tbuckley/cabot-search huggingface dataset:
Abstract 1085: Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis
Authors: Hema Adhikari, Walaa Kattan, John F. Hancock, Christopher M. Counter
Journal: Cancer Research (2020)

Abstract Activating mutations in one of the three RAS genes (HRAS, NRAS, and KRAS) are detected in as much as a third of all human cancers. As oncogenic RAS mediates it tumorigenic signaling through protein-protein interactions primarily at the plasma membrane, we sought to document the protein networks engaged by each RAS isoform to identify new vulnerabilities for future therapeutic development. To this end, we determined interactomes of oncogenic HRAS, NRAS, and KRAS by BirA-mediated proximity labeling. This analysis identified roughly ** proteins shared among multiple interactomes, as well as a smaller subset unique to a single RAS oncoprotein. To identify those interactome components promoting RAS oncogenesis, we created and screened sgRNA library targeting the interactomes for genes modifying oncogenic HRAS-, NRAS-, or KRAS-mediated transformation. This analysis identified the protein EFR3A as not only a common component of all three RAS interactomes, but when inactivated, uniformly reduced the growth of cells transformed by any of the three RAS isoforms. EFR3A recruits a complex containing the druggable phosphatidylinositol (Ptdlns) 4 kinase alpha (PI4KA) to the plasma membrane to generate the Ptdlns species PI4P. We show that EFR3A sgRNA reduced multiple RAS effector signaling pathways, suggesting that EFR3A acts at the level of the oncoprotein itself. As lipids play a critical role in the membrane localization of RAS, we tested and found that EFR3A sgRNA reduced not only the occupancy of RAS at the plasma membrane, but also the nanoclustering necessary for signaling. Furthermore, the loss of oncogenic RAS signaling induced by EFR3A sgRNA was rescued by targeting PI4K to the plasma membrane. Taken together, these data support a model whereby EFR3A recruits PI4K to oncogenic RAS to promote plasma membrane localization and nonclustering, and in turn, signaling and transformation. To investigate the therapeutic potential of this new RAS enhancer, we show that EFR3A sgRNA reduced oncogenic KRAS signaling and transformed growth in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. Encouraged by these results we are exploring whether genetically inactivating the kinase activity of PI4KA inhibits oncogenic signaling and transformation in PDAC cell lines. If true, pharmacologically targeting PI4K may hold promise as a way to enhance the anti-neoplastic activity of drugs targeting oncogenic RAS or its effectors. Citation Format: Hema Adhikari, Walaa Kattan, John F. Hancock, Christopher M. Counter. Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1085.
Abstract 3491: COX-2 inhibitor use and risk of skin cancer: three prospective cohort studies
Authors: Hsuan Yen, Hsi Yen, Aaron Drucker, Jiali Han, Wen-Qing Li, Tricia Li, Abrar Qureshi, Eunyoung Cho
Journal: Cancer Research (2020)

Abstract Skin cancer is the most commonly diagnosed type of cancer, with continually rising incidence rates. Cyclooxygenase-2 (COX-2) inhibitor use has been associated with lower risk of several cancers, though epidemiological studies on skin cancer risk have been limited and inconclusive. To evaluate whether COX-2 inhibitor use is associated with decreased risk of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma, we analyzed COX-2 inhibitor use and risk of skin cancer based on three prospective cohorts–the Nurses' Health Study (NHS, 2000-2012), NHS II (2001-2011), and the Health Professionals Follow-up Study (HPFS, 2002-2012). COX-2 inhibitor use and duration were assessed by biennial questionnaires, with cSCC and melanoma cases verified by pathological records. Over 1.54 million person-years of follow-up, 16,098 BCC, 1,973 cSCC, and 625 invasive melanoma cases were documented. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of COX-2 inhibitor use with risk of BCC, cSCC, and melanoma were estimated using Cox proportional hazards models. We pooled the results between the three cohorts using a fixed effects model. For ever vs. never users, COX-2 inhibitor use was associated with a modestly increased risk of BCC (multivariable HR 1.10, 95% CI 1.06–1.15) and cSCC (multivariable HR 1.12, 95% CI 1.00–1.27). The effect estimate was similar for melanoma, but was non-significant (multivariable HR 1.10, 95% CI 0.89–1.38). In conclusion, COX-2 inhibitor use was not associated with decreased skin cancer risk and instead was associated with modestly increased risk of BCC and cSCC. Further investigation is necessary to replicate these results. Citation Format: Hsuan Yen, Hsi Yen, Aaron Drucker, Jiali Han, Wen-Qing Li, Tricia Li, Abrar Qureshi, Eunyoung Cho. COX-2 inhibitor use and risk of skin cancer: three prospective cohort studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3491.
Abstract 5666: A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer
Authors: Barzin Y. Nabet, Mohammad S. Esfahani, Emily G. Hamilton, Jacob J. Chabon, Everett J. Moding, Hira Rizvi, Chloe B. Steen, Aadel A. Chaudhuri, Chih Long Liu, Angela B. Hui, Henning Stehr, Linda Goljenola, Michael C. Jin, Young-Jun Jeon, Diane Tseng, Taha Merghoub, Joel W. Neal, Heather A. Wakelee, Sukhmani K. Padda, Kavitha J. Ramchandran, Millie Das, Rene F. Bonilla, Christopher Yoo, Emily L. Chen, Ryan B. Ko, Aaron M. Newman, Matthew D. Hellmann, Ash A. Alizadeh, Maximilian Diehn
Journal: Cancer Research (2020)

Abstract Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICI) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we analyze 211 samples from 99 patients and demonstrate that pre-treatment circulating tumor DNA (ctDNA) and circulating immune profiles are independently associated with DCB. We further show that ctDNA dynamics after a single ICI infusion can identify the majority of patients who will achieve DCB. Integrating these determinants, we describe an entirely noninvasive multi-analyte assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA- On-treatment) that robustly predicted DCB, and that was validated in two independent cohorts (AUC = 0.89-0.93, PPV = 92-100%, HR = 0.04-0.11). Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICI. Citation Format: Barzin Y. Nabet, Mohammad S. Esfahani, Emily G. Hamilton, Jacob J. Chabon, Everett J. Moding, Hira Rizvi, Chloe B. Steen, Aadel A. Chaudhuri, Chih Long Liu, Angela B. Hui, Henning Stehr, Linda Goljenola, Michael C. Jin, Young-Jun Jeon, Diane Tseng, Taha Merghoub, Joel W. Neal, Heather A. Wakelee, Sukhmani K. Padda, Kavitha J. Ramchandran, Millie Das, Rene F. Bonilla, Christopher Yoo, Emily L. Chen, Ryan B. Ko, Aaron M. Newman, Matthew D. Hellmann, Ash A. Alizadeh, Maximilian Diehn. A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5666.
Abstract 3788: CircHMGCS1 interacts with RNA binding protein HuR and maintains stem-like cells in gliomas
Authors: Jiehua He, Zuoyu Huang, Dong Yin
Journal: Cancer Research (2020)

Abstract Malignant Glioma account for the largest class of primary brain tumor, and its high malignant degree, therapy resistance and high recurrence rate are widely accepted to be caused by existence of glioma stem-like cells (GSCs). But the mechanisms underlying GSCs maintain are not completely clear. Recent evidences have shown that circular RNAs (circRNAs) are frequently dysregulated and play paramount roles in various cancers. circRNAs are abundant in central nervous system (CNS); however, few studies describe the clinical significance and role of circRNAs in gliomas, In our preliminary study, we used a vitro differentiation model upon inducing human neural progenitor cells (hNPCs) to mature glia cells, and identified a circRNA, circHMGCS1 (hsa_circ_0072391), which was highly expressed in hNPCs but was gradually downregulated in mature glia cells. In this study, we found that circHMGCS1 was inversely elevated in gliomas, and was positively correlated with malignant degree (III+IV vs I +II, P&amp;lt;0.05). Next, we verified that circHMGCS1 enhanced formation of neurosphere, and leaded to the resistance to TMZ treatment in vitro. Furthermore, we proved that circHMGCS1 could maintain the protein level of stemness relative transcription factor SOX2. RNA binding protein HuR, which was reported to stabilize the SOX2 mRNA, could be pulled down by circHMGCS1 in our ChIRP-MS assay. Inhibition of circHMGCS1 could partly decrease the binding of HuR with SOX2 mRNA 3’UTR. Finally, silencing of circHMGCS1 significantly inhibited formation of xenograft brain tumors and increased mice overal survival time in vivo. Taken together, our findings suggest that circHMGCS1 is a critical player in maintaining the stemness of GSCs via stablilized SOX2 by strengthening its interaction with RNA binding protein HuR. Therefore, we suggest that circHMGCS1 may serve as a new biomarker and therapeutic target for treatment of gliomas. Citation Format: Jiehua He, Zuoyu Huang, Dong Yin. CircHMGCS1 interacts with RNA binding protein HuR and maintains stem-like cells in gliomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3788.
Abstract 4703: Role of REST in the regulation of MMP24 and estrogen sensitivity in breast cancer
Authors: Aditya M. Vargheese, Ashley Cloud, Sumedha Gunewardena, Raeann Shimak, Easwari Kumaraswamy, Roy A. Jensen, Vargheese M. Chennathukuzhi
Journal: Cancer Research (2020)

Abstract Breast cancer, the most common malignancy in women, is very difficult to detect and treat due to its heterogeneity. An important subset of breast cancers, Luminal or ER/PR positive tumors, lack REST (repressor element 1 silencing transcription factor) protein but not its mRNA. REST is a tumor suppressor and is known to play a role in regulating neurodegenerative diseases such as Alzheimer's. The loss of REST leads to the dysregulation of its target genes, many of which are involved in tumorigenesis. About 20% of breast cancers show loss of REST expression, yet little to nothing is currently known about the role REST plays in tumor growth. We hypothesized that the loss of REST promotes breast cancer growth by altering cell signaling. Our results show that knockdown of REST in MCF7 cells (ER/PR positive) causes similar gene dysregulation as seen in aggressive forms of breast cancers. Also, Ingenuity Pathway Analysis (IPA®) of our RNA sequencing results showed that REST knockdown leads to significant increase in estrogen receptor signaling in MCF7 cells. Upregulation of estrogen receptor expression has been associated with tumor progression. In addition, REST knockdown led to significant increases in the expression of MMP24 (&amp;gt;20-fold, p&amp;lt;10−85), a matrix modifying enzyme which could play a role in tumor metastasis, as well as KCNK3 (19-fold, p&amp;lt;10−40), a biomarker associated with poor patient survival. Thus, the poor survival of patients with RESTless breast cancers may be related to the activation of its target genes and elevated estrogen receptor signaling. Furthermore, these patients may respond differently to estrogen receptor antagonists compared to those with REST positive breast cancers. Our results will help with the future development of individualized therapies for breast cancer. Citation Format: Aditya M. Vargheese, Ashley Cloud, Sumedha Gunewardena, Raeann Shimak, Easwari Kumaraswamy, Roy A. Jensen, Vargheese M. Chennathukuzhi. Role of REST in the regulation of MMP24 and estrogen sensitivity in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4703.
Abstract 2898: A biparatopic HER2xHER2 antibody drug conjugate with potent anti-tumor activity
Authors: Andres Perez Bay, Devon Faulkner, Shiwani Tiwari, Carla Castanaro, Xiang Zheng, Arthur Kunz, Thomas Nittoli, Amy Han, William Olson, Gavin Thurston, Christopher Daly, Julian Andreev
Journal: Cancer Research (2020)

Abstract A biparatopic HER2xHER2 antibody drug conjugate with potent anti-tumor activity. The antibody drug conjugate (ADC) Trastuzumab-emtansine (T-DM1) targets the well-characterized breast cancer oncogene HER2 and is active in tumors that express very high levels of HER2 protein. However, tumors expressing intermediate levels of HER2 remain resistant to T-DM1 therapy, apparently due to insufficient lysosomal trafficking of T-DM1. We generated a series of biparatopic HER2xHER2 antibodies in which each arm recognizes a distinct epitope of HER2. One of our HER2xHER2 antibodies bound to cells with greater avidity than Trastuzumab and formed visible cell surface clusters that were efficiently internalized. While some of the internalized HER2xHER2 antibody trafficked to lysosomes and promoted HER2 degradation, a significant fraction recycled back to the plasma membrane through recycling endosomes. To exploit the increased internalization and recycling of the HER2xHER2 antibody, ADCs were generated by site-specific conjugation of Tubulysin A payload through a protease-cleavable linker. Recent data suggest that cleavage of this linker does not require lysosomal trafficking, but can occur in recycling endosomes as well. HER2xHER2-Tubulysin killed cell lines expressing high (IHC3+) and intermediate (IHC2+) HER2 levels with subnanomolar IC50, while exhibiting very weak killing of cells expressing low (IHC1+) HER2 levels (IC50 greater than 10nM). HER2xHER2-Tubulysin induced complete and durable tumor regression and outperformed T-DM1 in a collection of IHC3+ and 2+ tumor xenograft models (including PDX). Our work shows that a detailed understanding of antibody trafficking can enable the design of more effective ADCs and suggests that HER2xHER2-Tubulysin is a potential clinical candidate for HER2 IHC2+ breast cancer. Citation Format: Andres Perez Bay, Devon Faulkner, Shiwani Tiwari, Carla Castanaro, Xiang Zheng, Arthur Kunz, Thomas Nittoli, Amy Han, William Olson, Gavin Thurston, Christopher Daly, Julian Andreev. A biparatopic HER2xHER2 antibody drug conjugate with potent anti-tumor activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2898.
Abstract 5814: Emergent functions of cyclin-dependent kinase 4 regulating aurora b and cenpp transcription
Authors: Sung Hyun Lee, Liliana R. Rodriguez, Paula L. Miliani de Marval, Marcelo L. Rodriguez-Puebla
Journal: Cancer Research (2020)

Abstract A better understanding of the precise molecular mechanisms that control cell proliferation is crucial for the identification of novel cancer therapeutic targets. A critical molecule in this process is the Cyclin-Dependent Kinase 4 (CDK4), which regulates key aspects of the G1 to S phase transition through phosphorylation of the retinoblastoma (Rb) family of proteins. Since dysregulation of this cell cycle mechanism is a hallmark of most cancers, drugs have been developed to inhibit the kinase activity of CDK4. However, such drugs have been met with variable degrees of success and, in some cases, little efficacy. Research performed in the last few years has suggested that CDK4 have alternative targets other than the Rb proteins. Consistent with this idea, we found that CDK4 plays additional roles not related to the canonical function in the CDK-Rb axis. Here, we show that CDK4 remains attached to the chromatin fraction of Balb/MK2 keratinocytes upon the extraction of the soluble components (nucleoplasm and cytoplasm). Chromatin-immunoprecipitation (ChIP) analysis shows that CDK4 occupies the regulatory sites of genes associated with chromosomal segregation, such as Aurkb (Aurora B) and Cenpp (Centromere Protein P). Moreover, gain- and loss-of-function experiments showed that the AurkB and Cenpp promoters are regulated through CDK4 binding. In line with these findings, studies in skin carcinogenesis revealed that transgenic expression of CDK4 in mouse epidermis induces chromosome instability (CIN) and centrosome amplification (CA), two events linked to overexpression of Aurora B. Moreover, Aurora-B has a crucial role in chromosome bi-orientation and the spindle-assembly checkpoint, whereas Cenpp is required for proper kinetochore function. Remarkably, a persistent dysregulation of Aurora B has been reported in numerous human cancers. Thus, our results suggest that CDK4 plays a role in the maintenance of chromosomal stability, implying that additional functions could be inhibited by therapeutically targeting CDK4. Our conclusions are supported by previous reports showing that pharmacological inhibition of CDK4 led to delayed progression from G2 to mitosis in Rb-positive and as well as Rb-negative cells. Citation Format: Sung Hyun Lee, Liliana R. Rodriguez, Paula L. Miliani de Marval, Marcelo L. Rodriguez-Puebla. Emergent functions of cyclin-dependent kinase 4 regulating aurora b and cenpp transcription [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5814.
Abstract 3772: Comprehensive characterization of the phosphoproteome of gastric cancer from endoscopic biopsy specimens
Authors: Jun ADACHI, Yuichi Abe, Hidekazu Hirano, Hirokazu Shoji, Daigo Gunji, Kazufumi Honda, Narikazu Boku, Takeshi Tomonaga
Journal: Cancer Research (2020)

Abstract Cancer phosphoproteomics can provide insights regarding kinases that can be targeted for therapeutic applications. Monitoring the phosphoproteomics in cancer is expected to play a key role in optimizing treatments with kinase inhibitors. Clinical phosphoproteomics in surgical tissues and patient-derived models has been studied intensively. However, the reported data may not accurately reflect the phosphosignaling status in patients due to the effect of ischemia occurring during surgery or changes in the characteristics of cancer cells when establishing the models. In contrast, endoscopic biopsies have an advantage for clinical phosphoproteomics because they can be rapidly cryo-preserved. We aimed to develop a highly sensitive method for phosphoproteomics in endoscopic biopsies of gastric cancer.Three tumor/normal biopsies from gastric cancer tissue were obtained by endoscopy, and subjected to our optimized phosphoproteomics. Phosphopeptides were enriched with an immobilized metal affinity chromatography, and labeled with Tandem Mass Tag reagent. Quantified phosphosites were compared between the pairs of tumor/normal biopsies within same patient. Cancer-specific activated pathways and kinases were identified by pathway enrichment analysis and kinase-substrate enrichment analysis.Our protocol enabled the identification of more than 10,000 class-1 phosphosites from endoscopic biopsies. A comparison between samples from cancer tissue and normal mucosa demonstrated differences in the phosphosignaling, including biomarkers of response to DNA damage. Finally, cancer-specific activation of DNA damage response signaling was validated by additional phosphoproteomics of other patients and western blotting of gastric cancer/normal cells. In summary, our pioneering approach will facilitate more accurate clinical phosphoproteomics in endoscopic biopsies, which can be applied to monitor the activities of therapeutic kinases and, ultimately, can be a useful tool to precision medicine. Citation Format: Jun ADACHI, Yuichi Abe, Hidekazu Hirano, Hirokazu Shoji, Daigo Gunji, Kazufumi Honda, Narikazu Boku, Takeshi Tomonaga. Comprehensive characterization of the phosphoproteome of gastric cancer from endoscopic biopsy specimens [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3772.
Abstract 5448: Integrative analysis of microRNA expression identifies two biologically distinct and clinically relevant subtypes of head and neck squamous cell carcinoma
Authors: Jeremiah R. Holt, Heejoon Jo, Vonn Walter, Xiaobei Zhao, David Neil Hayes, Yoon Ho Ko
Journal: Cancer Research (2020)

Abstract Purpose: The objective of this study is to investigate the potential role of microRNAs (miRNA) as molecular markers of tumor heterogeneity in head and neck squamous cell carcinoma (HNSCC). Experimental Design: Here, we analyzed 562 HNSCC samples, 88 from a novel cohort and 474 from The Cancer Genome Atlas (TCGA), using miRNA-microarray and miRNA-seq, respectively. Using an integrative correlations method followed by miRNA expression-based hierarchical clustering, we validated miRNA clusters across cohorts, and evaluation of clusters by logistic regression and gene ontology approaches revealed subtype-based clinical and biological characteristics. Results: We identified two statistically significant tumor subtypes and named them ‘epithelial' and ‘stromal' based on correlations with functional target gene ontology in relation to differing stages of epithelial cell differentiation. Each subtype demonstrated significant differences in terms of mRNA signature (p &amp;lt; 0.001), primary tumor sites (p &amp;lt; 0.001) and HPV status (p &amp;lt; 0.001), and multivariate analysis associated the stromal subtype with a worse prognosis (HR = 1.5646, p = 0.006). We also observed several dysregulated miRNA families and clusters that function as regulators of subtype-specific gene expression networks in HNSCC. Conclusion: Our findings suggest miRNAs determine HNSCC subclassifications through coordinating growth and differentiation programs in epithelial cells. These results delineate developmental miRNA signatures characterizing the phenotypic diversity between HNSCC subtypes, providing an expanded framework for the pathogenesis and personalized treatment of HNSCC. Citation Format: Jeremiah R. Holt, Heejoon Jo, Vonn Walter, Xiaobei Zhao, David Neil Hayes, Yoon Ho Ko. Integrative analysis of microRNA expression identifies two biologically distinct and clinically relevant subtypes of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5448.