bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2303: The WEE1 inhibitor Debio 0123 enhances the efficacy of standard of care DNA damaging agents in lung cancer models
Authors: Piggott Luke , Vaslin-Chessex Anne , Luong Noemie , Tschumi Benjamin , Vuagniaux Gregoire 
Published: June 2022

Abstract
Introduction: The WEE1 tyrosine kinase is activated upon DNA damage and regulates the G2-M and S phase cell cycle checkpoints. Inhibition of WEE1, in conjunction with genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treating cancer. Debio 0123 is a WEE1 specific inhibitor previously shown to sensitize cancer cells to DNA damaging agents which is currently being assessed in combination with carboplatin in patients with advanced solid malignancies. Small cell lung cancer (SCLC) is an aggressive disease with poor clinical outcomes that carries a high mutational burden and genomic instability. Here we investigated the ability of Debio 0123 to enhance SCLC response to standard of care (SOC) DNA damaging agents carboplatin and etoposide in vitro and in vivo.
Methods: SCLC cell lines were treated with Debio 0123 alone or in combination with etoposide or carboplatin in vitro and apoptosis assessed by flow cytometry. In vivo SCLC patient derived- or cell line derived-xenograft (PDX or CDX, respectively) models were treated with Debio 0123 orally in combination with either carboplatin or etoposide alone or as a triple combination. Tumor growth inhibition was assessed over 3 cycles of treatment and tolerability of the combinations evaluated by monitoring body weight changes.
Results: Debio 0123 synergized with carboplatin and etoposide in vitro leading to a significant increase in the induction of apoptosis. Additionally, Debio 0123 significantly improved the tumor growth inhibitory effect of etoposide and carboplatin in both PDX and CDX models of SCLC in vivo. Triple combination of carboplatin, etoposide and Debio 0123 was well tolerated at therapeutically relevant dosing and resulted in significantly improved tumor response when compared to carboplatin and etoposide treatments alone or to the double combination.
Conclusions: Taken together these results highlight that inhibiting WEE1 with Debio 0123 significantly improves tumor response to SOC DNA damaging agents in models of SCLC, providing the foundation for future clinical exploration of Debio 0123 in SCLC.
Citation Format: Luke Piggott, Anne Vaslin-Chessex, Noemie Luong, Benjamin Tschumi, Gregoire Vuagniaux. The WEE1 inhibitor Debio 0123 enhances the efficacy of standard of care DNA damaging agents in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2303.
Abstract 2315: Synergic antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 (CLIC1) inhibition in human glioblastoma primary culture
Authors: Mazzanti Michele , Castiglione Stefania , Ranucci Matteo , Cannavale Gaetano , Cianci Francesca , Verduci Ivan 
Published: June 2022

Abstract
Glioblastoma relapse inevitably occurs in the majority of patients after surgery. Chemo- and radio- therapy are in most cases ineffective, while Tumor Treating Fields (TTFields) therapy delays average tumor recurrence by a few months. It is widely accepted that tumor reappearance is a result of the proliferation of residual glioblastoma stem cell (GSC) subpopulation, which escaped surgery. Long-term TTFields stimulation in in vitro experiments mimic glioblastoma cells recrudescence. After the first three days of TTFields exposure, cell growth is totally inhibited. However, in prolonged experiments, despite the chronic presence of TTFields stimulation, glioblastoma cells reestablish the ability to proliferate, even if at low rate. At the end of twelve days, exponentially growing cells show an increase of stemness markers, a drop of the membrane resistance with a related increase of membrane current, and an average depolarized membrane potential. Twelve days of TTFields treatment resulted in progressive increase in GSCs in the tumor cell population from 10% to more than 30%. Our long-term goal is to improve TTFields antitumoral activity by linking brain stimulation with a pharmacological strategy targeting GSC proliferation. The objective of our study is to test the therapeutic potential of combining TTFields exposure with the inhibition of the protein transmembrane Chloride Intracellular Channel 1 (tmCLIC1), which is crucial for GSCs proliferation. tmCLIC1 activity increases under oxidative stress conditions. Preliminary experiments using the INOVITRO-LIVE system showed a cytoplasmic oxidation increase under acute TTFields stimulation. tmCLIC1 impairment by ion channel specific antagonists affected the G1/S checkpoint and hence, tumor cell proliferation. Targeting synergically different glioblastoma cell cycle checkpoints, G2/M with TTFields stimulation and G1/S with tmCLIC1 inhibition, would include the vast majority of glioblastoma cell population. Combination TTFields exposure and tmCLIC1 ion channel inhibition could represent an efficacious step forward in the treatment of glioblastoma.
Citation Format: Michele Mazzanti, Stefania Castiglione, Matteo Ranucci, Gaetano Cannavale, Francesca Cianci, Ivan Verduci. Synergic antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 (CLIC1) inhibition in human glioblastoma primary culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2315.
Abstract 2327: Dysregulated TCA cycle is associated with endocrine therapy resistance in ER+ breast cancer cells
Authors: Sengupta Surojeet , de Oliviera Karla Andrade , Jin Lu , Clarke Robert 
Published: June 2022

Abstract
Estrogen receptor positive (ER+) breast cancer is the most common breast cancer subtype. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), along with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are the current mainstays of treatment. Despite being initially effective, the majority of advanced ER+ breast cancers become resistant to the endocrine therapies. Therefore, it is important to understand the underlying molecular mechanisms that enable or promote resistance to endocrine therapies. Rapidly proliferating cells have a high energy demand and consequently consume greater quantities of glucose to fulfill their energy and anabolic demands to support cell growth. Using endocrine therapy sensitive and resistant breast cancer cell models we investigated the metabolic flux of glucose by growing the cells in the presence of the stable glucose isotope, UC13-Glucose and measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. The TCA cycle was noticeably impaired in LCC9 cells as the C-13 labelled citrate (m+4 and m+6) isotopomer was absent in these cells. In addition, C-13 labelled fumarate was very low in LCC9 cells with a concurrent increase in the succinate:fumarate ratio. These observations show that in LCC9 cells the TCA cycle is dysregulated at the succinate to fumarate conversion step, which is catalyzed by the succinate dehydrogenase (SDH) enzyme. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Further investigation revealed that SDHAF2 was under expressed in LCC9 cells compared with LCC1 cells, likely contributing to lower SDH activity. Intriguingly, SDH inhibition by dimethyl-malonate re-sensitized LCC9 cells to both Fulvestrant and 4-hydroxytamoxifen. Clinically, lower expression levels of SDHAF2 correlates with poor relapse free survival in ER+ breast cancer patients. In summary, our study suggests that accumulation of succinate driven by deficient SDH activity is functionally associated with endocrine therapy resistance in ER+ breast cancer cells.
Citation Format: Surojeet Sengupta, Karla Andrade de Oliviera, Lu Jin, Robert Clarke. Dysregulated TCA cycle is associated with endocrine therapy resistance in ER+ breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2327.
Abstract 2406: Mechanism of mSin1 regulation of cell migration
Authors: Huang Shile , Liu Lei , Luo Yan 
Published: June 2022

Abstract
Studies have shown that mSin1, a major component of mTORC2, plays an important role in tumor cell migration and invasion as well as cancer metastasis. However, how mSin1 regulates cell migration is poorly understood. In this study, we found that knockout of mSin1 suppressed cell spreading and migration in mouse embryo fibroblasts (MEFs). Similarly, knockdown of mSin1 also inhibited cell spreading and migration in rhabdomyosarcoma (Rh30) and cervical cancer (HeLa) cells. Furthermore, we observed that knockout or knockdown of mSin1 reduced the activities of the small GTPases (RhoA and Rac1) in the cells. Ectopic expression of constitutively active Rac1, but not RhoA, partially attenuated the reduced cell spreading and migration induced by mSin1 deficiency. In addition, depletion of mSin1 remarkedly inhibited the phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK) at Tyr397 and paxillin at Tyr118 in the cells. The results suggest that mSin1 controls cell spreading and migration at least partly by mediating the activity of Rac1 and the phosphorylation of FAK. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA)
Citation Format: Shile Huang, Lei Liu, Yan Luo. Mechanism of mSin1 regulation of cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2406.
Abstract 242: TCTP is a target for cancer immunotherapy modulating myeloid-derived suppressor cells
Authors: Ryou Jeong-Hyun , Lee Gwanghee , Taniguchi Tadatsugu , Yanai Hideyuki , Hangai Sho 
Published: June 2022

Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogenous group of myeloid cells that are highly suppressive to antitumor lymphocyte function and trafficking to the tumor. The accumulation of MDSCs in the tumor immune microenvironment (TIME) makes immunosuppressive TIME and progressive tumor. In fact, despite notable clinical outcomes in cancer immunotherapy, many patients are refractory or relapsed to immune checkpoint inhibitor therapy, wherein obstacles imposed by TIME contribute to a great extent. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME in mouse models. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME, which is Toll-like receptor-2 (TLR2) dependent. For human translation, we confirmed that human TCTP binds directly to human TLR2 extracellular domain and stimulates human PBMC to produce multiple cytokines. To explore therapeutic applicability, we generated anti-TCTP antibodies for TCTP inhibition. The antibodies successfully neutralized TCTP in molecular and cellular level. The antibodies also suppressed PMN-MDSC accumulation and tumor growth. The combination of anti-TCTP antibody and immune checkpoint inhibitor showed synergistic effect on tumor growth inhibition. In conclusion, extracellular TCTP is an immunomodulator recruiting PMN-MDSCs to TIME. When TCTP is removed or neutralized, PMN-MDSC counts in TIME decreased. Anti-TCTP therapy may offer a new immunotherapy strategy.
Citation Format: Jeong-Hyun Ryou, Gwanghee Lee, Tadatsugu Taniguchi, Hideyuki Yanai, Sho Hangai. TCTP is a target for cancer immunotherapy modulating myeloid-derived suppressor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 242.
Abstract 2422: Migration of V600E-expressing cells is suppressed by ERK-dependent feedback inhibition of RAC1 and rescued in melanoma by secondary mutations
Authors: Gadal Sunyana , Boyer Jacob A. , Li Hongyan , Fan Ning , Chan Eric , Romin Yevgeniy , De Stanchina Elisa , Yeager Rona , Bosenberg Marcus , Todorova Katia M. , Rosen Neal 
Published: June 2022

Abstract
Oncogenic activation of ERK occurs in as many as 50% of human tumors and in the majority of melanomas. Activated BRAF V600E hyperactivates ERK signaling and causes ERK dependent dysregulation of proliferation. However, BRAF V600E alone is insufficient to drive melanoma formation in genetically engineered mice models. Moreover, 82% of benign nevi harbor BRAF V600E mutations. In contrast, in BRAF V600E/PTEN-/- GEMM models, rapid onset of aggressive and disseminated melanomas occurs. We show here that cell migration and invasion of melanocytes expressing BRAFV600E is depressed in vitro and in vivo and significantly accelerated by pharmacologic inhibition of ERK signaling or by deletion of PTEN. Upon ERK inhibition, cells lose their cell-cell junctions and become single cells with actin rich protrusions and a mesenchymal morphology. ERK pathway activation affects each step of the migration cycle, impeding cell spreading, assembly of stress fibers, and focal contact formation, all of which are associated with decreased mobility and invasion. Hyperactivation of ERK signaling by BRAF V600E has been shown to cause potent feedback inhibition of RTK signaling and wild type RAS. We now show that this is associated with feedback inhibition of RAC1, a RAS-like small GTPase required for cell migration. Moreover, ERK pathway inhibition reactivates RAC in an RTK-dependent manner. Consistent with these findings, expression of RAC1 P29S, an activating mutant, and overexpression of PREX2, an activator of RAC1, both rescue migration in BRAF V600E cells, as does loss of PTEN expression, which converges with RAC1 activation downstream. Taken together, these data suggest that whereas hyperactivation of ERK signaling by BRAFV600E dysregulates proliferation, ERK dependent feedback inhibition of RAC1 inhibits cell mobility and invasiveness and prevents full transformation. Selection of secondary genetic events that overcome or bypass RAC1 feedback is thus required for full transformation. In support of this view, RAC1 mutation, PTEN loss, or PREX2 amplification occurs in 38% of human melanomas. Thus, oncogene induced feedback may be deleterious and directs tumor evolution by causing selection of mutations that restore functions necessary for transformation
Citation Format: Sunyana Gadal, Jacob A. Boyer, Hongyan Li, Ning Fan, Eric Chan, Yevgeniy Romin, Elisa De Stanchina, Rona Yeager, Marcus Bosenberg, Katia M. Todorova, Neal Rosen. Migration of V600E-expressing cells is suppressed by ERK-dependent feedback inhibition of RAC1 and rescued in melanoma by secondary mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2422.
Abstract 2435: EZH2 engages TGFb signaling to promote breast cancer bone metastasis via Integrin b1-FAK activation
Authors: Zhang Lin , Qu Jingkun , Qi Yutao , Duan Yimin , Huang Yu-Wen , Zhou Zhifen , Li Ping , Yao Jun , Huang Beibei , Zhang Shuxing , Yu Dihua 
Published: June 2022

Abstract
Bone metastasis is a frequent complication of breast cancer, occurring in about 50-70% of breast cancer patients with late-stage disease. The lack of effective therapy suggests that the precise molecular mechanisms underlying bone metastasis are still unclear. Enhancer of zeste homolog 2 (EZH2) is considered a breast cancer oncogene and its expression is correlated with metastasis of breast cancer, but its function in bone metastasis has not been well explored. Herein we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling, a key pathway in bone metastasis. Knocking down EZH2 decreases bone metastasis incidence and outgrowth in vivo. EZH2 induces cancer cell proliferation and osteoclast maturation, when breast cancer cells are co-cultured with osteoblasts and osteoclasts together in vitro. Mechanistically, EZH2 increases transcription of ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182, thus enhances the binding of TGFβRI to TGFβ receptor type II (TGFβRII), therefore activates Smad2 and increases parathyroid hormone-like hormone (PTHLH) expression. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitor effectively inhibits breast cancer bone metastasis in vivo. Overall, our data signify integrin β1-FAK as a new downstream effector of EZH2 in breast cancer cells, and EZH2-integrin β1-FAK axis cooperates with TGFβ signaling pathway to promote bone metastasis of breast cancer.
Citation Format: Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang, Dihua Yu. EZH2 engages TGFb signaling to promote breast cancer bone metastasis via Integrin b1-FAK activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2435.
Abstract 2436: CIRBP is a functional mediator of leptomeningeal metastasis
Authors: Ezzeddine Rima , Dankner Matthew , Savage Paul , Hebert Steven , Brothers William , Annis Matthew G. , Maritan Sarah M. , Fabian Marc R. , Kleinman Claudia , Park Morag , Siegel Peter M. 
Published: June 2022

Abstract
Background: Cold-Inducible RNA Binding Protein (CIRBP) has been implicated in cancer initiation. Moreover, we have previously identified an association of CIRBP with the invasive growth of parenchymal brain metastases. Using a patient-derived xenograft (PDX) model, in which cells implanted in the mouse mammary fat pad spontaneously metastasize to the leptomeninges, we identified CIRBP as being elevated in leptomeningeal metastases (LM) compared to matched primary mammary tumors. LM grow in the subarachnoid space that harbors the cerebral spinal fluid (CSF). The leptomeninges represent an inhospitable environment for disseminated cancer cells since the CSF is mitogen and nutrient poor. To investigate the importance of CIRBP for metastatic breast cancer cells in the leptomeninges, we stably reduced CIRBP expression in MDA-MB-231 cells and performed mammary fat pad and cranial injections. CIRBP knockdown had no influence on primary tumor growth, but diminished growth within the brain.
Hypothesis: We hypothesize that CIRBP functions as a stress response protein enabling cancer cells to grow in the harsh environment of the CSF.
Results: In response to various cellular stressors, such as hypothermia, hypoxia or UV irradiation, CIRBP can translocate from the nucleus to the cytoplasm. We show that culturing MDA-MB-231 cells in artificial CSF (aCSF) also causes CIRBP relocation from nucleus to cytoplasm. Using RNA-IP approaches, we have identified mRNAs bound by CIRBP in breast cancer cells treated with aCSF. Ultimately, we will determine whether any of the identified CIRBP-regulated targets contribute to the formation of LM. Finally, we have generated CIRBP variants that are confined either to the nucleus or the cytoplasm. We are currently assessing the ability of these compartment-restricted CIRBP proteins to promote the formation of central nervous system metastases.
Conclusions: We have identified CIRBP as a promoter of leptomeningeal metastasis. Our results have begun to reveal the mechanisms through which CIRBP mediates this process.
Citation Format: Rima Ezzeddine, Matthew Dankner, Paul Savage, Steven Hebert, William Brothers, Matthew G. Annis, Sarah M. Maritan, Marc R. Fabian, Claudia Kleinman, Morag Park, Peter M. Siegel. CIRBP is a functional mediator of leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2436.
Abstract 2443: Knocking out SNCA in SKMEL28 melanoma cells suppresses EMT and prevents invasion
Authors: Gajendran Nithya , Rajasekaran Santhanasabapathy , Aloy Nirjhar M. , Shekoohi Sahar , Witt Stephan N. 
Published: June 2022

Abstract
Malignant melanoma is one of the most aggressive and fifth most prevalent cancer among men and women. Clinical and epidemiological studies shows that Parkinson’s disease (PD) patients have higher risk of developing invasive melanoma, and, reciprocally, patients with invasive melanoma have a higher risk of developing PD. Alpha-synuclein (α-syn; SNCA), an intrinsically disordered protein expressed in neurons, is also highly expressed in malignant melanoma and is a common molecular signature between Parkinson’s disease and melanoma. We have previously reported that SK-Mel-28 SNCA-knockout (KO) cells exhibit suppressed tumor growth and proliferation in vivo and in vitro, and that putting back SNCA via lenti virus restored the phenotype to that of the control cells. The present study is designed to investigate the role of α-syn in melanoma progression in SK-MEL-28 cells in the context of metastasis and the epithelial-to-mesenchymal transition (EMT). The SK-Mel-28 SNCA-KO clones showed a significant decrease in the cell-surface protein L1CAM, a major cell adhesion molecule highly expressed in various melanoma and correlates with melanoma progression, whereas the knock in clones resembled the control. Migration and invasion assay were performed using transwell chambers showed a profound migratory and invasive defect in SNCA-KO clones. To explore further whether this is a proliferative or migratory defect, a single cell phagokinetic motility assay was performed with colloidal gold which showed a marked decrease in cell motility in knockout clones compared to control and knock in clones, which was consistent with our migration and invasion experiments. To determine the proteins involved in the inhibition of invasion mediated by α-syn, we immunoblotted for the mesenchymal markers N-cadherin and vimentin, and these were significantly downregulated in the SNCA-KO clones. These data reinforce that knocking out SNCA impedes melanoma cell migration and invasion in SK-Mel- 28 cell line, implying that α-syn might be a novel therapeutic target for malignant melanoma.
Citation Format: Nithya Gajendran, Santhanasabapathy Rajasekaran, Nirjhar M. Aloy, Sahar Shekoohi, Stephan N. Witt. Knocking out SNCA in SKMEL28 melanoma cells suppresses EMT and prevents invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2443.