bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2467: Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis
Authors: Manley Sharon J. , Jack Jarrid , Ambrose Joseph , Olou Appolinaire A. , VanSaun Michael N. 
Published: July 2021

Abstract
Understanding the impact of risk factors on the progression of pancreatic cancer is critical for the development of novel therapeutics. Multiple studies have clearly shown that obesity positively correlates with increased progression of pancreatic adenocarcinoma (PDAC). We have demonstrated that individual adipose derived cytokines (aka adipokines) can elicit either pro-tumorigenic or anti-tumorigenic effects on PDAC progression. We previously demonstrated that adiponectin receptor agonism effectively suppresses pancreatic cancer growth in vitro as well as in vivo, through suppression of MAPK as well as STAT3 pathways. Yet, adiponectin is well known to stimulate the AMPK pathway and therefore we hypothesized that adiponectin agonism could also be affecting metabolic function in PDAC. In our current studies, we defined multiple metabolic alterations in pancreatic cancer cells in response to adiponectin receptor agonism using a seahorse-based assay. Human and murine PDAC cell lines were seeded into XFe96 microplates and subjected to a mitochondrial stress test as well as the glycolysis stress test. Our results demonstrate that adiponectin receptor activation impairs pancreatic cancer mitochondrial function leading to a metabolic switch from mitochondrial respiration to glycolysis. We further demonstrate that this switch is associated with AMPK phosphorylation-mediated inhibition of Acetyl Coenzyme A Carboxylase (ACC), the lipogenic enzyme whose inhibition induces fatty acid breakdown. Thus, our results support a role for adipose-secreted factors to influence the metabolic phenotype of pancreatic cancer. Since metabolic rewiring is often associated with development of chemotherapeutic resistance in cancer, we are currently testing whether dual therapeutic targeting of the mitochondrial respiration, via adiponectin receptor agonism, and glycolysis would provide an efficacious therapeutic.
Citation Format: Sharon J. Manley, Jarrid Jack, Joseph Ambrose, Appolinaire A. Olou, Michael N. VanSaun. Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2467.
Abstract 2468: The role of autophagy in lymphangiosarcoma development
Authors: Yang Fuchun , Haas Michael , Guan Jun-Lin 
Published: July 2021

Abstract
Lymphangiosarcoma is a rare malignant vascular tumor which is formed from aberrant proliferation of endothelial cells (ECs). We previously established an endogenous mouse model of lymphangiosarcoma by conditional knockout of Tsc1 gene in ECs and revealed that hyper-activated mTORC1 is required for the vascular tumor development and progression through increased VEGF autocrine signaling. Using this model, we investigated the role of an essential autophagy gene FIP200 (FAK family interacting protein of 200 kDa) and its canonical autophagy function in lymphangiosarcoma development and progression by generating a FIP200 knockout (designated as Tsc1/Fip200 2cKO mice) or introducing a knockin allele that specifically blocks its canonical autophagy function (designated as Tsc1/Fip200 cKI mice) in combination with Tsc1 cKO in this study. We found that while both Tsc1/Fip200 cKO and Tsc1/Fip200 cKI mice exhibited lymph edema phenotype as Tsc1 cKO mice, they did not develop lymphangiosarcoma, suggesting that autophagy is required for lymphangiosarcom formation. Consistent with the above results, we also found that CRISPR-Cas9 mediated Fip200 KO in an immortalized vascular tumor cell line Tsc1ΔEC from Tsc1 cKO mice blocked their ability to grow tumors in xenograft transplants. Mechanistically, we found that autophagy was required for maintaining mTORC1 hyper-activation under nutrient stress condition. Moreover, the impaired lipophagy by Fip200 knockout affected lipid catabolism under glucose free condition and thus reduced the substrate for fatty acid oxidation (FAO). Our data showed that Fip200, Atg5 or Atg7 ablation in Tsc1ΔEC inhibited mitochondria respiration and decreased ATP contents as measured by Seahorse assays. Either lipase inhibitor Orlistat or carnitine palmitoyltransferase-1 (Cpt1) inhibitor Etomoxir treatment decreased Tsc1ΔEC mitochondria respiration and ATP production. Collectively, our data suggested that autophagy is required for lymphangiosarcoma initiation and progression by modulating FAO to supply cellular energy under stress for sustaining mTORC1 hyper-activation for tumor growth.
Citation Format: Fuchun Yang, Michael Haas, Jun-Lin Guan. The role of autophagy in lymphangiosarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2468.
Abstract 2472: Effective ER antagonists resist conformational restrictions imposed by somatic mutation but do not correlate with effects on receptor stability in live cells
Authors: Hosfield David , Li Nan-Sheng , Han Ross , Laine Muriel , Weber Sandra , Sauvage Madaline , Madar Sylvie , Greene Geoffrey , Fanning Sean 
Published: July 2021

Abstract
Approximately 50% of luminal breast cancer patients become resistant to first-line endocrine therapies after an average of 5 years. Acquired activating mutations to the ESR1 ligand binding domain enable hormone therapy resistance in approximately 25-40% of these patients. Competitive estrogen antagonists function by maintaining the receptor in a transcriptionally inactive state by forcing estrogen receptor alpha ligand binding domain (ERα LBD) helix 12 into the AF-2 cleft to prevent the docking of LXXLL-containing transcriptional coactivators. Multiple next-generation ERα antagonists that function as molecular degraders of the receptor have been described and shown activity in breast cancers harboring the activating ESR1 mutations. To understand whether ERα antagonism correlates with receptor stability, we examined a comprehensive panel of structurally diverse antagonists in live breast cancer cell assays using WT, Y537S, and D538G-mutant receptors. We found that potent antagonists are able to both stabilize and degrade the receptor and further demonstrate that the D538G mutation reduces turnover with ICI due to specific defects in receptor ubiquitination and SUMOylation. High resolution x-ray crystal structures of WT and Y537S ERα LBD in complex with stabilizing and degrading antiestrogens suggest that modulators that enforce the classical antagonist-like helix 12 conformation in the mutant receptor achieve the greatest activity in transcriptional assays, regardless of their effects on receptor stability
Citation Format: David Hosfield, Nan-Sheng Li, Ross Han, Muriel Laine, Sandra Weber, Madaline Sauvage, Sylvie Madar, Geoffrey Greene, Sean Fanning. Effective ER antagonists resist conformational restrictions imposed by somatic mutation but do not correlate with effects on receptor stability in live cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2472.
Abstract 2487: disrupting binding of p53 mutants to PEPD unleashes their tumor suppressor activities
Authors: Yang Lu 
Published: July 2021

Abstract
Background & Goals: The p53 tumor suppressor is one of the most important determinants of cell fate and is critical for tumor suppression. It functions by regulating the expression of a plethora of genes via sequence-specific DNA binding and also by transcription-independent, mitochondria-mediated mechanisms. Not surprisingly, the TP53 gene, which encodes p53, is frequently mutated in human cancer. For example, TP53 is mutated in about 75% of HER2-positive breast cancer and about 85% of triple negative breast cancer. The majority of TP53 mutations are missense mutations, changing one amino acid per mutant, most of which occur in its DNA-binding domain. p53 mutants show loss of tumor suppressor functions or gain of oncogenic functions. We recently found that peptidase D (PEPD), also known as prolidase, binds via its C-terminal sequence to the proline-rich domain (PRD) of wild type p53 and that disrupting the binding activates p53. The enzymatic activity of PEPD is not required for this function. Our objective in the present study is to determine whether PEPD also regulates p53 mutants. We focused on some of the most common oncogenic p53 mutants, including R175H, R248Q, R273H and R280K.
Results: Our study shows that 1) each p53 mutant binds directly to PEPD and binds to PEPD in cells in a significant quantity, 2) disrupting their binding in cells by PEPD knockdown reactivates each p53 mutant, unleashing both transcription-dependent and -independent tumor suppressing activities, 3) after leaving PEPD, p53 mutants undergo acetylation, mono-ubiquitination and phosphorylation, which drive their refolding and reactivation, 4) Lysine 373 acetylation is essential for their reactivation, and 5) p53 mutants and p53WT show almost no difference in PEPD-binding and response to PEPD KD.
Conclusions & Therapeutic Relevance: In conclusion, we have identified a cellular mechanism by which the tumor suppressor functions of p53 mutants are strongly reactivated, which is neither cell-specific nor mutant-specific. Mainly, p53 mutants bind to PEPD in cancer cells, and disrupting the complex causes posttranslational modifications of mutants freed from PEPD, which drive their refolding and unleash their tumor suppressor activities. This discovery advances our understanding of the function and regulation of p53 mutants and breaks new ground for developing novel cancer treatment strategies.
Citation Format: Lu Yang. disrupting binding of p53 mutants to PEPD unleashes their tumor suppressor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2487.
Abstract 2497: Inositol Polyphosphate 4-Phosphatase Type-II B protects mice from benign prostatic hyperplasia
Authors: Ceyhan Yasemin , Zhang Manqi , Agoulnik Irina U. 
Published: July 2021

Abstract
BPH is the most common tumor-like condition that afflicts more than 50% of men between the ages of 51-60 and over 90% in men older than 80. While connection between obesity and BPH is well established, the driving signaling pathways are not clear. BPH is a nonmalignant enlargement of prostate epithelium that requires androgen receptor (AR) signaling. INPP4B and EZH2 are highly expressed in prostate epithelium where they regulate AR signaling and play an important role in prostate cancer etiology. EZH2 is an epigenetic silencer that methylates histone H3 on K9 and K27 residues and INPP4B is a dual specificity phosphatase that dephosphorylates PI(3,4)P2 and PI(4,5)P2, membrane lipids that activate Akt and PKC signaling pathways respectively. We discovered that Inpp4b-/- male mice develop BPH at 3 months old of age and subsequently prostate intraepithelial neoplasia (PIN) when fed high fat diet. While expression of AR in the prostates of these mice is similar, AR activity is reduced. The loss of INPP4B caused reduction in EZH2 protein levels in prostate cancer cell lines and in mouse prostate. Inhibition of Akt and PKC signaling reduced EZH2 levels in ventral and dorsolateral prostate lobes of Inpp4b-/- males, suggesting that INPP4B upregulates EZH2 levels by suppressing Akt and PKC signaling pathways. Consistent with decline in EZH2 levels, Inpp4b-/- males have reduced levels of H3K27me3 and H3K9me2 in the ventral prostate, and high fat diet exacerbated this phenotype. Our data suggests that INPP4B modulates epigenetic profile of prostate epithelium by stabilizing EZH2 levels. Both loss of INPP4B and high fat diet treatment lead to decline in EZH2 levels and activity and contribute to development of BPH in mouse model.
Citation Format: Yasemin Ceyhan, Manqi Zhang, Irina U. Agoulnik. Inositol Polyphosphate 4-Phosphatase Type-II B protects mice from benign prostatic hyperplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2497.
Abstract 2501: Functional properties and regulation of the catechol-O-methyltransferase gene in prostate cancer
Authors: Tanaka Yuichiro , Hashimoto Yutaka , Shiina Marisa , Shahryari Varahram , Kulkarni Priyanka , Yamamura Soichiro , Majid Shahana , Tabatabai Z Laura , Dahiya Rajvir 
Published: July 2021

Abstract
The catechol-O-methylase (COMT) gene has been shown to play a protective role in the cell by reducing catechol-compounds that can cause genetic mutations and enhance the carcinogenesis process. In this study, we determined the functional effects and regulation of COMT in prostate cancer. Both The Cancer Genome Atlas (TCGA) and immunohistochemical analysis of clinical specimens demonstrated a reduction of COMT expression in prostate cancer. Also, western analyses of prostate cancer cell lines show COMT levels to be minimal in DuPro and DU145 and thus, these cells were used for further analyses. Re-expression of COMT led to suppressed migration ability (wound healing assay) and enhanced apoptosis (flow cytometric analyses), and when challenged with 4-hydroxyestradiol, a marked reduction of cell proliferation (MTT assay) was observed. Xenograft growth in athymic mice also resulted in inhibition due to COMT. As a mechanism, western analyses show cleaved CASP3 and BID were increased whereas XIAP and cIAP2 were reduced due to COMT. As COMT expression is low in prostate cancer, its regulation was determined. Databases identified several miRNAs capable of binding COMT and of these, miR-195 was observed to be increased in prostate cancer according to TCGA. Real-time PCR validated upregulation of miR-195 in clinical prostate cancer specimens as well as DuPro and DU145 and interestingly, luciferase reporter showed miR-195 capable of binding COMT. These results demonstrate COMT to play a protective role by activating the apoptosis pathway and for miR-195 to regulate its expression. COMT may thus be a potential biomarker or a therapeutic target for prostate cancer.
Citation Format: Yuichiro Tanaka, Yutaka Hashimoto, Marisa Shiina, Varahram Shahryari, Priyanka Kulkarni, Soichiro Yamamura, Shahana Majid, Z Laura Tabatabai, Rajvir Dahiya. Functional properties and regulation of the catechol-O-methyltransferase gene in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2501.
Abstract 2502: Co-existing P53 and ARID1A mutations promote metastatic endometrial tumorigenesis
Authors: Reske Jake J. , Wilson Mike R. , Holladay Jeanne , Risinger John I. , Chandler Ronald L. 
Published: July 2021

Abstract
P53 and ARID1A are frequently mutated across cancer but rarely in the same tumor. Uterine endometrial cancer displays the highest P53-ARID1A mutual exclusivity rate. The genetic basis underlying P53-ARID1A mutual exclusivity and the relationship between molecular programs imposed by either mutation have not been elucidated in vivo mouse models. Here, genetically engineered mice were used to discern both unique and overlapping roles of P53 and ARID1A in the endometrium. Endometrial epithelial hyperplasia is driven by P53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium. Sorted hyperplastic endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A-PIK3CA mutant endometrium. Both P53 and ARID1A mutations lead to activation of inflammatory pathways but differ on other gene expression programs, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with respective genetic alterations. ARID1A co-regulates P53 transcriptional gene targets, and the P53 pathway is activated in ARID1A mutant endometrial tumors. Finally, TP53 and ARID1A mutations co-occur more frequently in metastatic lesions, and co-existing TP53-ARID1A mutations are viable in the endometrium and lead to invasive endometrial cancer. These data suggest P53 and ARID1A mutations stimulate shared and distinct tumorigenic programs in the endometrium and promote metastasis when existing simultaneously. We propose that ARID1A loss in P53 mutant endometrial cancer promotes metastasis.
Citation Format: Jake J. Reske, Mike R. Wilson, Jeanne Holladay, John I. Risinger, Ronald L. Chandler. Co-existing P53 and ARID1A mutations promote metastatic endometrial tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2502.
Abstract 2519: Targeting glucose metabolism in HER2+breast cancer
Authors: Chang Simone , Chesney Jason , Trent John O. , Telang Sucheta 
Published: July 2021

Abstract
Primary and metastatic breast cancers are driven by oncogenic mutations to rely on glucose metabolism to support their rapid proliferation. Of these genetic changes, the increased activity of the human epidermal growth factor receptor 2 (HER2/ErbB2) is observed in a third of all breast tumors. HER2 has been shown to activate downstream effectors (e.g. Ras, HIF-1α) that stimulate glycolysis - in part by activation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family of enzymes (PFKFB1-4). The PFKFBs produce fructose-2,6-bisphosphate (F26BP) which activates a key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK1).
In preliminary studies, we found that the PFKFB4 family member was highly expressed in a series of patient-derived HER2+ breast tumors relative to normal breast with markedly higher expression in their matched metastatic lymph nodes. We next determined that silencing PFKFB4 markedly reduced F26BP, glycolysis and cell survival in HER2+ breast cancer cells and inhibited tumor growth in vivo. Through virtual screening, we have discovered a first-in-class small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits PFKFB4 activity with a resultant decrease in F26BP, glycolysis and cancer cell growth. 5MPN also caused a significant decrease in the invasion and migration of HER2+ breast cancer cells in vitro, importantly at concentrations well below levels that affect cell viability and marked suppression in the growth of established tumors, without systemic toxicity.
In additional studies, we have found that the related PFKFB3 isoform is also expressed in HER+ breast tumors. Our previous work found that the PFKFB4 enzyme localizes to the cytoplasm (where PFK1 and the glycolytic pathway function) indicating a possible dominant role for PFKFB4 in glycolytic regulation. PFKFB3 however largely localized to the nucleus where it serves an important function in proliferation via activation of cyclin-dependent kinases. Based on the different roles played by these enzymes in cancer cells, we next evaluated the effects of simultaneous administration of 5MPN ± a clinical candidate PFKFB3 inhibitor on survival and proliferation in HER2+ breast cancer and found that the combination synergistically and significantly decreased viability and growth in several examined HER2+ breast cancer cell lines. Our data indicate that targeting PFKFB4 may be a viable therapeutic option against breast cancer and strongly support the further exploration of co-targeting PFKFB4 and PFKFB3 as a potential therapeutic strategy for the successful treatment of HER2+ breast cancer.
Citation Format: Simone Chang, Jason Chesney, John O. Trent, Sucheta Telang. Targeting glucose metabolism in HER2+breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2519.
Abstract 252: Navigating networks of oncology biomarkers mined from the scientific literature: A new open research tool
Authors: Wager Kim , Chari Dheepa , Ho Steffan , Rees Tomas J. , Schijvenaars Robert J. 
Published: July 2021

Abstract
Introduction: Oncology biomarkers have a pivotal role in diagnosis, prognosis, assessment of disease progression and the prediction of treatment efficacy. There are &gt; 5000 known biomarkers; some are well characterised, while others are emerging as biomarkers of potential interest. Biomarker panels, incorporating combinations of biomarkers, are increasingly used to enhance the power and precision of testing.
Objective: We sought to identify key emerging biomarkers and biomarker relationships by applying analytical techniques to the corpus of recent scientific publications using an artificial intelligence (AI)-driven platform.
Methods: Biomarker targets were obtained from the Early Detection Research Network. Recent (&lt;5 years old) publications mentioning biomarkers in six cancer types (bladder, breast, colorectal, lung, prostate and renal) were identified using Dimensions (a linked research knowledge system); emerging biomarkers were identified by number and growth in publications. For selected biomarkers, full text proximity searching was used to identify biomarker co-occurrence, which was visualized and characterized using network analysis and co-occurrence heatmaps per cancer type. Relationships between biomarkers were also assessed in an indication-agnostic dataset. Key biomarkers were identified by a measure of their network importance.
Results: A total of 720 biomarkers were analyzed, and 41 clusters identified across the cancer types. Data visualizations are available at https://reports.dimensions.ai/mined-oncology-biomarkers/
Conclusion: Using large-scale analytics of published literature, biomarkers across six cancer types were successfully characterized in terms of their emergence in the published literature and the context in which they are described. This novel AI-driven approach could help identify biomarkers and biomarker panels for exploration in a clinical setting.
Example clusters - growth rate is compound annual growth rate (CAGR)Cancer typeBiomarkers (n)Publications (n)Cluster key biomarkersCluster publication growth rate (%)Bladder49168CAV1/CXCL8/THBS153.1Breast2651593AREG/CXCL10/CXCL832.6Colorectal193921CAV1/CDCP1/MTHFR31.6Lung2231061SFTPC/C9/GPI41.4Prostate166717FABP5/FLNA/CAV131.6Renal44185CXCL10/CXCL8/CSNK2A149.5
Citation Format: Kim Wager, Dheepa Chari, Steffan Ho, Tomas J. Rees, Robert J. Schijvenaars. Navigating networks of oncology biomarkers mined from the scientific literature: A new open research tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 252.