bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 139: Dock7 regulates the AKT/mTOR pathway to promote survival and sustain the transformative properties of cancer cells
Authors: Teran Oriana Y. , Lin Miao-chong J. , Zanotelli Matthew R. , Wilson Kristin F. , Cerione Richard A. 
Published: June 2022

Abstract
Akt is a well-known target of mitogenic signaling, which is activated by phosphoinositide 3-kinase, PDK1 and mTORC2, and is commonly regarded as a master regulator of cell survival. However, there is still a good deal to learn regarding how Akt can promote survival when cancer cells are faced by the multitude of challenges they need to overcome during the process of malignant transformation. While investigating the role of Dock7, a Cdc42 and Rac guanine nucleotide exchange factor of the Dock180 family, in tumorigenesis, we discovered an unexpected connection between Dock7, Akt and cell survival. Specifically, we found that Dock7 is necessary for cancer cells to survive under the stressful conditions that arise due to the loss of a substratum or serum deprivation, through its ability to stabilize a low, basal level of Akt kinase activity. Dock7 binds to Akt, as well as associates with the known Akt substrate, TSC2, promoting its phosphorylation. Since the phosphorylation of TSC2 eliminates its ability to work with its partner TSC1 to deactivate the Rheb GTPase, a direct activator of mTORC1, we probed whether mTORC1 function is also necessary for Dock7-dependent cancer cell survival. Indeed, we determined that Dock7, as well as its signaling partner Cdc42, is required to maintain a functional level of S6 kinase activity, a downstream target of mTORC1, which was prevented by the mTORC1 inhibitor rapamycin. We further show an association between mTOR, Rheb and Dock7, but not Raptor, the defining component of mTORC1. Additionally, Raptor is dispensable for the Dock7-dependent S6 kinase activity, despite its rapamycin sensitivity. Together, these findings elucidate a novel Dock7-Akt-mTOR signaling node which promotes cancer cell survival in the absence of classical mTORC1 function to allow cells to overcome stresses faced during the development of cancer.
Citation Format: Oriana Y. Teran, Miao-chong J. Lin, Matthew R. Zanotelli, Kristin F. Wilson, Richard A. Cerione. Dock7 regulates the AKT/mTOR pathway to promote survival and sustain the transformative properties of 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 139.
Abstract 1406: Design and synthesis of novel cardiac glycosides by targeting the DNA damage response for cancer therapy
Authors: Ainembabazi Diana , Geng Xinran , Gavande Navnath , Zhang YouWei , Turchi John 
Published: June 2022

Abstract
Cardiac Glycosides (CGs) are used to treat congestive heart disease. Their application has since been extended to cancer treatment. While the mechanism of action is still unknown, it was previously believed that Na+/K+ ATPase might play a crucial role in cancer mitigation. However, we recently reported that cardiac glycosides could specifically enhance the anti-cancer effect of chemotherapy in KRAS mutant lung cancer by inhibiting the DNA Damage Response (DDR), and these effects were independent of the Na+/K+ ATPase. Mechanistically, we showed that cardiac glycosides induced the degradation of UHRF1, an important player in promoting DNA double strand break (DSB) repair through homologous recombination. These results suggest the promise of derivatizing cardiac glycosides into potential chemo sensitizing agents. Yet, one of the major challenges with these compounds is their cardiotoxicity. This has created a need for developing a strategy to generate less cardiotoxic drugs that are effective in inhibiting the DNA damage response to safe and effective anticancer activity. Herein we report a multi-step synthetic route utilizing k-strophanthidin as the initial building block. A systematic structural design was applied that included modification of the sugar moiety, glycoside linker, stereochemistry, and lactone ring to create a library of O-glycosides and MeON-neoglycosides. These molecules were screened for anti-cancer properties by exploring their influence on the signaling/expression of various downstream kinases in the DDR pathway. We discovered the inhibitory activity of O-glycosides to be more potent than the MeON-neoglycosides or benzylidene-lactone modified compounds. These results demonstrate the ability to chemically synthesize CG derivatives to optimize for anticancer activity with the goal of identifying less cardiotoxic CGs.
Citation Format: Diana Ainembabazi, Xinran Geng, Navnath Gavande, YouWei Zhang, John Turchi. Design and synthesis of novel cardiac glycosides by targeting the DNA damage response for cancer therapy [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 1406.
Abstract 1417: A non-systemic phosphodiesterase-5 inhibitor for colon cancer prevention
Authors: Islam Bianca N. , Lee Avelina , Lebedyeva Iryna , Browning Darren D. 
Published: June 2022

Abstract
Phosphodiesterase 5 inhibitors (PDE5i) are under investigation for potential repurposing as an intervention for colon cancer prevention. A drawback to conventional drugs in this class are drug-drug interactions and side-effects and that would be poorly tolerated when taken on a chronic basis for prevention. To address this issue we designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity. This modification did not affect pharmacology as malonyl-sildenafil had an IC50 of 1.8 nM, but exhibited almost 100-fold reduced cell entry compared to sildenafil. Using an LC-MS/MS approach, malonyl-sildenafil was undetectable in mouse plasma 1 hour after gavage, even at a dose up to 36 mg/kg, but was readily detected in the feces collected 2-4 hours after administration. This contrasted with sildenafil that was detected in the plasma, but not in the feces. While sildenafil exhibited the established Cmax at 1-2 hr, malonyl sildenafil was not detected in the plasma up to 24 hr after an oral dose of 9 mg/kg, but continued to be shed at high levels in the feces for up to 8 hrs. Treatment of mice with malonyl-sildenafil in the drinking water for 8 days was well-tolerated, and resulted in a suppression of proliferation in the colon epithelium that is consistent with results published previously for mice treated with PDE5i. Taken together, the results demonstrate that a carboxylic acid-containing analog of sildenafil prohibits systemic delivery but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generate a first in class drug for colon cancer chemoprevention.
Citation Format: Bianca N. Islam, Avelina Lee, Iryna Lebedyeva, Darren D. Browning. A non-systemic phosphodiesterase-5 inhibitor for colon cancer prevention [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 1417.
Abstract 1419: Single molecule detection of human heparanase
Authors: Wang Zhishen 
Published: June 2022

Abstract
Heparanase, a mammalian endo-β-D-glucuronidase, is the only known enzyme responsible for the cleavage of heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs). Its activity is implicated in various disease conditions such as tumor growth, angiogenesis, metastasis, chronic inflammation and diabetic nephropathy. Detecting the activity of heparanase thus is a promising approach for the discovery of diagnostics and therapeutics for these diseases. We have developed an activity-based disaccharide probe for heparanase, which offers over 700-fold of fluorescence increase in the presence of human heparanase. In this project, we aim to build up an ultrasensitive single heparanase detection system by coupling a sensitive fluorogenic probe with a microwell-based device. The microwell-based device is designed to achieve single enzyme separation and significantly increase the sensitivity of detection. This system is being validated using recombinant human heparanase and will be used to analyze clinical samples from breast cancer patients.
Citation Format: Zhishen Wang. Single molecule detection of human heparanase [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 1419.
Abstract 1440: Identifying inherited genetic variation that impacts individuals’ ability to metabolize arsenic and susceptibility to toxicity
Authors: Tamayo Lizeth I. , Tong Lin , Kibriya Muhammad G. , Jasmine Farzana , Ahsan Habibul , Pierce Brandon L. 
Published: June 2022

Abstract
Inorganic arsenic (iAs) is a class I human carcinogen, and exposure to iAs affects &gt;200 million individuals worldwide. In Bangladesh, &gt;57 million individuals are chronically exposed to iAs through drinking-water. There is inter-individual variation in arsenic metabolism efficiency (AME) due to inherited genetic variation, and this variability impacts individuals’ internal dose of arsenic and their susceptibility to toxicity. Identifying genetic determinants of AME to help identify individuals at higher risk for toxicity has been a focus within genetic epidemiology research. Consumed arsenic enters the blood in as iAs. Sequential reduction and methylation reactions are catalyzed by glutathione and arsenic methyltransferase (AS3MT) respectively, producing monomethylated (MMA) and dimethylated (DMA) forms of arsenic. Generation of DMA is beneficial because DMA is more easily expelled from the body in urine compared to MMA or iAs. AME is often represented by the percent of the arsenic species in urine that exists as DMA. Previous studies have identified genetic variants in the AS3MT (10q24.32) and FTCD (21q22.3) regions as showing clear association with AME. However, additional regions containing variants showing robust and replicable association with AME have not yet been identified, although studies of AME heritability suggest that additional variants are likely to exist. We used data from &gt;7,000 participants from two studies of Bangladesh individuals with varying levels of exposure to arsenic through drinking water (The Health Effects of Arsenic Longitudinal Study, HEALS, and the Bangladesh Vitamin E and Selenium Trial, BEST) to identify genetic variation that impacts individuals’ ability to metabolize arsenic and their susceptibility to toxicity (i.e., arsenic-induced skin lesions). Our preliminary results suggest novel associations with AME in the 1q24.3 region (p= 5.16 x10-14) and with skin lesion risk in the 6p21.33 region (p=1.37x10-9). The identified variants in the 1q24.3 region reside in and around the FMO3 gene. FMOs are enzymes involved in xenobiotic metabolism; therefore, it is plausible that they may play a role in arsenic metabolism. The 6p21.33 signal is in the major histocompatibility complex (MHC) region, which contains numerous key immune response genes (e.g., HLA genes). These results suggest the existence of additional variants associated with AME and arsenic toxicity risk.
Citation Format: Lizeth I. Tamayo, Lin Tong, Muhammad G. Kibriya, Farzana Jasmine, Habibul Ahsan, Brandon L. Pierce. Identifying inherited genetic variation that impacts individuals’ ability to metabolize arsenic and susceptibility to toxicity [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 1440.
Abstract 1471: Over-expression of WW domain containing transcription regulator 1 (TAZ/WWTR1) in prostate cancer and its modulation by prostate-derived ETS factor (PDEF)
Authors: Jaiswal Praveen K. , Mohajan Suman , Koul Sweaty , Koul Hari K. 
Published: June 2022

Abstract
Objective: WW domain containing transcription regulator 1 (TAZ/WWTR1), one of the two downstream effectors of the Hippo pathway, is known to regulate cancer cell proliferation, migration and apoptosis by acting as a transcriptional co-activator. Recently, we described altered expression of yes-associated protein (YAP1) (a paralog of TAZ) in prostate cancer. However, the expression and function of TAZ and its regulation in prostate cancer is not well characterized. In the present study, we profiled expression patterns of TAZ in clinical data sets of PCa and evaluated the effects of PDEF on TAZ phosphorylation in prostate cancer (PCa) cells in culture.
Material & Method: We analyzed the publicly available PCa datasets through Ualcan and c-Bioportal webservers. We transfected prostate cancer PC3 cells with PDEF or respective vector control. Protein levels of TAZ were analyzed by western blotting. Global changes in gene expression were analyzed using Affymetrix arrays followed by Gene Set Enrichment analysis.
Results: Our analysis of publicly available PCa patient data in TCGA dataset, revealed a significant increase in TAZ mRNA levels in prostate cancer tissues as compared to normal prostate tissues (p=4.95E-08). Furthermore, we also found a significant gradual increase in TAZ mRNA expression during disease progression and metastasis. Our analysis of data sets in c-Bio portal revealed that patients with neuroendocrine PCa harbor much higher levels of TAZ mRNA as compared to CRPC phenotype. We also observed a negative correlation between PDEF and TAZ expression in CRPC/NEPC data set. We observed that the PC3 cells transfected with PDEF (PDEF-PC3) showed an increased phospho-TAZ as compared to the respective PC3 vector control (VC-PC3) suggesting that PDEF plays a critical role in modulating TAZ activity an important effector in Hippo signaling.
Conclusions: These results provide first direct demonstration of elevated expression of TAZ in PCa, suggesting potential role of TAZ in prostate cancer. We also show for the first time increased TAZ phosphorylation in PCa cells by PDEF. Taken together with our recent work, our data suggest that PDEF modulates Hippo signaling by targeting both YAP1 and TAZ in PCa.
Citation Format: Praveen K. Jaiswal, Suman Mohajan, Sweaty Koul, Hari K. Koul. Over-expression of WW domain containing transcription regulator 1 (TAZ/WWTR1) in prostate cancer and its modulation by prostate-derived ETS factor (PDEF) [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 1471.
Abstract 1505: Exploring the role of CRM1 in DNA repair pathway in prostate cancer cells
Authors: Kumar Rajendra , Mendonca Janet , Boyapati Kavya , Yang Yuhan , Topiwala Deven , Kanacharoen Suthicha , Soundappan Keerti , Wilson Lillian , Panagopoulos Eleni , Carducci Michael , Kachhap Sushant K. 
Published: June 2022

Abstract
Background: Prostate cancer continues to show challenges in disease management and ultimately leads to advanced disease with poor survival. These unmet needs, despite recent advances, are leading researchers to identify novel targets to develop next-generation therapeutics. Considerable evidence from the published reports and TCGA database analysis indicates that CRM1, which functions as a nuclear export protein, amplifies prostate cancer, resulting in dysregulated nuclear export machinery. This dysregulation is also seen to correlate with mislocalization of p53, FOXO-1, and 3a, cyclinD1, p16, p21, and p27 in prostate cancer. Besides these mislocalized proteins, key DNA repair pathway members such as BRCA1 and Rad51 exhibit a nuclear export signal (NES) and are putative CRM1 cargoes. Nuclear-cytoplasmic shuttling of these repair proteins may play an essential role in repairing damaged DNA. We hypothesize that inhibition of CRM1 would result in defective DNA repair through disruption of nuclear-cytoplasmic shuttling of important repair protein cargoes.
Methods: PCa cells (both AR-positive and negative lines) were treated with Selinexor to estimate the subtoxic doses. Cell lysates and total mRNA were collected to evaluate the relative levels of BRCA-1, RAD51, p53, ATM, ATR transcripts, and proteins. Activation of the DNA damage pathway was measured through a phosphorylated form of these proteins, and functional assessment of homologous recombination(HR) was measured through an HR sensor plasmid construct.
Results: Treatment of PCa cells with Selinexor affected expression, localization, and kinetics of DNA repair leading to unrepaired DNA and induced apoptosis.
Citation Format: Rajendra Kumar, Janet Mendonca, Kavya Boyapati, Yuhan Yang, Deven Topiwala, Suthicha Kanacharoen, Keerti Soundappan, Lillian Wilson, Eleni Panagopoulos, Michael Carducci, Sushant K. Kachhap. Exploring the role of CRM1 in DNA repair pathway in prostate 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 1505.
Abstract 1525: Inhibition of HGF maturation overcomes cetuximab resistance in colorectal cancer
Authors: Graves-Deal Ramona , Bogatcheva Galina , Truong Vivian T. , Damalanka Vishnu , Klampfer Lidija , Coffey Robert J. , Janetka James W. , Singh Bhuminder 
Published: June 2022

Abstract
We have previously identified that activation of receptor tyrosine kinases (RTKs) MET and RON contributed to resistance to the EGF receptor (EGFR)-directed therapeutic antibody cetuximab. These findings originated from our in vitro 3D type I collagen cultures of human colorectal cancer (CRC) cell line HCA-7 derivatives CC, SC, and CC-CR. CC are sensitive to cetuximab, while SC and CC-CR are resistant. Both de novo and acquired modes of cetuximab resistance in SC and CC-CR, respectively, could be overcome by crizotinib, a multi-RTK inhibitor that also targets MET and RON. Conversely, exogenous administration of MET ligand, HGF could transiently induce cetuximab resistance which could be further overcome by crizotinib addition. HGF/HGFL are synthesized as inactive precursors and require cleavage by proteases (HGFA, Matriptase, and Hepsin) to be biologically active. To inhibit HGF/HGFL cleavage in cetuximab-resistant cells, we employed inhibitors of HGF/HGFL proteases (ZFH7116 and VD2173) and were able to overcome both de novo and acquired cetuximab resistance. A survey of TCGA datasets indicated that HGF/HGFL were overexpressed in several CRC CMS subtypes. We next expressed human HGF in cetuximab-sensitive CC cells and observed that HGF overexpression imparts cetuximab resistance. Moreover, cetuximab resistance induced by HGF overexpression could be overcome by the downstream MET inhibition (with crizotinib) and we are now testing if the upstream inhibition of HGF proteases (with ZFH7116/VD2173) also overcomes cetuximab resistance. Combined these results indicate that inhibition of HGF cleavage and maturation may be a novel way to overcome resistance to EGFR-targeted therapies in CRC.
Citation Format: Ramona Graves-Deal, Galina Bogatcheva, Vivian T. Truong, Vishnu Damalanka, Lidija Klampfer, Robert J. Coffey, James W. Janetka, Bhuminder Singh. Inhibition of HGF maturation overcomes cetuximab resistance in colorectal 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 1525.
Abstract 1529: Role of bitter taste receptor in colon cancer
Authors: Jain Krishan , Bhattacharyya Sangita , Sayed Afreen , Standing David , Benich Kathy , Umar Shahid , Anant Shrikant , Weir Scott , Jansen Roy , Dandawate Prasad Ravindra 
Published: June 2022

Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the US with 53,200 deaths projected in 2020. Although the disease affects older people, recent statistics show an increase in the younger population. CRC is a major problem in veterans and every year ~4,000 veterans are diagnosed with CRC within VA facilities. Hence, there is a dire need to identify novel signaling pathways as targets for therapy. Based on a bedside discovery in CRC patients, we observed that CRC patients complained about dysgeusia or taste alterations. There are 25 bitter taste receptors (TAS2R1-50, TAS2R60). Taste receptors utilize G-protein coupled receptors (GPCRs) and signal through calcium release. In preliminary studies, mining the Cancer Genome Atlas (TCGA) database, we have determined that TAS2R38 is upregulated in multiple cancers, including CRC. Moreover, the higher expression of TAS2R38 transcript in CRC compared to other cancers. Furthermore, we confirmed overexpression of TAS2R38 in CRC tissues and cell lines by immunohistochemistry and RT-PCR. Moreover, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a TAS2R38 agonist, treatment activated calcium mobilization in HCT116 and DLD1 cells suggesting the functionality of the receptor. OdDHL also enhanced mRNA of interleukin (IL)-6 and IL-8 levels in the CRC cells. To determine whether expression of the receptor is affected in vivo, we conducted the dextran sodium sulfate (DSS)-induced acute colitis and colitis-associated cancer model (azoxymethane (AOM)-DSS) in C57BL/6 mice. TAS2R138, the mouse homolog of human TAS2R38 is overexpressed in crypt epithelial cells in the colitis and tumor tissues. These observations suggest that TAS2R38 is overexpressed in the CRC and may play a critical role in disease progression.
Citation Format: Krishan Jain, Sangita Bhattacharyya, Afreen Sayed, David Standing, Kathy Benich, Shahid Umar, Shrikant Anant, Scott Weir, Roy Jansen, Prasad Ravindra Dandawate. Role of bitter taste receptor in colon 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 1529.