tbuckley/cabot-search huggingface dataset:
Abstract 5761: C-Fos drives non-tumorigenic head and neck squamous cell carcinoma cells to tumorigenic by promoting cancer stem cells like properties
Authors: Naoshad Muhammad, Sourav Bhattacharya, Robert Steele, Nancy Phillips, Ratna B. Ray
Journal: Cancer Research (2017)

Abstract Purposes of the study: Head and neck squamous cell carcinoma (HNSCC) is the sixth most widespread cancer and leading cause of cancer related death world widely. Regardless of the advancement in treatment processes the overall survival rate of patients having this cancer has not substantially improved in the past few decades. Development of tumor and its progression exclusively resides in a small population of cancer cells, termed as cancer stem cells (CSCs). This population of cells can self-renew and re-form the ordered organization of tumors. CSCs contribute to HNSCC and may offer prominent therapeutic strategy for the management of HNSCC. We previously observed that c-Fos was highly up-regulated in the HNSCC sphere forming cells. In the present study, we explored the role of c-Fos in the tumor initiation in relation with cancer stemness and EMT. Experimental procedures: We examined whether overexpression of c-Fos has an effect on tumorigenicity and stemness. For this, c-Fos was overexpressed in non-tumorigenic HNSCC cell lines and tumor growth was investigated. We also examined the expression of different CSC marker genes expression by Western blot analysis. Summary: Our results demonstrated that exogenous expression of c-Fos in non-tumorigenic MDA1386Tu cells makes the cells tumorigenic in nude mice. Mechanistic investigations showed that c-Fos overexpression in MDA1386Tu cells enhanced epithelial-mesenchymal transition (EMT)/CSC properties and increased numbers of oralspheres when grown in ultra-low binding plate. Conclusions: Collectively, our data strongly demonstrate that c-Fos plays a critical role in the modulation of EMT and cancer stem cell reprogramming in HNSCC cells and enhance tumor growth. Note: This abstract was not presented at the meeting. Citation Format: Naoshad Muhammad, Sourav Bhattacharya, Robert Steele, Nancy Phillips, Ratna B. Ray. C-Fos drives non-tumorigenic head and neck squamous cell carcinoma cells to tumorigenic by promoting cancer stem cells like properties [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 5761. doi:10.1158/1538-7445.AM2017-5761
Abstract SY25-02: Antigenic strength vs. tumor microenvironment in determining cancer immunosurveillance
Authors: Robert H. Vonderheide
Journal: Cancer Research (2017)

Abstract We evaluated immune surveillance in pancreatic ductal adenocarcinoma (PDA), which exhibits far fewer missense mutations and potential neoepitopes than classically described carcinogen-induced, highly mutated tumors. In contrast to these immunogenic tumor models from which the theory of elimination-equilibrium-escape was determined, we found no evidence for immunoediting in a mutant Kras-driven murine model of PDA. These tumors progress the same with or without a functional adaptive immune system, similar to other mouse tumors that have also been shown to grow independently of T cells. Tumors arising in T cell–depleted mice grew unchecked in immune-competent hosts. We further show that KPC pancreatic tumors have few if any predicted neoepitopes derived from somatic tumor missense mutations and that an immunoediting phenotype can be rescued by ectopic expression of a neoantigen (OVA) in the same tumor model. Thus, the manifestations of cancer immune surveillance in the KPC model depend on tumor antigenic strength; the lack of neoepitopes is not a consequence of immunoediting in this model. These findings suggest an alternative biologic mechanism in which tumor outgrowth reflects immune quiescence, which is linked to, and regulated by, poor tumor antigenicity—a conclusion with potential relevance to human cancers with a low burden of mutations and minimal neoepitopes. Citation Format: Robert H. Vonderheide. Antigenic strength vs. tumor microenvironment in determining cancer immunosurveillance [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 SY25-02. doi:10.1158/1538-7445.AM2017-SY25-02
Abstract 5232: The molecular basis for specific recognition of the biologically relevant hybrid-2 type human telomeric G-quadruplex by epiberberine
Authors: Clement Lin, Guanhui Wu, Yong Shao, Danzhou Yang
Journal: Cancer Research (2017)

Abstract G-quadruplex structures have been shown to form in human telomeres, and the formation of G-quadruplexes can inhibit telomerase, which plays a key role in cancers by stabilizing telomere length and integrity thereby granting limitless replicative potential. The human telomeric G-quadruplex is thus considered to be a potential target for cancer therapeutics. In physiologically relevant potassium solution, human telomeric DNA sequences form two equilibrating hybrid-type G-quadruplex structures, with the hybrid-2 structure being the predominant form in extended sequences. We discovered that epiberberine (EPI), a naturally occurring protoberberine alkaloid, can specifically bind the hybrid-2 human telomeric G-quadruplex and can induce the conversion to the hybrid-2 structure. Using nuclear magnetic resonance (NMR) spectroscopy, we determined the solution structure of the 1:1 complex of EPI and hybrid-2 human telomeric G-quadruplex. Our NMR structure shows EPI bound at the 5’ end of the hybrid-2 telomeric quadruplex with an unexpectedly large drug-induced conformational change in the flanking and loop regions, creating a very well-defined drug binding pocket with extensive capping structures. The EPI molecule and 5’ flanking adenine form an induced quasi-triad plane which is intercalated between the external 5’ tetrad and capping structures. Two layers of new capping structures are formed with the 5’ flanking segment and the second TTA lateral loop to cover the “intercalated quasi-triad”. Notably, the well-defined EPI-induced multi-layer binding-site arrangement is only possible in the hybrid-2 folding topology of telomeric DNA. Our results provide important insights into specific targeting of the physiologically relevant hybrid-2 human telomeric G-quadruplex by a small molecule compound; EPI’s asymmetric crescent-shape and the positioning of its dioxolane moiety, as well as the hybrid-2 folding and the loop and flanking bases in the human telomeric DNA sequence, all contribute toward the specific recognition of EPI. In addition, we have conducted polymerase stop assays, which confirmed that EPI can stabilize the human telomeric G-quadruplex to inhibit polymerase activity. Citation Format: Clement Lin, Guanhui Wu, Yong Shao, Danzhou Yang. The molecular basis for specific recognition of the biologically relevant hybrid-2 type human telomeric G-quadruplex by epiberberine [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 5232. doi:10.1158/1538-7445.AM2017-5232
Multidisciplinary tumor clinic results in improved five year overall and disease-free survival in patients with colorectal cancer.
Authors: Michael Honaker, Ceazon Edwards, Samer Ballouz, Harry Wasvary
Journal: Journal of Clinical Oncology (2015)

e14672 Background: Colorectal cancer remains a significant cause of cancer related mortality. The introduction of a colorectal multidisciplinary tumor clinic at our institution revealed better adherence to NCCN guidelines in a 2009 study. The purpose of this study was to determine if the implementation of a multidisciplinary clinic resulted in improved five year survival outcomes. Methods: Patients treated in a multidisciplinary colorectal cancer clinic were compared to patients cared for outside of the tumor clinic. Patient outcomes were followed for five years and included recurrence rates, overall and disease-free survival. Stage for stage, clinic patients were compared to non-clinic patients with regards demographics and outcomes using appropriate statistical analysis. A two-tailed p-value of less than 0.05 was considered statistically significant. Results: 78 patients were identified who had been cared for in the tumor clinic and 177 patients were cared for outside of the tumor clinic. The clinic group by cancer stage included; stage I (n = 17), stage II (n = 20), stage III (n = 22) and stage IV (n = 19). In the group of patients treated outside of the clinic, the number of patients by stage included; stage I (n = 51), stage II (n = 52), stage III (n = 42) and stage IV (n = 32). The only significant difference between the two groups was an increased number of female patients treated in the clinic for stage III colorectal cancer (86% vs. 42%; p = 0.0008). Recurrence rates were similar across all stages regardless of the site of treatment. When overall five year survival was examined, there was a statistically significant improvement for patients treated in the clinic with stage III disease (81% vs 53.8%; p = 0.0377). There was also a statistically significant increase in the length of disease-free survival (mean 35 vs 25.7 months; p = 0.0326) and overall survival (mean 33.3 vs 25 months; p = 0.0214) in patients with stage III disease in the clinic group compared with those patients treated outside of the clinic. Conclusions: Five year survival, overall survival, and disease-free survival are significantly improved in patients with stage III disease when cared for at a multidisciplinary colorectal tumor clinic.
Abstract 43: ASN004, a novel 5T4-targeted Dolaflexin ADC, achieves complete regressions and tumor-free survivors in a broad variety of solid tumor models
Authors: Roger A. Smith, David J. Zammit, Sanjeeva P. Reddy
Journal: Cancer Research (2017)

Abstract ASN004 is an Antibody Drug Conjugate (ADC) that targets the 5T4 oncofetal antigen (trophoblast glycoprotein). High expression of 5T4 is observed in a wide range of malignant tumors, while very limited expression is found in normal tissues. ASN004 incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and several cytotoxic dolastatin (auristatin) analog warheads per ADC molecule with a drug/antibody ratio of ~15:1. ASN004 shows high affinity for the 5T4 antigen (Kd &amp;lt; 30 pM) and 5T4-expressing tumor cells; rapid cellular internalization; and potent, selective cytotoxicity. ASN004 provides complete tumor regressions and tumor-free survivors in multiple tumor xenograft models, derived from human tumor cell lines having both high and low 5T4 expression levels. Tumor-free survivors were achieved at doses that are well-tolerated, based on xenograft body weight measures and exploratory toxicology studies in pharmacologically-relevant non-human primates. As well, tumor-free survivors were achieved in xenograft tumor models following administration of a single dose of ASN004, as low as 1 mg/kg iv. The broad activity of ASN004 has been demonstrated by its superior efficacy in a head-to-head study against trastuzumab-DM1, in a low-5T4, high-HER2 expressing tumor xenograft model. Finally, tumor xenografts that initially responded to ASN004 and later showed tumor regrowth, had not developed resistance and responded well to subsequent treatment with ASN004. Overall, ASN004 is demonstrated to be an ADC with high therapeutic potential in multiple tumor types, encompassing a wide range of 5T4-expression levels. IND-enabling toxicology studies are ongoing, in preparation for advancement to clinical studies in patients with solid tumors. Citation Format: Roger A. Smith, David J. Zammit, Sanjeeva P. Reddy. ASN004, a novel 5T4-targeted Dolaflexin ADC, achieves complete regressions and tumor-free survivors in a broad variety of solid tumor models [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 43. doi:10.1158/1538-7445.AM2017-43
Abstract 53: Antibody-drug conjugates (ADCs) of peptide-linked Indolino-Benzodiazepine (IGN) DNA-alkylator provides improved anti-tumor activity over that of a crosslinker
Authors: Michael L. Miller, Manami Shizuka, Jose F. Ponte, Leanne Lanieri, Dilrukshi Vitharana, Qifeng Qiu, Emily E. Reid, Katie E. Archer, Rui Wu, Erin K. Maloney, Olga Ab, Jan Pinkas, Ravi V. Chari
Journal: Cancer Research (2017)

Abstract We recently disclosed highly active antibody-drug conjugates (ADCs) that incorporated the novel DNA alkylating indolino-benzodiazepine (termed IGN) dimer, DGN549 (IGN-P1). The stereochemistry of the alanyl moiety of the protease-cleavable alanine-alanine linker used was shown to impact ADC catabolism, bystander killing activity, and in vivo efficacy (Shizuka, et al., AACR 2016 #2959). Building upon these results, here we describe preclinical results from a head-to-head comparison of ADCs of the mono-imine containing DGN549 with its corresponding DNA cross-linking diimine version, IGN-P1 diimine. IGN-P1 diimine and DGN549 were conjugated to a folate receptor-α (FRα)-binding antibody and an EpCAM-binding antibody. The resulting ADCs demonstrated similar high in vitro potency (IC50 ~3-100 pM) and specificity towards several cancer cell lines. Further in vitro studies revealed that the DNA alkylating anti-FRα-DGN549 ADC demonstrated superior bystander cell-killing activity compared to its DNA crosslinking counterpart, anti-FRα-IGN-P1 diimine. In vivo, this improved bystander killing ability translated into better in vivo activity for the DNA alkylating ADC. In an endometrial tumor xenograft model established with Ishikawa cells, the anti-FRα-DGN549 induced complete regressions at a single dose of 140 µg/kg Ab dose (equivalent to 5 µg/kg linked IGN). The cross-linking anti-FRα-IGN-P1 diimine had to be used at twice the dose to achieve the same level of anti-tumor activity. The in vivo tolerability in CD-1 mice also displayed differences in the two ADCs. We found that the ADC of the DNA crosslinker was at least two-fold less tolerated than the corresponding ADC of the DNA alkylator. These results indicate that a ~4 fold greater therapeutic index can be achieved when using a DNA alkylating mono-imine DGN549 ADC as compared to the DNA crosslinking IGN-P1 diimine ADC. Citation Format: Michael L. Miller, Manami Shizuka, Jose F. Ponte, Leanne Lanieri, Dilrukshi Vitharana, Qifeng Qiu, Emily E. Reid, Katie E. Archer, Rui Wu, Erin K. Maloney, Olga Ab, Jan Pinkas, Ravi V. Chari. Antibody-drug conjugates (ADCs) of peptide-linked Indolino-Benzodiazepine (IGN) DNA-alkylator provides improved anti-tumor activity over that of a crosslinker [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 53. doi:10.1158/1538-7445.AM2017-53
Abstract 2154: P53 pathway restoring compound P306 inhibits colorectal cancer growth
Authors: Xiaobing Tian, Shengliang Zhang, Amriti Lulla, wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract We recently reported that P01 is a potent p53 pathway-restoring small molecule that acts through increasing levels of TAp73. Further, it also interferes with the p73-mutant p53 protein-protein interaction and by downregulation of ΔNp73 (Tian, Zhang and El-Deiry, abstract# 3830, AACR 2016). P01 is a member of the natural products that have been shown to have potent anti-cancer activity against tumors with mutated p53. Based on the structure of the pharmacophore of compound P01, we designed and synthesized new analogs based on published structure-activity relationship and organic synthesis papers. The newly synthesized analogs were potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines such as HT29, SW480, DLD-1, MDA-MB-231and H1975 with EC50s in the range of 0.16 μM to 0.26 μM. We are currently evaluating the anti-cancer effects of three analogs P301, P304 and P306, of which only two of these analogs induce TAp73 as assayed by western blot. We are currently characterizing the analog P306, which is the most potent compound among them. P306 engages the apoptosis pathway by upregulation of pro-apoptotic proteins like PUMA, DR5, and BIM and downregulation of anti-apoptotic markers such as Mcl-1 in a time-and dose-dependent manner in colorectal cancer cell lines. P306 treatment also downregulates both mRNA and protein level of MET and EGFR in HT29 cells that overexpress MET and EGFR receptors. We are currently investigating the mechanisms of induction of both PUMA and DR5 in mutant p53 cells and determining whether either gene is necessary for the apoptotic effects of P306 in colorectal cancer cells. Our preliminary data indicates that upregulation of DR5 is through the ATF4/CHOP pathway post-P306 treatment. It has been reported that Puma is a target gene of ATF4, CHOP and p73, however, we found that none of them is responsible for P306-induced upregulation of PUMA in p53 mutated DLD1, SW480 or HCT116 p53-null cell lines. Thus, our ongoing in vitro studies are focused on further understanding the mechanism of action of P306 in mutant p53 cells and potentially exploring combinations with FDA-approved therapies. We are also in the process of conducting, first-in animal studies of P306 as single agent or in combination with chemotherapy or targeted therapy. Citation Format: Xiaobing Tian, Shengliang Zhang, Amriti Lulla, wafik S. El-Deiry. P53 pathway restoring compound P306 inhibits colorectal cancer growth [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 2154. doi:10.1158/1538-7445.AM2017-2154
Abstract 4459: Glycine decarboxylase inhibits proliferation of ovarian cancer cells via SIRT1-mediated apoptosis
Authors: So-Jin Shin, Jin-Young Kim, Eun-Young Ha, Chi-Heum Cho
Journal: Cancer Research (2017)

Abstract Glycine decarboxylase (GLDC) is a very recently identified metabolic oncogene that links glycine metabolism with tumorigenesis. We designed this study to determine the mechanistic role of GLDC in in ovarian cancer cells. First, we confirmed the expressions of GLDC in eight different ovarian cancer cell lines. And colony formation assay revealed decreased proliferation of OVCAR3 ovarian cancer cells transfected with siGLDC compared with that of control. Intriguingly, we found that knockdown of GLDC induced decreased S-adenosylmethionine (SAM)/ S-adenosylhomocysteine (SAH) ratio, which implicates methyl donor deficient state in OVCAR3 cells. Expressions of sirtuin 1 (SIRT1), heat shock protein (HSP) 90 and heat-shock factor protein 1 (HSF1) decreased while that of p53 increased in GLDC knock-downed cells, suggesting heat shock response. Addition of SAM into siGLDC knock-downed cell restored the expression of SIRT1. Inhibition of SIRT1 decreased Bcl2 and increased cytochrome c expressions. In summary, these results suggest GLDC induces methyl donor deficient state in OVCAR3 ovarian cancer cells, which in turn leads to apoptosis via SIRT1-mediated pathway. Citation Format: So-Jin Shin, Jin-Young Kim, Eun-Young Ha, Chi-Heum Cho. Glycine decarboxylase inhibits proliferation of ovarian cancer cells via SIRT1-mediated apoptosis [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 4459. doi:10.1158/1538-7445.AM2017-4459
Abstract 2533: Sox2 promotes cell proliferation of esophageal squamous cell carcinoma through the miR-17-92 cluster ,PTEN,AKT,mTORC1 pathway
Authors: Kei Terasaki
Journal: Cancer Research (2017)

Abstract SOX2, a member of the SOX family of transcription factors, play an important role of differentiation and morphogenesis of the esophagus. We previously revealed that SOX2 is the target of gene amplification at 3q26 in esophageal squamous cell carcinoma (ESCC) (Cancer Genet Cytogenet. 2010), and that SOX2 promotes ESCC cell proliferation in vitro and in vivo through the activation of the AKT/mTORC1 signaling pathway (Cancer Sci. 2013). However, the mechanisms by which SOX2 promotes AKT/mTORC1 signaling remain unknown. It is known that PTEN is a negative regulator of AKT and the PTEN gene is a target of the miR-17-92 cluster. In the present study, we showed that SOX2 up-regulated the expression of miR-17-92 cluster and repressed PTEN expression using RNA interference (RNAi)-mediated knockdown of SOX2 and enforced expression of SOX2. In summary, SOX2 promotes cell proliferation of ESCC through the miR-17-92 cluster /PTEN/AKT/mTORC1 pathway. Citation Format: Kei Terasaki. Sox2 promotes cell proliferation of esophageal squamous cell carcinoma through the miR-17-92 cluster ,PTEN,AKT,mTORC1 pathway [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 2533. doi:10.1158/1538-7445.AM2017-2533
Selecting the model that best fits the data
Authors: Willemijn van Woerkom, Willem Zuidema
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. argue that that none of the experiments they review really establishes that human adults, infants, or nonhuman animals are sensitive to numerosity independent of a range of continuous quantities. We do not dispute their claim that the empirical record is inconclusive but argue that model-based data analysis does offer a way to make progress.