tbuckley/cabot-search huggingface dataset:
Abstract 2290: The serine-threonine kinase Mink1 as a potential therapeutic target in triple negative breast cancer
Authors: Avais Daulat, Monica Silveira Wagner, Malgorzata Kowalczewska, Pascal Finetti, Rémy Castellano, Stéphane Audebert, François Bertucci, Luc Camoin, Jean-Paul Borg
Journal: Cancer Research (2021)

Abstract The developmental Wnt/planar cell polarity (PCP) pathway is the most recently described branch of the Wnt signaling pathways and is strongly implicated in cancer development at early and late stages (PMID: 28718442 and PMID: 30952630). Upregulation of the Wnt/PCP components is observed in many cancers and is associated with cancer progression. However, how their molecular functions are regulated remains an open question. Recent data from our laboratory showed that Prickle1 and Vangl2, two core Wnt/PCP components, are overexpressed in Triple Negative Breast Cancers (TNBC) and associated with poor prognosis (PMID: 27184734 and 26754771). Prickle1 is a cytoplasmic protein phosphorylated by the serine/threonine kinase Mink1, which triggers Prickle1 localization at the plasma membrane and regulates its activity (PMID: 22037766). Activation of this axis contributes to breast cancer cell motility and metastatic spreading in vitro and in vivo (PMID: 27184734). To extend our knowledge of the Mink1 substrates, we carried out a phosphoproteomic strategy and identified LL5β. LL5β is a membrane scaffold molecule that anchors microtubules (MTs) at the cell cortex through its association with CLASP, a plus-end MT protein, to trigger focal adhesion disassembly. We found that LL5β is a prominent member of the Prickle1-associated protein complex and harbors a consensus motif for Mink1 phosphorylation. At the molecular level, we demonstrated a two-step phosphorylation cascade carried out by Mink1 that phosphorylates sequentially Prickle1 to mediate its association with LL5β, then LL5β to promote its interaction with CLASP. Finally, analysis of gene expression data suggests that the concomitant up-regulation of Prickle1 and LL5β mRNA levels is associated with a poor metastasis-free survival for TNBC patients. In an effort to counteract the Mink1-Prickle1-LL5β prometastatic pathway, we selected a Mink1 inhibitor that recapitulates all the phenotypes observed following the knockdown of Mink1 expression. This chemical compound is currently under investigation in preclinical assays using xenografted TNBC cell lines and patient-derived xenografts in nude mice. Citation Format: Avais Daulat, Monica Silveira Wagner, Malgorzata Kowalczewska, Pascal Finetti, Rémy Castellano, Stéphane Audebert, François Bertucci, Luc Camoin, Jean-Paul Borg. The serine-threonine kinase Mink1 as a potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2290.
Abstract 3164: Modeling the metastatic niche interactions between patient tumor and mesenchymal cells to identify drivers of chemotherapy drug resistance
Authors: Liam Deems, Amit Shahar, Amy Pepicelli, Cheryl Murphy, Daniel Solomon, David Deems, Dmitry Shvartsman
Journal: Cancer Research (2021)

Abstract Cancer research relies on a plethora of disease-relevant tumor models, but patient specific models are still being developed. In this study, we show the utility of patient-specific pancreatic, ovarian and breast cancer models in the context of the metastatic niche, composed of co-cultured mesenchymal stem cells (MSC) in three-dimensional tumor spheroids. Additionally, different ratios of MSC's were seeded with the cancer spheroids to interrogate the effect of MSC's on chemotherapeutic drug response in defined media conditions. The patient-specific and treatment-naive cancer models represent a diverse range of disease type, progression grade, and genetic profiles. These models were co-cultured with MSC's sourced from both bone marrow and adipose tissue. These co-culture models were tested with a panel of common, broad-range chemotherapeutic agents as well as several disease-specific drugs. The resulting drug responses show that the presence of MSC's within the context of the metastatic niche causes attenuation towards a higher chemotherapeutic drug resistance. The tumor models exhibit a varied chemotherapeutic response when MSC's are seeded in 50:1, 5:1, or 1:1 ratio with cancer cells, suggesting that even a small presence of MSC's may have a significant effect on the drug resistance of metastatic tumor spheroids. While this MSC-induced drug response attenuation is observed across the broad spectrum of patient profiles and disease types, the strength of the effect is not homogenous. The observed variability in the strength of the effect was impacted by the disease type of the cancer cells, the source of the MSC's, and the specific drug used in the metastatic tumor model. We propose that using these reproducible and easily scaled models of metastatic tumors to find effective chemotherapeutic drugs could increase our understanding of the tumor microenvironment, the onset of metastasis, and the process of cancer grafting into other tissues. Discovering effective and targeted therapies utilizing a more advanced model of the metastatic tumor niche could increase the success rate of an eventual clinical trial. Citation Format: Liam Deems, Amit Shahar, Amy Pepicelli, Cheryl Murphy, Daniel Solomon, David Deems, Dmitry Shvartsman. Modeling the metastatic niche interactions between patient tumor and mesenchymal cells to identify drivers of chemotherapy drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3164.
Extrathymic <i>Aire</i> -expressing cells support maternal-fetal tolerance
Authors: Eva Gillis-Buck, Haleigh Miller, Marina Sirota, Stephan J. Sanders, Vasilis Ntranos, Mark S. Anderson, James M. Gardner, Tippi C. MacKenzie
Journal: Science Immunology (2021)

Maternal extrathymic Aire -expressing cells support maternal-fetal tolerance and prevent intrauterine growth restriction in mice.
Abstract LB213: ACTL6A (Actin-like Protein 6A) enhances the cancer phenotype
Authors: Suruchi Shrestha, Gautam Adhikary, Wen Xu, Sivaveera Kandaysamy, Richard L. Eckert
Journal: Cancer Research (2021)

Abstract Epidermal squamous cell carcinoma (SCC) is an extremely common, invasive and metastatic cancer. ACTL6A, an important protein subunit of the SWI/SNF epigenetic regulatory complex, is frequently overexpressed in cancer cells. In the present study, we show that ACTL6A drives SCC cell proliferation, invasion, migration and tumor formation, and that this aggressive phenotype is markedly reduced in ACTL6A knockdown cells. Expression of ACTL6A is associated with reduced p21Cip1 level and treatment with ACTL6A-siRNA results in a marked increase in p21Cip1 and attenuation of the cancer phenotype. Molecular studies reveal that ACTL6A suppresses p21Cip1 promoter activity to reduce mRNA and p21Cip1 protein and that loss of p21Cip1 expression appears to be biologically meaningful, as p21Cip1 knockdown enhances the aggressive phenotype. ACTL6A suppression of p21Cip1 expression requires the p53 and Sp1 transcription response elements in the p21Cip1 gene promoter. In addition, ACTL6A knockdown results in increased p53 tumor suppressor expression. These studies show that ACTL6A facilitates an aggressive cancer phenotype by reducing p53 and p21Cip1 mRNA and protein and suggests that ACTL6A contributes to an aggressive cancer phenotype in epidermal squamous cell carcinoma. Citation Format: Suruchi Shrestha, Gautam Adhikary, Wen Xu, Sivaveera Kandaysamy, Richard L. Eckert. ACTL6A (Actin-like Protein 6A) enhances the cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB213.
The Role of Perfusion Computed Tomography of the Liver in the Assessment of Hemodynamics in Patients with Compensated Cirrhosis of the Liver and the Presence of Type 2 Diabetes Mellitus. Pilot Study
Authors: G. A. Stashuk, Ya. G. Moisyuk, D. Ya. Smirnova, O. V. Sumtsova
Journal: Radiology - Practice (2021)

Currently the relationship between liver diseases and glucose metabolism disorders is being studied. To characterize the negative impact of the mechanisms of insulin resistance on the liver parenchyma altered due to cirrhosis, we can use CT-perfusion of the liver — a method that allows us to assess hemodynamic disorders in the liver tissue. During the pilot study, it was found that the values of arterial perfusion and hepatic perfusion index in patients with compensated cirrhosis of the liver in the presence of type 2 diabetes mellitus were statistically significantly higher than in the absence of this pathology (p = 0,007 and p = 0,009 respectively). The values of portal and total perfusion in patients with compensated cirrhosis of the liver in the presence of type 2 diabetes mellitus were significantly lower than in the absence of this pathology (p &lt; 0,001 and p = 0,007 respectively). CT-perfusion of the liver can be used in patients with compensated cirrhosis and the presence of type 2 diabetes mellitus in the anamnesis as a non-invasive method of instrumental diagnosis of hemodynamic changes, including in assessing the progression of portal hypertension and the subsequent detection of concomitant complications.
Is whenever feasible-strategy for partial nephrectomy invariably justified? The impact of clinical tumour size on postoperative renal function
Authors: G. Colandrea, D. Cignoli, G. Basile, G. Rosiello, G. Fallara, G. Baiamonte, F. Cei, C. Giancristofaro, G. Musso, D. Canibus, A. Briganti, A. Salonia, R. Bertini, F. Montorsi, U. Capitanio, A. Larcher
Journal: European Urology (2021)
Abstract 2014: Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase
Authors: Shuai Zhao, Wafik S. El-Deiry
Journal: Cancer Research (2021)

Abstract The major adaptive response to hypoxia involves HIF-1α which is conventionally regulated by VHL E3 ligase. Our previous experiments suggested a stabilization of HIF-1α by CDK1 and CDK4/6 that is independent of VHL, hypoxia or p53, and that CDK4/6 inhibitors destabilizes HIF-1α under normoxia and hypoxia. To further investigate the molecular mechanism of HIF-1α destabilization by CDK1 or CDK4/6 inhibitors, we performed a proteomic screen on immunoprecipitated HIF-1α from hypoxic colorectal cancer cells that were either untreated or treated with CDK1 inhibitor Ro3306 and CDK4/6 inhibitor palbociclib. Our proteomics screen identified a number of candidates that were enriched in palbociclib-treated hypoxic cells including SMAD specific E3 ubiquitin protein ligase 2 (Smurf2). In addition, we identified a HIF-1α peptide that appeared to be differentially phosphorylated after palbociclib treatment. Gene knockdown of Smurf2 increased basal expression of HIF-1α that was further increased in the presence of Ro3306 or two different CDK4/6 inhibitors, palbociclib and abemaciclib. Overexpression of Smurf2 inhibited expression of HIF-1α and enhanced HIF-1α ubiquitination in normoxia. Proteasome inhibitor MG-132 partially rescued HIF-1α expression when Smurf2 was overexpressed. Overexpression of Smurf2 is correlated with improved disease-free survival and overall survival in clear cell renal cell cancer. Our results unravel a previously unknown mechanism involving Smurf2 for HIF-1α destabilization in CDK4/6 inhibitor-treated cells, thereby shedding light on VHL-independent HIF-1α regulation. Citation Format: Shuai Zhao, Wafik S. El-Deiry. Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2014.
A Review of Irritable Bowel Syndrome
Authors: Tiffany H. Taft, Daniel Keszthelyi, Lukas Van Oudenhove
Journal: JAMA (2021)

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Abstract 2786: A FcgR IIB tumor enriching anti-CD137 novel antibody to avoid liver Immuno-toxicity
Authors: Jie Xue, Jen-Kuan Chang, Chen Dong, Yi-Ting Mao, Pallavi Raghavendra, Ou Li, Hassan Issafras, Wenfeng Xu, Weidong Jiang
Journal: Cancer Research (2021)

Abstract CD137 (4-1BB/TNFRSF9) is a costimulatory T-cell receptor belonging to the TNF receptor superfamily which is transiently expressed on T cell and NK cells. Targeting CD137 or its natural ligand 4-1BB ligand (4-1BBL) has important implications in many clinical conditions, including cancer. Anti-CD137 agonistic anti-CD137 antibodies have shown potent, often curative anti-tumor activity in preclinical models. In depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes and high amounts of cytokines, including IFN-γ. However, this approach has suffered significant setback in the clinic due to either dose-dependent severe liver toxicity (e.g. Urelumab), or lack of single agent activity in the case of Utomilumab. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. Here we present a novel antibody targeting 4-1BB receptor, named HLX25 with engineered Fc region to enhance the binding to FcγR IIB. In vitro, HLX25 induces comparable or superior CD137 activation and IL-2 release compared to Urelumab and Utomilumab, suggesting potentially a better safety profile. We showed that HLX25 binds to unique non-ligand competing epitope, which is different from both Urelumab and Utomilumab. In vivo, HLX25 shows potent dose-dependent single agent anti-tumor activity as low as 0.3mg/kg in MC38 model without sign of liver toxicity up to 20 mg/kg, suggesting superior efficacy and better safety profile. Citation Format: Jie Xue, Jen-Kuan Chang, Chen Dong, Yi-Ting Mao, Pallavi Raghavendra, Ou Li, Hassan Issafras, Wenfeng Xu, Weidong Jiang. A FcgR IIB tumor enriching anti-CD137 novel antibody to avoid liver Immuno-toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2786.
Focal ablative salvage therapy for radio-recurrent prostate cancer: 6 year oncological and safety outcomes
Authors: D.T. Reddy, M. Peters, T. Shah, M. Van Son, F. Hosking-Jervis, S. Miah, M. Bertoncelli Tanaka, D. Eldred-Evans, S. Guillaumier, P. Huber, D. Lomas, A. Rakauskas, T. Dudderidge, S. Mccracken, R. Hindley, A. Emara, R. Nigam, R. Persad, J. Virdi, C. Moore, C. Orczyk, M. Emberton, M. Arya, M. Winkler, H. Ahmed
Journal: European Urology (2021)
Abstract 1601: Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma
Authors: Guozhen Yang, Xiaodong Su, Hong Yang, Guangyu Luo, Chan Gao, Yating Zheng, Wenzhuan Xie, Mengli Huang, Yuezong Bai, Zhiqiang Wang, Peiqiang Cai, Haoqiang He, Jin Xiang, Muyuan Cai, Yijun Zhang, Chunhua Qu, Jianhua Fu, Qianwen Liu, Yi Hu, Jiudi Zhong, Yuanheng Huang, Qiyu Guo, Xu Zhang
Journal: Cancer Research (2021)

Abstract Background: Immunotherapy is effective in treating unresectable esophageal squamous cell carcinoma (ESCC), but little is known about its activities in the preoperative setting. We aimed to evaluate the safety, feasibility and efficacy of neoadjuvant treatment with camrelizumab plus chemotherapy in locally advanced ESCC. Methods: Patients diagnosed with locally advanced ESCC were retrospectively included if they had received three courses of neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy between November, 2019 and June, 2020 at Sun Yat-sen University Cancer Center. Primary endpoints were safety and feasibility. Pathological response and association between tumor immune microenvironment (TIME)/tumor mutational burden (TMB) and treatment response were also explored. Results: Twelve patients were included. Neoadjuvant treatment with camrelizumab plus nab-paclitaxel/S1 was well tolerated without any grade 3 or higher toxicities. No surgical delay or perioperative death was reported. Nine patients (75%) responded to the treatment, four with a complete pathological response and five with a major pathological response. Treatment response by radiography was discordant with surgical pathology for five cases while endoscopic ultrasonography was accurate for the entire cohort. Neither programmed death-ligand 1 expression nor TMB was correlated with treatment response. In the TIME, higher abundance of CD56dim natural killer cells was associated with better pathological response in the primary tumor while lower density of M2-tumor-associated macrophages was associated with better pathological response in the lymph nodes. Conclusions: Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective in locally advanced ESCC and is worth further investigation. Citation Format: Guozhen Yang, Xiaodong Su, Hong Yang, Guangyu Luo, Chan Gao, Yating Zheng, Wenzhuan Xie, Mengli Huang, Yuezong Bai, Zhiqiang Wang, Peiqiang Cai, Haoqiang He, Jin Xiang, Muyuan Cai, Yijun Zhang, Chunhua Qu, Jianhua Fu, Qianwen Liu, Yi Hu, Jiudi Zhong, Yuanheng Huang, Qiyu Guo, Xu Zhang. Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1601.
Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional <i>STK11</i> Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown
Authors: Nabendu Pore, Song Wu, Nathan Standifer, Maria Jure-Kunkel, Melissa de los Reyes, Yashaswi Shrestha, Rebecca Halpin, Raymond Rothstein, Kathy Mulgrew, Stephen Blackmore, Philip Martin, John Meekin, Matthew Griffin, Ina Bisha, Theresa A. Proia, Ricardo J. Miragaia, Ronald Herbst, Ashok Gupta, Shaad E. Abdullah, Rajiv Raja, Melanie M. Frigault, J. Carl Barrett, Phillip A. Dennis, Maria Libera Ascierto, Michael D. Oberst
Journal: Cancer Discovery (2021)

Mutations in the STK11 (LKB1) gene regulate resistance to PD-1/PD-L1 blockade. This study evaluated this association in patients with nonsquamous non-small cell lung cancer (NSCLC) enrolled in three phase I/II trials. STK11 mutations were associated with resistance to the anti-PD-L1 antibody durvalumab (alone/with the anti-CTLA4 antibody tremelimumab) independently of KRAS mutational status, highlighting STK11 as a potential driver of resistance to checkpoint blockade. Retrospective assessments of tumor tissue, whole blood, and serum revealed a unique immune phenotype in patients with STK11 mutations, with increased expression of markers associated with neutrophils (i.e., CXCL2, IL6), Th17 contexture (i.e., IL17A), and immune checkpoints. Associated changes were observed in the periphery. Reduction of STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical STK11 knockout models. These results suggest that STK11 mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy. SIGNIFICANCE: Patients with nonsquamous STK11-mutant (STK11mut) NSCLC are less likely than STK11 wild-type (STK11wt) patients to respond to anti-PD-L1 ± anti-CTLA4 immunotherapies, and their tumors show increased expression of genes and cytokines that activate STAT3 signaling. Preclinically, STAT3 modulation reverses this resistance, suggesting STAT3-targeted agents as potential combination partners for immunotherapies in STK11mut NSCLC.This article is highlighted in the In This Issue feature, p. 2659.
Abstract 1590: An experimental tumor model resistant to anti-PD-1 is sensitive to local mRNA immunotherapy
Authors: Marie Bernardo, Tatiana Tolstykh, Yu-an Zhang, Dinesh S. Bangari, Hui Cao, Kerstin A. Heyl, Joon Sang Lee, Natalia Malkova, Jack Pollard, Hui Qu, Fangxian Sun, Dmitri Wiederschain, Timothy R. Wagenaar
Journal: Cancer Research (2021)

Abstract Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or β2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFβ and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFβ and Notch in combination with PD-1 blockade decelerated tumor growth, local administration of a mixture of mRNAs encoding immune-stimulatory cytokines (IL12sc, GM-CSF, IL15s and IFNα) potently induced regression of resistant tumors and resulted in complete tumor remission. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade. Citation Format: Marie Bernardo, Tatiana Tolstykh, Yu-an Zhang, Dinesh S. Bangari, Hui Cao, Kerstin A. Heyl, Joon Sang Lee, Natalia Malkova, Jack Pollard, Hui Qu, Fangxian Sun, Dmitri Wiederschain, Timothy R. Wagenaar. An experimental tumor model resistant to anti-PD-1 is sensitive to local mRNA immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1590.