bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1036: Targeting bone morphogenetic protein 6 as a therapeutic target for LKB1-inactivated lung cancer
Authors: Koo Junghui , Seong Chang-Soo , Dwivedi Bhakti , Tucker-Burden Carol , Marcus Adam I. , Gilbert-Ross Melissa 
Published: June 2022

Abstract
Lung cancer is among the most commonly diagnosed cancers and the leading cause of cancer-related death globally, with approximately 85% of all lung cancers having non-small cell lung cancer (NSCLC). The protein kinase LKB1 is the 3rd most frequently mutated gene in lung adenocarcinoma, and serves as a master regulator of cell metabolism and growth. LKB1-inactivating mutations have a significant impact on NSCLC development. Although KRAS mutation is most frequently co-mutated with the tumor suppressor p53, the strongest cooperation was seen with homozygous inactivation of LKB1. Loss of LKB1 on a KRAS-mutant (KL) background leads to increased tumor burden, shortened survival time and increased metastasis compared to loss of TP53 (KP). Furthermore, inactivation or loss of LKB1 correlated with poor prognosis, where tumors are typically aggressive and chemoresistant. To discover therapeutic vulnerabilities for this aggressive genetic subtype of lung adenocarcinoma, we evaluated the contribution of multiple single- and double-genetic alterations (KRAS G12D (K), LKB1 knockdown (L), and p53 knockdown (P)) to 3D invasion phenotypes using immortalized human bronchial epithelial cells (HBEC3-KT) and conducted RNA transcriptome profiling of the invading HBEC3-KT 3D spheroids. We found that bone morphogenetic protein 6 (BMP-6) is upregulated in invasive KL spheroids only compared to K and KP, suggesting that the loss of both KL drives increased BMP6 expression. Consistent with this finding, the iron regulator hepcidin, which is regulated by BMP6 is also upregulated in KL spheroids. Both BMP-6 and hepcidin expression can be repressed by restoring exogenous LKB1 in KL spheroids suggesting that LKB1 loss is at least in part responsible for the overexpression of the BMP6/hepcidin pathway. In addition, inhibition of BMP-6 signaling via BMP type I receptor ALK2 using small molecule inhibitor LDN214117 suppressed of cell invasion in 3D culture and decreased tumor growth in a KL syngeneic mouse model. Collectively, our findings show that upregulation of hepcidin via BMP6 signaling and followed by iron sequestration in tumor cells is part of the metastatic invasion strategy of LKB1 inactivated NSCLC. Therefore, current clinical strategies targeting BMP6 signaling could improve outcomes for LKB1-mutant lung cancer patients.
Citation Format: Junghui Koo, Chang-Soo Seong, Bhakti Dwivedi, Carol Tucker-Burden, Adam I. Marcus, Melissa Gilbert-Ross. Targeting bone morphogenetic protein 6 as a therapeutic target for LKB1-inactivated lung cancer [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 1036.
Abstract 105: Inhibitory effect of Wnt/β-Catenin inhibitor CWP232228 on the growth of ovarian cancer cells
Authors: Shin So-Jin , Lee Seungmee , Chung Hyewon , Cho Chi-Heum , Ha Eunyoung , Kim Jin Young , Seo Ji Hae 
Published: June 2022

Abstract
Ovarian cancer is a leading cause of death of women in worldwide. Frequent recurrence and becoming resistant to chemotherapy are one of the causes that makes ovarian cancer deadly. Since recent studies have demonstrated that aberrant Wnt signaling plays an important role in cancer stem cells (CSCs) which are responsible of recurrence, metastasis and treatment failure, we tested whether regulation of Wnt signaling can be effective in ovarian cancer treatment. By treating CWP232228 which is a potent inhibitor of Wnt signaling to ovarian cancer cell lines and to a mouse model, we found CWP232228 effectively inhibits the growth of ovarian cancer cells which expresses high level of b-catenin and induce apoptosis of ovarian cancer cells. Furthermore CWP232228 reduces ovarian cancer cell migration, invasion and colony formation ability. Moreover CWP232228 reduces key features of CSCs. Taken together, our study suggests CWP232228 as a potential substance which might be effective in treating epithelial ovarian cancer with avoiding treatment failure.
Citation Format: So-Jin Shin, Seungmee Lee, Hyewon Chung, Chi-Heum Cho, Eunyoung Ha, Jin Young Kim, Ji Hae Seo. Inhibitory effect of Wnt/β-Catenin inhibitor CWP232228 on the growth of ovarian 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 105.
Abstract 109: The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation
Authors: Morel Marion , Long Weiwen 
Published: June 2022

Abstract
F-box proteins are essential components of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligases in that they bind to SKP1 through the F-box motif and bring the substrate to the E3 ligase complex for ubiquitination. FBXL16 is a poorly studied F-box protein. FBXL16 doesn’t interact with Cul1 and might not form a functional SCF-E3 ligase complex. Unexpectedly, we recently found that FBXL16 upregulates several oncoproteins targeted by SCF-E3 ligases, such as SRC-3 and c-myc, by antagonizing the activity of another F-box protein, FBW7. By data mining, we found that FBXL16 is highly upregulated in many cancers, including lung adenocarcinomas (LUADs), and its upregulation is associated with poor overall survival. LUAD is the most common form of lung cancer, and about 30% of LUADs harbor constitutively active oncogenic KRAS mutants. However, currently no drug is available for effectively treating LUADs expressing KRAS mutants. Hence, there is an unmet need to identify new therapeutic targets. Here, we report that FBXL16 protein level is selectively upregulated and is strongly correlated with insulin receptor substrate-1 (IRS1) protein expression in LUAD cell lines with activating KRAS mutations. By cycloheximide treatment, we found that FBXL16 greatly increases IRS-1 protein stability and level, leading to upregulation of IGF-1 (Insulin)/IRS1/PI3K Akt signaling. Importantly, the upregulation of IRS1 protein and its signaling by FBXL16 was confirmed in mouse lungs with conditional overexpression of FBXL16 transgene. Moreover, depletion of FBXL16 by RNA interference inhibits IGF-1-induced lung cancer cell proliferation and migration. Taken together, our findings reveal FBXL16 as a potential target for treating LUADs with KRAS activating mutations.
Citation Format: Marion Morel, Weiwen Long. The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation [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 109.
Abstract 110: Elevation of pro-apoptotic protein, PUMA, contributes to the growth suppression of lung cancer by platycodin D
Authors: Wang Qing , Yang Hsin-Sheng 
Published: June 2022

Abstract
Lung cancer is the most devastating disease and leading cause of cancer death in men and women. Platycodin D is one of the major bioactive components of the Platycodon grandiflorum, a herb that is frequently used for the treatment of lung diseases in Chinese medicine. Platycodin D is a triterpenoid monomer with activities of antioxidant, anti-obesity, and anti-inflammatory. Studies have also shown that platycodin D has an anti-tumor effect on various types of cancer. However, the mechanism by which platycodin D suppresses tumorigenesis remains elusive and some experimental results are controversial. In this study, we aim to understand the effect of platycodin D on the growth of non-small lung cancer cells (NSCLC) and the underlying mechanism. We found that NSCLC cells (H1299, H2030, and A549 cells) treated with platycodin D significantly reduced the cell viability, decreased the number of colonies, impaired the mitochondrial function, and induced apoptosis. To understand the mechanism, the protein levels of the Bcl-2 protein family were examined and p53 upregulated modulator of apoptosis (PUMA) was found elevated by platycodin D treatment. The induction of PUMA expression by platycodin D treatment was through activation of the c-Jun N-terminal kinase (JNK) and AP-1 dependent transcription since JNK inhibitor or over-expression of dominant negative c-Jun abolished the elevated PUMA expression. Moreover, knockdown of JNK1, but not JNK2, significantly decreased the level of platycodin D-induced PUMA and cleaved caspase 3, indicating the essential role of JNK1 in platycodin D-induced apoptosis. Furthermore, platycodin D efficiently suppressed the tumor growth in the H1299 xenograft. Taken together, activation of JNK1 by platycodin D is essential for induction of apoptosis in suppression of growth of NSCLC, providing a new mechanism of how platylcodin D suppresses NSCLC.
Citation Format: Qing Wang, Hsin-Sheng Yang. Elevation of pro-apoptotic protein, PUMA, contributes to the growth suppression of lung cancer by platycodin D [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 110.
Abstract 113: Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa cells
Authors: Campbell Taaliah , Hawsawi Ohuod , Bowen Nathan , Odero-Marah Valerie 
Published: June 2022

Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies among men worldwide and remains the second leading cause of cancer related death in the United States. Oxidative stress has been shown to be increase in several cancers including prostate cancer. In fact, oxidative stress in prostate cancer is suggested to be a direct result of cell exposure to reactive oxygen species (ROS). High mobility group A 2 (HMGA2), a non-histone protein, is an oncogene that is up-regulated in several cancers. This protein has ability to undergo chromosomal rearrangement and alternative splicing, causing its full length/wild type HMGA2 (HMGA2-WT) to become the truncated losing its 3’UTR leading to the generation of HMGA2 truncated (HMGA2-TR). We have previously shown HMGA2-WT’s involvement in epithelial mesenchymal transition (EMT), however, the functional role of HMGA2-TR has not yet been dissected. We hypothesize that truncated HMGA2’s involvement with oxidative stress leads to prostate cancer progression. We analyzed the baseline expression of wild-type vs.truncated HMGA2 in prostate patient tissue and cells lines by real-time PCR and western blot analyses. Prostate cancer patient tissue and some cell lines expressed increasing amounts of both wild-type and truncated HMGA2with increasing tumor grade, when compared to normal epithelial cells. RNA-Seq analysis of LNCaP prostate cancer cells stably overexpressing HMGA2-WT, HMGA2-TR, or empty vector (Neo) control revealed thatHMGA2-TR cells display increased oxidative stress compared to HMGA2-WT or Neo control cells. This was also confirmed by analysis of basal reactive oxygen species (ROS) levels, and the ratio of GSH/GSSG andNADP/NADPH utilizing metabolomics. Additionally, proteomic analysis showed that HMGA2-TR protein interacted with several proteins, including a cytoplasmic stress granule protein G3BP1 that responds to oxidative stress. Transient knockdown of G3BP1 increased ROS in HMGA2-TR cells. These studies may therefore uncover novel role for truncated HMGA2 in oxidative stress.
Acknowledgements: These studies were supported by the NIH/NIMHD/RCI Grant #5G12MD007590-31,NIH/NIGMS/RISE Grant #5R25GM060414
Citation Format: Taaliah Campbell, Ohuod Hawsawi, Nathan Bowen, Valerie Odero-Marah. Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa 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 113.
Abstract 1130: CETSA interaction proteomics define specific RNA modification pathways as key components of fluorouracil based cancer drug cytotoxicity
Authors: Bacanu Smaranda , Liang Ying Yu , Ramos Anderson D. , Prabhu Nayana , Nordlund Pär 
Published: June 2022

Abstract
Introduction: Our current understanding of the mechanism of action (MoA) of many cancer drugs is still incomplete. This hampers efforts in establishing efficient personalised medicine regimens, the optimisation of combination therapies, and the development of next generation drugs.
Results: Here, we apply a high-resolution implementation of the proteome-wide cellular thermal shift assay (CETSA) to follow protein interaction changes induced by the antimetabolite 5-fluorouracil (5-FU) and related nucleosides. We focus on the relatively early drug effects, up to 12 hours, when this time frame is less accessible to other omics methods, while critical for defining drug MoAs. We confirm anticipated effects on the known main target, thymidylate synthase (TYMS), and enzymes in pyrimidine metabolism and DNA damage pathways. However, most interaction changes we see are for proteins previously not associated with the MoA of 5-FU, including wide-ranging effects on RNA modification and processing pathways. Attenuated responses of specific proteins in a resistant cell model identify key components of the 5-FU MoA, where intriguingly the abrogation of TYMS inhibition is not required for cell proliferation.
Conclusions: When 5-FU is one of the most used and studied cancer drugs, this novel information significantly expands our understanding of the 5-FU MoA and will be important to direct further work towards dissecting its complete MoA. Furthermore, the CETSA responses of several proteins now provide ideal readouts for directly monitoring whether the required 5-FU effects are accomplished and can now be examined as CETSA-based candidate biomarkers in clinical studies. Together, this work also validates an efficient strategy for dissecting the MoA of cancer drugs, which could be broadly applicable to other cancer drugs in clinical use or in development.
Citation Format: Smaranda Bacanu, Ying Yu Liang, Anderson D. Ramos, Nayana Prabhu, Pär Nordlund. CETSA interaction proteomics define specific RNA modification pathways as key components of fluorouracil based cancer drug cytotoxicity [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 1130.
Abstract 1146: A novel anti-Galectin-3 antibody therapeutic for the treatment of glioblastoma
Authors: BARRETTE ANNE MARIE , Deshpande Krutika , Cadiente Marvin , Bei Anji , Wang Xi , Mirabella Teodelinda , Sun Dongxu 
Published: June 2022

Abstract
Characterized by rapid growth and diffusely infiltrative spread, glioblastoma (GBM) is the most common and most malignant primary brain cancer with a very poor prognosis and a standard of care that hasn’t been improved in over 15 years. The need for new therapies that can directly or indirectly target heterogeneous tumor cell populations to inhibit cell migration in addition to proliferation is highlighted by the recent efforts to develop targeted therapies to treat the vast majority of GBM patients whose tumors impede gross-total resection and develop resistance to chemoradiation. Galectin-3, a carbohydrate-binding protein overexpressed in astrocytes, microglia/macrophages, and the stroma of GBM tumors is a potent modulator of cell proliferation, migration, angiogenesis, T-cell inhibition, and M2 macrophage polarization. We and others have confirmed the association of Galectin-3 expression to lower survival in glioma patients. Additionally, tumor Galectin-3 levels have been shown to increase following exposure to temozolomide or radiation alone or in combination, thus more greatly increasing the need for targeting Galectin-3 in GBM patients following initial treatment. Here, we characterize the therapeutic effects of the anti-Galectin-3 antibody (Gal3 Ab) we have developed for the ability to inhibit GBM tumorigenic and metastatic potential in several in vitro assays and in vivo in heterotopic and orthotopic mouse models. Human GBM cells treated with Gal3 Ab show a significant decrease in cell viability, migration, and invasion in vitro. In vivo, the Gal3 Ab decreases tumor burden and provides a survival benefit in combination with temozolomide compared to the current standard-of-care treatment alone. Our studies indicate the potential for our novel anti-Galectin-3 to be added to the very limited arsenal of potential treatments for GBM.
Citation Format: ANNE MARIE BARRETTE, Krutika Deshpande, Marvin Cadiente, Anji Bei, Xi Wang, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of glioblastoma [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 1146.
Abstract 1160: Multi-scale deep learning feature distributions distinguish invasive ductal and lobular breast cancer slides
Authors: Mukashyaka Patience , Pour Ali Foroughi , Chuang Jeffrey H. 
Published: June 2022

Abstract
Advances in digital pathology have streamlined use of deep learning methodologies to connect morphology and phenotype in hematoxylin and eosin(H&E) stained images. Whole slide images (WSIs) are gigantic, necessitating a tile-based analysis: a WSI is broken into smaller images called tiles, each tile is analyzed separately, and tile level information are then combined to get a slide level prediction. Context aware models integrating tiles of different sizes have been used to combine morphological features present at different scales, and attention-based pipelines have successfully been used to combine tile level information. Pipelines that combine attention-based and context aware learning are less studied. While both methodologies have shown utility when used individually, models that combine both tend to suffer from a large number of parameters to estimate, which frustrates reliable training. Here we show percentiles of deep learning features extracted at different scales serve as a crude multiscale attention mechanism. The proposed model separates TCGA-BRCA invasive ductal and lobular carcinoma FFPE WSIs (AUC=0.85±0.02), which improves upon the performance of the fully tile-based model of [1] (AUC=0.80 ±0.04). The proposed approach enjoys higher average AUC and lower standard deviation across multiple random train/test splits of data. Our results suggest percentile-based feature construction is an interesting alternative when reliable training of fully deep learning models is challenging.
References:
[1] Noorbakhsh, J., Farahmand, S., Foroughi pour, A. et al. Deep learning-based cross-classifications reveal conserved spatial behaviors within tumor histological images. Nat Commun 11, 6367 (2020). https://doi.org/10.1038/s41467-020-20030-5
Citation Format: Patience Mukashyaka, Ali Foroughi Pour, Jeffrey H. Chuang. Multi-scale deep learning feature distributions distinguish invasive ductal and lobular breast cancer slides [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 1160.
Abstract 1180: Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation
Authors: Xu Shuichan , Tran Tam , Zhu Dan , Shi Tao , Mikolon David , Leisten Jim , Chamberlain Philip , LeBrun Laurie , Bahmanyar Sogole , Jiang Ning , Zhao Jingjing , Malek Mehnaz , Filvaroff Ellen , Raymon Heather , Hubbard Robert , Boylan John 
Published: June 2022

Abstract
CC-91516 (also called CC0776314), a selective and potent inhibitor of ERK1/2 and NLK, was discovered via a phenotypic screen of a kinase-focused library for compounds that synergize with mTOR kinase inhibitor CC-223 to induce apoptosis in combination with CC-223. Broad kinase selectivity profiling identified ERK1/2 and NLK as targets of CC-91516. Crystal structure of CC-91516 in complex with ERK2 reveals that its 2, 4, 6-trichlorophenyl moiety binds to a unique back pocket of the adenosine-5′-triphosphate (ATP) binding site of ERK2, which is not accessible to other ERK inhibitors such as BVD-523 and GDC-0994. This unique binding mode of CC-91516 leads to a slow off-rate for its ERK binding with long residence time disrupting both the active and inactive ERK forms. Consequentially, CC-91516 causes sustained inhibition of the MAPK pathway in BRAF mutant colorectal cancer cells. In addition, CC-91516 also regulates Wnt/β-catenin and YAP pathways in multiple cancer cell lines. CC-91516 shows potent yet selective anti-proliferative activity against a large panel of cancer cell lines. Activating mutations in BRAF or CTNNB1 gene associate with sensitivity to CC-91516-mediated anti-proliferative activity while mutations in RB and PI3K/PTEN pathway associate with resistance. CC-91516 inhibits ex vivo colony formation of PDX models with BRAF and CTNNB1 mutations. In addition, CC-91516 potently induces apoptosis, inhibits survival, and overcomes resistance to MEK inhibitor trametinib of BRAF or CTNNB1 mutant cancer cells in long-term culture assay in vitro. CC-91516 has good oral bioavailability and shows excellent anti-tumor activity in vivo against both BRAF and CTNNB1 mutant xenograft models. DMPK and toxicology studies showed robust oral exposure across preclinical species. In summary, CC-91516 has demonstrated preclinical anti-tumor activities and DMPK and safety profiles in support of its clinical development.
Citation Format: Shuichan Xu, Tam Tran, Dan Zhu, Tao Shi, David Mikolon, Jim Leisten, Philip Chamberlain, Laurie LeBrun, Sogole Bahmanyar, Ning Jiang, Jingjing Zhao, Mehnaz Malek, Ellen Filvaroff, Heather Raymon, Robert Hubbard, John Boylan. Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation [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 1180.