Sakamori, Takashi Nomizo, Tomoko Funazo, Yuto Yasuda, Hironori Yoshida, Hiroki Nagai, Young Hak Kim
Journal: Cancer Research (2017)

Abstract Activation of c-MET through hepatocyte growth factor (HGF) increases tumorigenesis, induces resistance, and is associated with poor prognosis in various solid tumors. We previously reported that lung cancer cell lines had increased expression of c-MET due to gene amplification-induced cytotoxic drug resistance, and that resistant cells paracrine HGF and promote its resistance. However, the clinical significance of sHGF in patients with advanced or recurrent NSCLC, especially in patients treated with cytotoxic chemotherapy, is yet to be identified. Here, we present sHGF may be useful to predict tumor response and PFS in patients with advanced NSCLC. A total of 81 patients with 101 treatment regimens were investigated; 53 patients received first-line therapy and 48 patients received second-line therapy during the observation period. sHGF levels were evaluated using ELISA at 4 time-points: at pre-treatment, at response-evaluation (1-2 months after treatment initiation), at the best tumor response, and at the disease progression. As a control biomarker, serum carcinoembryonic antigen (CEA) was also evaluated. sHGF at response-evaluation in patients with progressive disease was higher compared with that of disease controls in both first-line and second-line treatment (median value (MV): under the limited of detection (LOD) vs. 0.40; P=0.0086 and MV: under the LOD vs. 0.41; P=0.0035, respectively). Positive-sHGF at response-evaluation predicts poor progression-free survival (PFS) compared with negative-sHGF in both first-line (median, 153.5 vs. 288.0; P=0.047) and second-line treatment (87.0 vs. 219.5; P=0.014). Lung adenocarcinoma subgroup analysis showed that in patients receiving second cytotoxic chemotherapy, there were no significant differences in PFS or HR between patients with low-CEA compared with those with high-CEA, but positive-sHGF at pre-treatment or at response-evaluation predicts poor PFS (35 vs. 132; P=0.0045, 50 vs. 215; P=0.0047, respectively). Simple and repeatable markers for activation of the HGF/c-MET pathway would provide rationale for future research investigating the merit of sHGF as a potential clinical biomarker to indicate administration of MET inhibitors. Citation Format: Takahiro Tsuji, Hiroaki Ozasa, Yuichi Sakamori, Takashi Nomizo, Tomoko Funazo, Yuto Yasuda, Hironori Yoshida, Hiroki Nagai, Young Hak Kim. Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5736. doi:10.1158/1538-7445.AM2017-5736
Abstract 54: The many faces of antibody in G protein-coupled receptor biology
Authors: Lei Chen, Wing-Tai Cheung
Journal: Cancer Research (2017)

Abstract G protein-coupled receptors (GPCRs), the largest family of cell-surface receptor proteins mediating signal transmission, play a pivotal role in many physiological functions and are involved in multiple diseases. Although receptor activities of GPCRs are successfully modulated by many small molecules which represent 30% of all marketed drugs today, in fact only a few GPCR members are targeted and many more GPCRs of interest are intractable targets of small molecules, like orphan GPCRs and GPCRs with large binding sites. Besides, small molecule drugs rarely trigger GPCR-mediated apoptosis or induce direct cell killing, which is crucial for cancer therapies. Therefore, for these GPCRs, antibody-based drug would be a good alternative. Despite being eagerly sought for, the production of monoclonal antibody (mAb) targeting GPCR is hindered by the low expression of recombinant GPCR on cell surface, and relatively small exposed regions with glycosylation and conformational heterogeneity. Therefore those conventional methods that were well established for generation of mAbs targeting soluble proteins usually showed frustrating results in the case of GPCRs. To bypass the production and purification of recombinant GPCR proteins, we developed a novel approach of transplanting immunogenic conformational epitopes of GPCR into an antibody scaffold to make a water soluble surrogate antigen of GPCR, named as GPCR-antigenized antibody which can be easily and abundantly produced in bacteria for animal immunization. In coupled with phage display technology and cell panning strategy, which allow the retrieval of specific binders from a huge number of candidates, we have successfully isolated scFv antibodies for two human GPCRs, the MAS1 receptor and the chemokine receptor CXCR4. These antibodies showed good specificity in immunofluorescent staining, flow cytometry analysis, western protein immunoblot and immunoprecipitation assay. The results demonstrated this novel approach may offer a generic and effective method to generate specific monoclonal antibody targeting GPCR for diagnostic and therapeutic applications. [The project is partly funded by a CUHK direct grant (4054300)] Citation Format: Lei Chen, Wing-Tai Cheung. The many faces of antibody in G protein-coupled receptor biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 54. doi:10.1158/1538-7445.AM2017-54
Abstract 5790: Assessing the effects of TIMP2 knockout on lung cancer cell lines cultured in 3D
Authors: David Peeney
Journal: Cancer Research (2017)

Abstract Tissue inhibitor of matrix metalloproteinases (TIMPs) are a small family of endogenous proteins that classically function to inhibit metalloproteinase activity. Since the original description of this protein family in the 80s and 90s, various MMP-independent biological functions of TIMPs have been described. This built the impression that MMP/TIMP ratios may play an important role in tissue homeostasis, an idea which is supported by the observation that altered MMP/TIMP expression ratios are often associated with a number of human conditions such as cancer, cardiovascular and CNS disease. TIMP2 is the most abundantly expressed protein in this family and has previously been shown to interact with several membrane proteins including MT1-MMP, insulin-like growth factor-1 receptor (IGF-I-R) and alpha3 beta1 integrin (α3β1) to mediate downstream intracellular signaling. In addition, TIMP2 has been shown to inhibit growth factor stimulated proliferation, angiogenesis and tumor cell invasion and metastasis, highlighting the potential for TIMP2-based cancer bio-therapies that can be used in conjunction with conventional treatments. Recent studies in our lab highlight that syngeneic lung tumors (LL2 cells; Lewis lung carcinoma) developed in C57BL mice harboring a loss-of-function mutation in TIMP2 are significantly larger than tumors grown in their WT counterparts. To gain a deeper understanding of the role of TIMP2 in tumor initiation and progression we have used CRISPR-Cas9 to develop stable TIMP2 knockout (T2KO) human lung cancer cell lines. Although indistinguishable in 2D culture, T2KO tumor cells display a morphologically distinct phenotype when grown in spheroids. Preliminary data show that, when grown in spheroids, T2KO cells exhibit enhanced EGFR activation in comparison to WT cells. By assessing the functional characteristics and gene expression of T2KO cells grown in 3D culture conditions we hope to gain further insight into the biological functions of TIMP2 and to provide a mechanistic link between the loss of TIMP2 activity and enhanced tumor formation that is observed in our mouse model. Citation Format: David Peeney. Assessing the effects of TIMP2 knockout on lung cancer cell lines cultured in 3D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5790. doi:10.1158/1538-7445.AM2017-5790
Abstract 4253: Expression profiling of paired benign and breast cancer lesions in African American women
Authors: Andreana Natalie Holowatyj, Julie J. Ruterbusch, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Christine Mehner, Melody Stallings Mann, Gregory Dyson, Derek Radisky, Michele L. Cote
Journal: Cancer Research (2017)

Abstract Benign breast disease, a known risk factor for subsequent breast cancer, includes a histological spectrum of lesions that can be subdivided based on the overall impression into non-proliferative lesions, proliferative lesions without atypia, and atypical hyperplasia. Yet little is known about the molecular characteristics of benign breast tissue from African American women, who suffer from disproportionately high breast cancer mortality rates. 72 breast samples from African American women were obtained. RNA was extracted from archival formalin-fixed, paraffin-embedded (FFPE) blocks. Gene expression profiling was performed on these samples using the Affymetrix HTA2.0 exon array chip. A fit linear model using generalized least squares identified probe sets with differential expression in benign-in situ and benign-invasive breast cancer paired lesions. 36 benign and 36 breast cancer paired lesions were included in the study. In the benign-in situ set (n=20), 978 probe sets were differentially expressed (threshold: fold-change, 1.50; p &amp;lt; 0.05). Probe sets mapped to 125 annotated genes, of which 69 (55.2%) were involved in cancer. The benign-invasive set (n=52) identified 351 differentially expressed probe sets that mapped to 84 annotated genes, of which 61 (72.6%) had known cancer significance. Genes involved in cellular growth and proliferation were significantly over-expressed in both benign-in situ and benign-invasive lesions (p-values &amp;lt; 0.0104). In the population of 36 paired samples, differentially expressed genes were found to regulate the estrogen receptor (ESR1) through distinct network associations. Many genes are differentially expressed by benign and breast cancer lesions, and in situ/invasive histology contribute to the distinct molecular characteristics and pathways of breast malignancy. Our findings highlight the first study to assess expression profiling of paired benign and breast cancer lesions among African American women. Citation Format: Andreana Natalie Holowatyj, Julie J. Ruterbusch, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Christine Mehner, Melody Stallings Mann, Gregory Dyson, Derek Radisky, Michele L. Cote. Expression profiling of paired benign and breast cancer lesions in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4253. doi:10.1158/1538-7445.AM2017-4253
Abstract 4298: FTY720 induces necroptosis in lung cancer by modulating ceramide signaling at the plasma membrane
Authors: Rose Nganga
Journal: Cancer Research (2017)

Abstract Sphingolipids are important signaling molecules in cells and have recently been explored as cancer therapy targets. FTY720 (Fingolimod, Gilenya) is an FDA approved sphingosine analogue drug used for the treatment of multiple sclerosis (MS). FTY720 is phosphorylated by sphingosine kinase 2 (SK2), to generate P- FTY720 to exert its immunosuppressive properties through binding to sphingosine -1 phosphate receptors (S1PRs). FTY720 also exhibits anti-cancer properties. Our previous studies indicated that one of the mechanism by which FTY720 induces cell death is through necroptosis. FTY720 directly binds to I2PP2A/SET (Inhibitor 2 of PP2A), consequently activating the tumor suppressor protein phosphatase 2A (PP2A). The activated PP2A then induces cell death by stimulating the activity of Receptor-Interacting Protein kinase-1 (RIPK1), involved in necroptosis signaling. Previous studies have shown that FTY720 can modulate sphingolipids metabolism in cells. However, little is known about the roles of FTY720 in ceramide signaling and regulation of necroptosis in lung cancer. We hereby seek to investigate the mechanisms of FTY720 in inducing necroptosis with regard to ceramide signaling. Preliminary data indicate that inhibitors of ceramide generation partially protect cells against FTY720-induced cell death. Interestingly, FTY720 and non-phosphorylated FTY720 analogues do not affect ceramide generation, but lead to the formation of cancer specific ceramide-multi-protein complexes at the plasma membrane. Our studies show a role of these complexes in inducing plasma membrane rupture, a key phenomenon in necroptosis. Further elucidation of these novel structures will be helpful in improving cancer therapeutics that further promote the formation these structures hence more cell death. Citation Format: Rose Nganga. FTY720 induces necroptosis in lung cancer by modulating ceramide signaling at the plasma membrane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4298. doi:10.1158/1538-7445.AM2017-4298
Abstract 975: A multiscale computational model for spatio-temporal tumor immune response
Authors: Chang Gong, Oleg Milberg, Bing Wang, Paolo Vicini, Rajesh Narwal, Lorin Roskos, Aleksander S. Popel
Journal: Cancer Research (2017)

Abstract When the immune system responds to tumor development, patterns of immune infiltrates emerge, highlighted by expression of immune checkpoint-related molecules such as PD-L1 on cancer cells and its receptor PD-1 on cytotoxic T cells. Pre-treatment tumor spatial heterogeneity could bear information on intrinsic characteristics of the tumor lesion for individual patient, and thus has the potential to comprise biomarkers for anti-tumor therapeutics. We developed a systems biology computational multiscale agent-based model to capture the interactions between immune cells and cancer cells during tumor progression. Cytotoxic T cells and cancer cells are modeled as free-moving agents in a 3-dimensional grid, where each cell acts in response to its local microenvironment and carries out functions such as division, apoptosis, cytotoxic killing and switching between states with different PD-1 or PD-L1 expression levels. Subsequently, we analyzed the emergent behavior of tumor progression by looking at all these local interactions as a whole. Using this model, we are able to reproduce temporal dynamics of cytotoxic T cells and cancer cells during general tumor progression, as well as 3-dimensional spatial distributions of these cells over the time course of the simulation. By varying the characteristics of the neoantigen profile of individual patients, such as mutational burden and immunogenicity, a spectrum of pre-treatment spatial patterns of PD-1/PD-L1 expression is generated in our simulations, resembling immune-architectures obtained via immunohistochemistry from patient biopsies. We evaluate potential prognostic biomarkers by correlating these spatial characteristics with in silico treatment results with immune checkpoint inhibitors. Simulation results demonstrate that the percentage of PD-L1 positive cancer cells which are not in close proximity of the tumor boundary or vasculature is more indicative of successful anti-PD1/anti-PD-L1 treatment. Our findings suggest that tumor spatial heterogeneity, especially its immune-architecture, reflects the course of tumor progression as well as patient-specific properties, and is thus likely to carry important information about tumor susceptibility to treatment such as with immune checkpoint inhibitors. We demonstrated how prognostic biomarkers could be realistically simulated in a general cancer scenario. The model is further refined for use to predict treatment/biomarker combinations in specific cancer types. Citation Format: Chang Gong, Oleg Milberg, Bing Wang, Paolo Vicini, Rajesh Narwal, Lorin Roskos, Aleksander S. Popel. A multiscale computational model for spatio-temporal tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 975. doi:10.1158/1538-7445.AM2017-975
Abstract 911: Destabilizing β-catenin and Ras could be an ideal therapy for treating metastatic colorectal cancer
Authors: Yong-Hee Cho, Jeong-Soo Yoon, Kang-Yell Choi
Journal: Cancer Research (2017)

Abstract INTRODUCTION Aberrant activations of Wnt/β-catenin and Ras signaling pathways by APC (90%) and K-Ras (40-50%) mutations are closely interacted and accelerate CRC tumorigenesis. Protein level of β-catenin as well as Ras is increased by APC loss via inhibiting GSK3B-mediated poly-ubiquitination dependent Ras degradation through recruitment of β-TrCP E3 linker. Moreover, additional K-Ras mutation results in the liver metastasis by secondary activation of the Wnt/β-catenin signaling pathways via Ras-ERK and -AKT pathways in addition to the initial activation by APC loss. Consequently, both β-catenin and Ras were highly increased in human CRC patient tissues, especially in metastatic tumor. EXPERIMENT PROCEDURES To investigate the synergistic effects of aberrant Wnt/β-catenin and Ras signaling pathways on tumor development to metastasis, we established the APCMin/+/K-RasG12DLA2 compound mouse that harbor APC and K-Ras mutations in animal model. We also analyzed Ras protein level using human CRC patient tissues of normal mucosa and adenocarcinoma (N=24) and metastatic adenocarcinoma (N=26) and tumor budding (N=10). To recapitulate the metastatic tumor environment which have enriched receptor tyrosine kinases (RTKs), we maintained and experimented with EGF (20ng/ml) in every in vitro studies. RESULTS We observed that both β-catenin and Ras were increased in adenocarcinoma and metastatic adenocarcinoma of human CRC compared with normal mucosa. Interestingly, both β-catenin and Ras were most significantly increased in tumor budding regions which histopathologically represent epithelial mesenchymal transition (EMT). In murine model, the EMT phenomenon was effectively induced and invasion of small intestinal tumors were occurred in APCMin/+/K-RasG12DLA2 with increased level of β-catenin and Ras compared with APCMin/+. However, EMT phenomenon and its following events such as migration and invasion of CRC cells induced by APC and K-Ras mutations were abolished by destabilization of β-catenin and Ras. CONCLUSION Our results show that destabilizing β-catenin and Ras could be effective therapeutic targets for inhibiting metastasis in the early stage of CRC development Citation Format: Yong-Hee Cho, Jeong-Soo Yoon, Kang-Yell Choi. Destabilizing β-catenin and Ras could be an ideal therapy for treating metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 911. doi:10.1158/1538-7445.AM2017-911