bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5487: Targeting glycolysis for the treatment of cancer
Authors: Chesney Jason , Mojesky Aubrey , Imbert-Fernandez Yoannis , Trent John , Telang Sucheta 
Published: August 2018

Abstract
Tumors exhibit markedly increased glucose uptake and glycolysis and this metabolic phenotype serves to satisfy their increased requirement for energy and biosynthetic intermediates. Tumor glucose metabolism is stimulated in part by fructose-2,6-bisphosphate (F26BP), which is the product of a family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) and allosterically activates a key glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). Previous studies have found the PFKFB3 family member to be a dominant source of F26BP in cancer cells due to a high kinase activity, expression in multiple tumor types and the inhibition of tumor growth by specific PFKFB3 inhibitors including a compound, PFK158, that is currently under evaluation in a phase I trial. Recent data, however, indicate that the PFKFB4 enzyme plays a significant role in regulating glucose metabolism in neoplastic cells. We have found that PFKFB4 is highly expressed in multiple cancers, strongly induced by HIF-1α, and that its suppression markedly reduced F26BP and glycolytic flux, increased apoptosis and inhibited growth of xenograft tumors in vivo, thus providing strong rationale for the development of antineoplastic agents selectively targeting PFKFB4. Using virtual screening, we have discovered a first-in-class small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits recombinant PFKFB4 activity with a resultant decrease in F26BP, glycolytic flux and cancer cell growth in vitro and markedly reduces the growth of established tumors without systemic toxicity. During our studies, we unexpectedly observed that PFKFB4 expression is increased by PFKFB3 inhibition, suggesting that PFKFB4 may compensate for decreased PFKFB3 expression and activity. We examined the effects of simultaneous silencing of PFKFB4 and PFKFB3 on cancer cell lines and found that co-knockdown led to a significant decrease in cell viability and glycolysis and to a near-complete abrogation of anchorage-independent growth in vitro. We additionally examined the effect of simultaneous inhibition of PFKFB4 and PFKFB3 using 5MPN and several PFKFB3 inhibitors in vitro and found a synergistic increase in cell death. Taken together, our data indicate that targeting PFKFB4 may be a viable therapeutic option against cancer and strongly support the further development of PFKFB4 small-molecule inhibitors as well as the co-targeting of PFKFB4 and PFKFB3 as potential strategies for the treatment of cancer.
Citation Format: Jason Chesney, Aubrey Mojesky, Yoannis Imbert-Fernandez, John Trent, Sucheta Telang. Targeting glycolysis for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5487.
Abstract 5493: Targeted inhibition of glutaminase in GRM1-expressing melanoma cells inhibits cell proliferation by reducing glutamate bioavailability
Authors: Shah Raj , Zhu Mengying , Boreland Andrew , Filipp Fabian , Chen Suzie 
Published: August 2018

Abstract
Aberrant glutamatergic signaling has been implicated in many cancer types. Our laboratory has previously illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1 is also the predominant excitatory neurotransmitter in the central nervous system. We have demonstrated significant upregulation of glutaminase (GLS) expression in GRM1 expressing melanoma cells, resulting in excess glutamate production and the establishment of autocrine loops in vitro. GLS catalyzes the first step in glutamine metabolism–the conversion of glutamine to glutamate. Comparison of glutamate levels in circulating blood plasma between melanoma prone and wild type mice showed elevated glutamate levels in melanoma prone GRM1-transgenic mice, suggesting that aberrant GRM1 expression also promotes an increase in circulating glutamate, to ensure constitutive activation of the GRM1 receptor and its downstream signaling affecters in vivo. Inclusion of CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, resulted in significant inhibition of GRM1+ melanoma cell proliferation compared to GRM1- ones. We also demonstrated that treatment with Riluzole, an inhibitor of glutamatergic signaling by decreasing the available ligand, glutamate, led to significantly reduced melanoma cell proliferation in vitro and tumor progression in vivo. We found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1+ melanoma cells led to synergistic suppression of cell proliferation in vitro. Furthermore, we found that CB-839 altered the function not the expression of GLS in melanoma cells. Additionally, we also discovered that manipulation of GRM1 expression by genetic means led to robust parallel changes in gene expression levels and intracellular glutamate concentrations by mass spectrometry analysis, as well as the endogenous levels of GLS in melanoma cells, suggesting association between GRM1 and GLS. The sensitivity of GRM1+ melanoma cells to modulation of GLS point to the dependency of these cells to glutamate amounts via GLS activity. We are continuing to investigate the mechanisms and regulation of GLS in our experimental system, with the goal of developing a rational approach for the treatment of GRM1 expressing tumors.
Citation Format: Raj Shah, Mengying Zhu, Andrew Boreland, Fabian Filipp, Suzie Chen. Targeted inhibition of glutaminase in GRM1-expressing melanoma cells inhibits cell proliferation by reducing glutamate bioavailability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5493.
Abstract 5501: The role of G-protein coupled receptor 64 (GPR64) as a tumor suppressor in endometrial cancer
Authors: Yoo Jung-Yoon , Ahn Jong Il , Kim Tae Hoon , Broaddus Russell R. , Lim Jeong Mook , Yoon Ho-Geun , Jeong Jae-Wook 
Published: August 2018

Abstract
Endometrial cancer is the most common gynecologic cancer. G-protein coupled receptor 64 (GPR64) belongs to a family of adhesion GPCRs and plays an important role for male fertility. However, GPR64 function has not been reported in endometrial cancer. Our objective is to investigate the role of GPR64 in endometrial cancer. We examined the levels of GPR64 in human endometrial cancer tissue by immunohistochemistry analysis. GPR64 levels were significantly lower in 10 of 21 (47.62%) of endometrial carcinoma samples compared to control. To test whether GPR64 has a role of tumor suppressor in endometrial cancer, we used an siRNA loss-of-function approach in human endometrial adenocarcinoma cell lines. Depletion of GPR64 by siRNA transfection in Ishikawa and HEC1A cells showed an increase of colony formation ability and cell proliferation. Depletion of GPR64 also significantly increased the migration and invasion activity of Ishikawa and HEC1A cells. Furthermore, the phosphorylation of AMP-activated protein kinase (AMPK) and expression of Connexin 43 (Cx43), a member of the large family of gap junction proteins, were regulated in GPR64-deficient Ishikawa cells. These results suggest that GPR64 plays an important role for cell proliferation, migration, and invasion as a tumor suppressor in endometrial cancer.
Citation Format: Jung-Yoon Yoo, Jong Il Ahn, Tae Hoon Kim, Russell R. Broaddus, Jeong Mook Lim, Ho-Geun Yoon, Jae-Wook Jeong. The role of G-protein coupled receptor 64 (GPR64) as a tumor suppressor in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5501.
Abstract 5504: TRAF3 acts as a tumor suppressor through modulation of TP53 and RB in human papillomavirus associated head and neck squamous cell carcinomas
Authors: Chen Tony Wayne , Zhang Jialing , Yang Xinping , Chen Zhong , Waes Carter Van 
Published: August 2018

Abstract
The number of human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) cases has increased sharply in recent years, especially among tonsillar and oropharyngeal cancers. The Cancer Genome Atlas (TCGA) network identified novel loss-of-function genomic alterations of TNF receptor-associated factor 3 (TRAF3) in a subset of HPV+ HNSCC specimens. Previously, most studies of TRAF3 function are from the immune system and lymphoid malignancies, where TRAF3 has been implicated as a ring-finger E3 ubiquitin ligase that promotes anti-viral immunity, while inhibiting alternative NF-κB signaling by which DNA viruses can transform lymphoid cells. However, the function of TRAF3 and the mechanisms by which TRAF3 deficiency contributes to tumorigenesis are largely unknown. To explore the potential mechanisms of TRAF3 defects observed in the tumor subset identified by TCGA, we surveyed a panel of HPV+ HNSCC cell lines, and identified lines with lower steady-state protein levels of TRAF3 than normal oral keratinocytes. Functional studies show that TRAF3 expression leads to suppression of oncogenic phenotypes, including decreased alternative NF-κB signaling, cell proliferation, colony formation, and cell migration. Additionally, restoring TRAF3 increased anti-viral cytokine interferon alpha (IFNA) expression, and sensitivity to chemotherapy agent cisplatin. The anti-proliferative activity of TRAF3 was partially mediated by restoration of expression of classical tumor suppressor genes, TP53 and RB, which are degraded in HPV+ cancers. TRAF3 re-expression increased the steady-state protein levels of TP53 and gene expression of TP53AIP, which mediates cell cycle arrest and apoptosis. Knockdown of TP53 in TRAF3 transfected cell lines partially reversed the slowed cell growth rate, supporting the contribution of TP53 to TRAF3 mediated growth inhibition. TRAF3 expression also increased RB protein expression and decreased RB regulated transcription factor E2F1, which regulates cellular genes involved in cell proliferation and DNA synthesis. In conclusion, we have revealed a novel role whereby TRAF3 loss leads to enhanced HPV mediated repression of the TP53 and RB tumor suppressors that control cell growth and cell death in HPV+ HNSCCs.
(Supported by NIDCD intramural project ZIA-DC-000016, 73 and 74)
Citation Format: Tony Wayne Chen, Jialing Zhang, Xinping Yang, Zhong Chen, Carter Van Waes. TRAF3 acts as a tumor suppressor through modulation of TP53 and RB in human papillomavirus associated head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5504.
Abstract 5505: GAN gene exon 8 SNP is related to gigaxonin expression and increased expression of e-cadherin in head and neck cancer
Authors: Ko Albert , Venkatesan Natarajan , Chatoff Jenna , Morselli Marco , Fishbein Gregory , Bomont Pascale , Pellegrini Matteo , Wang Marilene , Srivatsan Eri 
Published: August 2018

Abstract
Gigaxonin is the protein product of Giant Axonal Neuropathy (GAN) gene and is involved in the processing of intermediate filaments of neural cells and vimentin fibers in fibroblasts. We have shown earlier that gigaxonin is associated with p16 in NFkB ubiquitination of cisplatin sensitive tumor cells. Our studies have shown that there is a direct relationship between the presence of exon 8 SNP (C&gt;T) and expression of giagxonin in cancer cell lines. We have also seen an inverse relationship between exon 8 SNP and tumor recurrence and metastasis. RNA-seq studies of cancer cell lines and primary tumors have shown a direct relationship in the expression of gigaxonin to the expression of e-cadherin and inverse relationship to the expression of Vimentin and Zeb1. Immunohistochemical (IHC) studies of primary head and neck cancers have confirmed the inverse relationship between e-cadherin and vimentin. We hypothesize therefore that gigaxonin is involved in the ubiquitination of vimentin and cancer stem cell markers such as zeb1 resulting in the chemo sensitization of human tumor cells.
Citation Format: Albert Ko, Natarajan Venkatesan, Jenna Chatoff, Marco Morselli, Gregory Fishbein, Pascale Bomont, Matteo Pellegrini, Marilene Wang, Eri Srivatsan. GAN gene exon 8 SNP is related to gigaxonin expression and increased expression of e-cadherin in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5505.
Abstract 552: PEPD is an essential regulator of p53 tumor suppressor
Authors: Yang Lu , Li Yun , Bhattacharya Arup , Zhang Yuesheng 
Published: August 2018

Abstract
Peptidase D (PEPD), also known as prolidase among other names, is an enzyme that hydrolyzes dipeptides with proline or hydroxyproline at the carboxy terminus and is believed to be important for collagen metabolism, as proline and hydroxyproline are very abundant in collagen. Interestingly, we recently found that eliminating cellular PEPD causes cell death and tumor regression due to p53 activation. Here, we show that PEPD binds to and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. Indeed, PEPD competes with MDM2 for p53 binding. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin (DOX) and hydrogen peroxide each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for stress response, but this also renders cells dependent on PEPD for survival as it suppresses p53. Our results reveal a major p53 regulatory mechanism and a critical physiological function of PEPD. The p53-PEPD system likely operates in most if not all cells, since both p53 and PEPD are expressed ubiquitously. Disrupting PEPD suppression of p53 may be an important therapeutic strategy in cancer, as our data show that PEPD knockdown by RNA interference in tumors in mice causes p53 activation in the tumor
tissues and tumor regression. Our study also reveals a previously unrecognized anticancer mechanism of DOX. We show that the key step in DOX-induced p53 activation is the disruption of p53 association with PEPD via reactive oxygen species. This finding also raises the intriguing question of whether other stress-inducing anticancer agents also disrupt the PEPD-p53 complex for p53 activation and suggests that antioxidants may inhibit the anticancer activity of DOX and other agents by inhibiting p53 separation from PEPD. This work is supported by NCI grants and Roswell Park Alliance Foundation Grants.
Citation Format: Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang. PEPD is an essential regulator of p53 tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 552.
Abstract 5526: Mapping signaling networks in Nf1 mutant tumors
Authors: Pucciarelli Daniela , Krishnamurthi Ganesh , Braunstein Steve , Nakamura Jean L. 
Published: August 2018

Abstract
Introduction: The tumor suppressor gene Neurofibromatosis type 1 (NF1) encodes the Ras-GTPase activating protein neurofibromin, which negatively regulates Ras signaling. Loss of NF1 increases signaling through Raf/MEK/ERK and PI3K/AKT/mTOR. Inhibition of each of these pathways can produce variable responses, suggesting compensatory mechanisms and heterogeneity in signaling mechanisms in cancers. To study the biochemical sources of signaling we sought to functionally characterize Nf1-mutant tumors based on their variable drug sensitivities and development of drug resistance.
Methods: We previously established Nf1 null tumor cell lines from malignancies arising in irradiated Nf1+/- mice. We functionally profiled this panel of tumor cell lines using a custom 94 compound drug library targeting core signaling pathways commonly activated in cancers. Phosphorylated and total ERK, AKT, and S6 were assessed by western blotting. Cell lines resistant to treatment with MAPK and mTOR inhibitors were generated from parental cell lines. Parental and resistant cell lines were compared using MTS, exome and transcriptome sequencing, western blotting and kinome analysis.
Results: Nf1 mutant tumor cell lines demonstrated heterogeneous drug responses and, based on this observation, they could be organized into 3 functional sub-classes sharing similar drug sensitivities. All 12 Nf1 null cell lines demonstrated heterogeneous basal Ras pathway activation, as indicated by phosphorylated ERK, AKT, and S6. This variability was associated with variable sensitivity to treatment with MAPK and mTOR inhibitors. Acquired resistance to MAPK or mTOR inhibition (MEKi and mTORi) revealed differences in Ras activation that distinguished resistant from parental lines. For example, in contrast to parental lines, Ras-GTP levels in mTORi resistant cell lines demonstrated stability after serum stimulation compared to the parental counterpart, suggesting a reprogrammed role for Ras activation when mTORi resistance is acquired. These data highlight the plasticity of Ras-driven signaling in Nf1 tumors, which likely must be addressed to optimize therapy and counter the emergence of resistant clones.
Conclusion: Our analysis indicates significant variability in Ras pathway signaling in the context of Nf1 loss, which has implications for the choice of specific kinase inhibitors to use therapeutically. Cancers, including Nf1 null tumors, develop resistance to therapy and our data points to specific reprogramming of signaling pathways that distinguish resistance mechanisms.
Citation Format: Daniela Pucciarelli, Ganesh Krishnamurthi, Steve Braunstein, Jean L. Nakamura. Mapping signaling networks in Nf1 mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5526.
Abstract 553: p53 target BRMS1A is a metastatic suppressor
Authors: Tokino Takashi , Koyama Ryota , Idogawa Masashi , Sasaki Yasushi 
Published: August 2018

Abstract
Tumor suppressor p53 plays an important role in the cell fate determination in response to diverse upstream signals. As a transcription factor, p53 regulates a number of genes that are involved in cell-cycle arrest, apoptosis, senescence, and maintenance of genomic stability. Recent studies revealed that p53 is critical for the regulation of cell invasion and migration. Microarray analysis showed that breast cancer metastasis-suppressor 1-like (BRMS1L) is upregulated by p53. We identified two responsive sequences of p53 in the first intron and upstream of the BRMS1L gene. These two response elements are well conserved among mammals. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration. In contrast, knockdown of BRMS1L by siRNA induced the opposite effect. Notably, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. Altogether, these results strongly indicate that BRMS1L is one of the mediators downstream of the p53 pathway, and inhibits cancer cell invasion and migration, which are essential steps in cancer metastasis. Collectively, our results demonstrate that BRMS1L is involved in cancer cell invasion and migration, and may be a therapeutic target for cancer.
Citation Format: Takashi Tokino, Ryota Koyama, Masashi Idogawa, Yasushi Sasaki. p53 target BRMS1A is a metastatic suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 553.
Abstract 5556: Combining adenosine receptor inhibition with AB928 and chemotherapy results in greater immune activation and tumor control
Authors: Walters Matt J. , Piovesan Dana , Tan Joanne , DiRenzo Daniel , Yin Fangfang , Miles Dillon , Leleti Manmohan R. , Park Tim , Soriano Ferdie , Sharif Eshan , Schindler Ulrike , Powers Jay P. 
Published: August 2018

Abstract
INTRODUCTION: Extracellular adenosine triphosphate (ATP) is efficiently hydrolyzed to adenosine by ecto-nucleotidases CD39 and CD73, which converts adenosine-monophosphate (AMP) into adenosine (ADO). ADO suppresses immune responses including those of T cells, natural killer (NK) cells, and dendritic cells (DC) through activation of A2aR and A2bR receptors. Treatment of cancer cells with platinum-based and anthracycline chemotherapy has been shown to induce immunogenic cell death (ICD), characterized by increased extracellular ATP levels, and upregulation of CD39 and CD73, leading to the enhanced generation of adenosine.
METHODS: The ability of AB928 to inhibit adenosine-mediated suppression of immune cell function was assessed using human CD4 and CD8 cells. BALB/c mice were inoculated with AT-3-OVA tumors, which express the model antigen ovalbumin, and subsequently treated with chemotherapy or AB928 alone, or a combination of both. The growth rate and immune composition of the tumors were assessed (flow cytometry).
RESULTS: Consistent with the ability of adenosine to suppress immune function, AB928 inhibited the ability of adenosine to suppress CD4 or CD8 T cell activation. Tumor-bearing mice that have been treated with either doxorubicin (DOX, an anthracycline) or oxaliplatin (OX) exhibit increased expression of CD39 and CD73. Established AT-3-OVA tumors treated with AB928 alone had a small but significant decrease in their growth rate; similarly, tumors treated with chemotherapy exhibited a reduction in growth rate. Consistent with the ICD hypothesis, treatment of AT-3-OVA-bearing mice with DOX or OX resulted in an increase in OVA-specific CD8 T cells in the tumor. Concurrent treatment with AB928 and chemotherapy resulted in significantly reduced tumor growth rates, when compared to chemotherapy alone. Analysis of the tumor-infiltrating cell populations showed a significant increase in OVA-specific CD8 T cells, relative to those treated with chemotherapy alone.
CONCLUSIONS: Treatment of tumor-bearing mice with a combination of AB928, a dual A2aR and A2bR antagonist, and ICD-inducing chemotherapy results in increased tumor antigen-specific CD8 T cell responses and significantly reduced tumor growth. AB928 is currently undergoing clinical evaluation.
Citation Format: Matt J. Walters, Dana Piovesan, Joanne Tan, Daniel DiRenzo, Fangfang Yin, Dillon Miles, Manmohan R. Leleti, Tim Park, Ferdie Soriano, Eshan Sharif, Ulrike Schindler, Jay P. Powers. Combining adenosine receptor inhibition with AB928 and chemotherapy results in greater immune activation and tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5556.