tbuckley/cabot-search huggingface dataset:
Abstract 5668: CCL2/CCR2-driven monocyte recruitment to the tumor following radiotherapy influences the outcome of the treatment of head and neck cancer
Authors: Michele Mondini, Pierre L. Loyher, Kevin Berthelot, Céline Clémenson, Alexandre Boissonnas, Eric Deutsch
Journal: Cancer Research (2017)

Abstract Local radiotherapy is the major treatment to control locally advanced head and neck cancer. Evidence supporting the importance of immune response in the response to radiation therapy is growing and the possibility to potentiate the effects of radiotherapy by modulating the function of the immune system offers new exciting therapeutic perspectives. Preclinical findings suggest that immunomodulatory agents may synergize with radiotherapy, increasing local response rates and inducing sustained systemic responses. The role of monocytes/macrophages in the response to radiotherapy is under extensive investigation. Among the many cytokines secreted by tumor cells, CCL2 is involved in inflammatory monocyte recruitment from bone marrow to the inflammatory site. We have recently developed a model of human papillomavirus (HPV)-related head and neck cancer using immunocompetent mice and validated its usefulness to evaluate the tumor response to radiotherapy. Using the same model, based on the injection of TC1/luciferase cells in the inner lip of C57Bl/6 mice, we show that local radiotherapy induces an increase of CCL2 levels in the bloodstream and intratumorally accompanied by a neo-infiltration of monocytes in the tumor that subsequently differentiate into tumor-associated macrophages (TAM). When TC1/Luc cells were engrafted in CCL2-/- or CCR2-/- mice, the tumor response to radiotherapy and survival were improved. This was accompanied by an impaired infiltration of inflammatory monocytes, and a subsequent decrease of TAM levels at later time points. In vitro, exposure to ionizing radiation increased the secretion of CCL2 by TC1/Luc cells, and such increase was significantly enhanced when tumor cells were co-cultured with irradiated RAW 264.7 macrophage-derived cells. This data suggests interplay between tumor and TAM that can amplify the effects of radiotherapy on the immune system. We propose that reducing radiation-induced monocyte recruitment may yield improved results in the treatment of HPV-related head and neck squamous cell carcinomas by radiotherapy. Immunologically-augmented radiotherapy could allow reduction of the delivered radiation dose, thus minimizing the risk of treatment sequelae while maintaining optimal tumor control. Citation Format: Michele Mondini, Pierre L. Loyher, Kevin Berthelot, Céline Clémenson, Alexandre Boissonnas, Eric Deutsch. CCL2/CCR2-driven monocyte recruitment to the tumor following radiotherapy influences the outcome of the treatment of head and neck 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 5668. doi:10.1158/1538-7445.AM2017-5668
Abstract 3981: The Shc1 scaffold protein simultaneously balances Stat1 and Stat3 activity in breast cancer to promote immune suppression and resistance to immunotherapy
Authors: Ryuhjin Ahn, Kévin Jacquet, Marc Fabian, Sidong Huang, Nicolas Bisson, Josie Ursini-Siegel
Journal: Cancer Research (2017)

Abstract Receptor and cytoplasmic tyrosine kinases are key signal integrators in poor outcome breast cancers that are central to the establishment of an immunosuppressive microenvironment. Immunotherapies represent an emerging approach within the armament of anti-cancer agents. Although the efficacy of tyrosine kinase inhibitors relies, in part, on their ability to augment adaptive immunity, the increased heterogeneity and functional redundancy of the tyrosine kinome in poor outcome breast cancers represents a significant hurdle to achieving durable responses to immunotherapies. We previously identified the Shc1 (ShcA) scaffold protein, a central regulator of tyrosine kinase signaling, as essential for promoting immune suppression. We recently showed that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired phosphorylation of select tyrosine residues on ShcA potently and selectively reduces STAT3 activation in breast tumors, profoundly sensitizing them to immune checkpoint inhibitors and tumor vaccines. Meanwhile, impaired phosphorylation of other select tyrosine residues on ShcA potently increased antigen presentation and sensitivity to tumor vaccines in preclinical mouse models. Based on these results, we have set out to elucidate protein interactors dependent on distinct ShcA phospho-tyrosines to regulate STAT1 and STAT3 signaling axis that aid tumor driven immune suppression. We combined affinity-purification mass spectrometry (AP/MS) and proximity-dependent biotin identification (BioID) followed by mass spectrometry (BioID/MS). Known interactors of ShcA as well novel interactors have been identified. Promising candidates that could be critical in immune suppression downstream of ShcA have been validated to be true interactors by co-IP and BioID assays. They have been screened for immune regulation in vitro for further modulation in vivo. Currently, inhibitors of phospho-tyrosine motifs of ShcA do not exists. Therefore, the development of pharmacological inhibitors to prevent phospho-tyrosine ShcA dependent STAT3 signaling or relieve suppression of STAT1 signaling may be an attractive method to strategically sensitize breast tumors to multiple immunotherapies. Citation Format: Ryuhjin Ahn, Kévin Jacquet, Marc Fabian, Sidong Huang, Nicolas Bisson, Josie Ursini-Siegel. The Shc1 scaffold protein simultaneously balances Stat1 and Stat3 activity in breast cancer to promote immune suppression and resistance to immunotherapy [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 3981. doi:10.1158/1538-7445.AM2017-3981
Abstract 313: Tbata induces G2/M cell cycle arrest and sensitizes osteosarcoma cells to etoposide in a p53-independent manner
Authors: Milos D. Miljkovic, Francis A. Flomerfelt, Ronald E. Gress
Journal: Cancer Research (2017)

Abstract Thymus, brain, and testes-associated (Tbata) is a negative control cell-cycle gene highly expressed in murine thymic epithelial cells (TECs). Tbata protein binds to Uba3, inhibiting formation of Nedd8 E1 and subsequent target degradation via neddylation of several cell cycle control proteins needed for G2/M transition, which may be a major mechanism of TEC growth arrest during thymic involution. Etoposide is a cytotoxic drug which targets the enzyme toposimerase II — increased 2-3 fold during the G2 phase. To further characterize effect of Tbata on the cell cycle, we modified p53 wild-type U2OS cells derived from human osteosarcoma to express a Tbata/mCherry fusion protein when mifepristone is added to culture media. Tbata-expressing cells identified on flow cytometry did exhibit growth arrest, with quantitative assessment of DNA content in U2OS cells by flow cytometry establishing that 32% of Tbata/mCherry-expressing cells were in the G2 phase when exposed to mifepristone for 24 hours, compared to 11% of mCherry-expressing cells. Gene expression studies were consistent with these results. Cells expressing Tbata/mCherry were also more sensitive to etoposide at 0.5, 1, and 5 times the IC50 dose. To test whether p53 function was required, we further modified the cells to overexpress a dominant negative p53 mutant along with Tbata/mCherry. Similar G2 arrest and increased sensitivity to etoposide were observed, indicating that the effects of Tbata did not require normal p53 function. Potential Tbata analogues or mimetics may therefore be used as an adjunct to G2-targeted chemotherapy. Citation Format: Milos D. Miljkovic, Francis A. Flomerfelt, Ronald E. Gress. Tbata induces G2/M cell cycle arrest and sensitizes osteosarcoma cells to etoposide in a p53-independent manner [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 313. doi:10.1158/1538-7445.AM2017-313
Outcomes after 18 months of eliglustat therapy in treatment‐naïve adults with <scp>G</scp>aucher disease type 1: The phase 3 ENGAGE trial
Authors: Pramod K. Mistry, Elena Lukina, Hadhami Ben Turkia, Suma P. Shankar, Hagit Baris, Marwan Ghosn, Atul Mehta, Seymour Packman, Gregory Pastores, Milan Petakov, Sarit Assouline, Manisha Balwani, Sumita Danda, Evgueniy Hadjiev, Andres Ortega, Sebastiaan J. M. Gaemers, Regina Tayag, M. Judith Peterschmitt
Journal: American Journal of Hematology (2017)

Abstract Eliglustat, an oral substrate reduction therapy, is a first‐line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (&gt;90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18‐month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double‐blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double‐blind period, eliglustat treatment during the 9‐month, open‐label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double‐blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment‐naïve patients. Eliglustat was well‐tolerated, and there were no new safety concerns with longer‐term exposure.
Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells
Authors: Y Lai, J Weng, X Wei, L Qin, P Lai, R Zhao, Z Jiang, B Li, S Lin, S Wang, Q Wu, Z Tang, P Liu, D Pei, Y Yao, X Du, P Li
Journal: Leukemia (2017)
Abstract 2791: CDC25A overexpression is correlated with tumor response to radiotherapy in locally advanced rectal cancer
Authors: Ming-Yii Huang
Journal: Cancer Research (2017)

Abstract Background. Radiotherapy is increasingly used in preoperative approaches for locally advanced rectal cancer to reduce local recurrence. However, the principal limitation is large variability in response among different individuals due to tumor heterogeneity. In current study, we compared gene expression profiles between radiation responder and non-responder in cancerous tissues to identify radiation-related molecules that can be used to evaluate the tumor response of radiation. Methods. We investigated five genes (CDC25A, VAV1, TP73, BRCA1 and ZAP70) which were significantly related to prognostic factors (tumor size, advanced stage, invasive depth, lymph node metastasis and differentiation) from 110 colorectal cancer tissues confirmed by membrane array and RT-PCR methods in our previous study. Therefore, we further investigate those protein overexpressions by immunohistochemical stain in pretherapeutic rectal cancerous tissues. The expression profiles were evaluated according to the frequency of positive staining in the cytoplasm and/or nucleus of cancer cells. Its expression was classified as positive in cases with more than 50% positive-stained cells, with other samples being classified as negative. Cancer tissues that expressed scores of + were regarded as the overexpression group, whereas those with scores of negative staining were regarded as the non-overexpression group. Results. We focused on these 5 genes and validated data with pretherapeutic biopsies from 36 locally advanced rectal cancer patients, and found that overexpression of CDC25A, VAV1 and ZAP70 were correlated with tumor response (P=0.001, 0.033, and 0.016, respectively). The multivariate logistic regressions with adjustment of age, sex and stage, CDC25A overexpression more than 2-fold were significantly correlated with tumor response (OR = 2.667, 95%CI = 1.591-4.470, P=0.03). Positive findings of CDC25A immunohistochemistry stain were also present in the tumor specimens of responders. Conclusion. We identified radiation-related genes in rectal cancer and demonstrated that CDC25A may play an important role in response to radiotherapy. These findings suggest that CDC25A may be a novel marker for predicting the effectiveness of radiotherapy in clinical patients. Note: This abstract was not presented at the meeting. Citation Format: Ming-Yii Huang. CDC25A overexpression is correlated with tumor response to radiotherapy in locally advanced rectal 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 2791. doi:10.1158/1538-7445.AM2017-2791
Abstract 1767: Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study)
Authors: Takashi Ishikawa, Kazutaka Narui, Mari S. Oba, Akimitsu Yamada, Kumiko Kida, Mikiko Tanabe, Yasushi Ichikawa
Journal: Cancer Research (2017)

Abstract AIM: We compared 6 cycles of docetaxel and cyclophosphamide (TC6) with 3 cycles of 5-fluorouracil and epirubicin and cyclophosphamide followed by 3 cycles of docetaxel (FEC-D) as neoadjuvant chemotherapy for patients with hormone receptor (HR)-negative breast cancer (BC) to identify biomarkers requiring anthracycline treatment. Methods: In total, 103 patients with operable HR-negative BC were administered TC6 or FEC-D. Triple-negative BC was subdivided by CK5/6 and EGFR into basal- and non-basal BCs. The primary endpoint was pathological complete response (pCR). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (Ki-67, P-53, ALDH1 and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: Of the 103 patients, 97 completed the study. Overall pCR was higher for patients treated with FEC-D (36%) than for those treated with TC6 (25.5%) (P=0.265). FEC-D was significantly superior to TC6 in basal BC (42.9% vs 13.6%; P=0.033), while no differences in HER2 and non-basal BCs. Aldehyde dehydrogenase 1 (ALDH1) positivity was inversely associated with pCR for both regimens, significantly for FEC-D (FEC-D: p=0.047, TC6: p=0.085). Patients who achieved pCR tended to have longer DFS (P = 0.287) and OS (P = 0.069). Patients with basal and non-basal BC treated with FEC-D had significantly better DFS (P = 0.016) and OS (P = 0.034) than those with TC6. Conclusion: We found TC6 was less effective than FEC-D for HR-negative BC because it was not sufficient to treat basal-BC. This suggests that DNA damaging agents like anthracyclines are required for treating basal-BC. Additionally, ALDH1 could be a marker for resistance to conventional chemotherapy. Citation Format: Takashi Ishikawa, Kazutaka Narui, Mari S. Oba, Akimitsu Yamada, Kumiko Kida, Mikiko Tanabe, Yasushi Ichikawa. Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study) [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 1767. doi:10.1158/1538-7445.AM2017-1767
Abstract 4029: Robust Ras inhibition assay utilizing fully synthetic Ras-binding domain
Authors: Lyuba Khavrutskii, Sergey G. Tarasov, Colin Fields, Karen Stefanisko, Nadya Tarasova
Journal: Cancer Research (2017)

Abstract Intensifying efforts to develop clinically useful inhibitors of Ras proteins resulted in increasing need for quantitative, reliable and robust in vitro assays of Ras activity. The vast majority of detection methods used in the assays require fusion, chemical modification or immobilization of the protein. We have found that K-Ras modifications have significant impact on its activity and function because of the highly allosteric nature of the protein. We have attached three different fluorescent moieties to two sites distant from the active site of the protein in a site-selective manner. All six modifications resulted in significant drops in affinity towards Ras-binding domain of one of Ras's major effectors c-Raf as determined by Microscale Thermophoresis (MST). Fluorescent labeling of recombinant Raf1 RBD also resulted in inhibition of K-Ras binding. To produce a pair that interacted as unlabeled proteins, we have generated RBD with a single-site attached fluorescent moiety utilizing microwave-assisted high efficiency solid phase peptide synthesis. Optimization of coupling and deprotection protocols and the type of the solid support allowed conducting the synthesis of 76 residues long protein in fully-automated manner in one run. Refolding of the product yielded RBD that was indistinguishable from the recombinant one in CD spectra, melting temperature and K-Ras binding affinity as determined by isothermal calorimetry and microscale thermophoresis. Fluorescent RBD produced significant changes in both thermophoretic signal and fluorescence anisotropy upon binding to K-Ras. Both MST and fluorescence polarization assays have proven sensitive, reproducible and straightforward for determination of Ras inhibition constant for Ras inhibitors identified by virtual screens and rational design. They can be easily adapted to high throughput screening formats. Developed synthetic protocols allow for straightforward generation of proteins with various natural and non-natural modifications. Citation Format: Lyuba Khavrutskii, Sergey G. Tarasov, Colin Fields, Karen Stefanisko, Nadya Tarasova. Robust Ras inhibition assay utilizing fully synthetic Ras-binding domain [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 4029. doi:10.1158/1538-7445.AM2017-4029
Abstract 5791: 3D tissue engineering bladder model for cancer invasion study
Authors: Cassandra Ringuette Goulet, Geneviève Bernard, Stéphane Chabaud, Frédéric Pouliot, Stéphane Bolduc
Journal: Cancer Research (2017)

Abstract INTRODUCTION: Our understanding of the biological processes involved in bladder cancer (BCa) is greatly limited by the models currently available. In fact, the combination of in vitro and in vivo models of BCa has failed to elucidate all the fundamental aspects of the disease. The eighth most commonly diagnosed cancer in Western societies, BCa has become a growing public health concern, and more realistic models are needed to reveal the mechanisms involved in tumor initiation and progression. METHODS: Bladder substitutes have been constructed by tissue engineering with healthy human fibroblasts and urothelial cells, using the self-assembly method. Meanwhile, spheroids have been produced from non-invasive (RT4) and invasive (T24) BCa cell lines expressing DsRed fluorescent protein. The invasive potential of these spheroids was characterized in a type-I collagen gel (2.5mg/mL). Then, the spheroids were implanted on the surface of bladder substitutes, after which their development was followed by fluorescence microscopy. RESULTS: Both of the cancer cell lines used were able to form compact spheroids and grow on bladder equivalents. The invasive behaviour of spheroids varied depending on the nature of the cells used. The non-invasive RT4 cell line was unable to cross the basal lamina whereas the invasive T24 cell line was able to do so. CONCLUSION: The establishment of such a model for studying cancer biology in a physiological environment will help bridge the gap between overly simple cell culture models and more complex transgenic mice models. This new model offers a unique opportunity to study separately the players involved in the development of BCa and thus represents a powerful tool for the mechanistic analysis of this complex pathology. Citation Format: Cassandra Ringuette Goulet, Geneviève Bernard, Stéphane Chabaud, Frédéric Pouliot, Stéphane Bolduc. 3D tissue engineering bladder model for cancer invasion study [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 5791. doi:10.1158/1538-7445.AM2017-5791