bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 959: FAS mutations induce therapeutic resistance in non-Hodgkin lymphomas
Authors: Johnson Nathalie , Gaucher Denis , Morin Ryan , Gascoyne Randy , Connors Joseph , Marra Marco , Pelletier Jerry , Rigsby Hawley , Mann Koren 
Published: May 2015

Abstract
Lymphomas are common (1/30 Canadians), but responses to chemotherapy depend on the tumour biology. We sequenced &gt; 300 lymphomas at diagnosis and at relapse, identified FAS as a possible tumour suppressor gene and found that mutant FAS is associated with therapeutic resistance. FAS is the death receptor that initiates the extrinsic apoptotic pathway once activated by FAS ligand (FASL). Our studies indicated that the most common FAS mutation is a dominant negative allele whose product inhibits FAS-mediated apoptosis. This allele induces resistance to doxorubicin in murine lymphoma cells transplanted into syngeneic immune competent C57BL/6 mice but, unexpectedly, the allele has no effect on chemosensitivity in cultured lymphoma lines in vitro. Because FAS signaling is initiated by FASL from neighboring cells, we asked whether chemotherapy induces FAS or FASL expression in immune cells, thereby activating apoptosis in vivo but not in vitro. Indeed, exposure to chemotherapy induced FAS in primary and malignant B cells and increased FASL in benign T cells. Thus, we hypothesize that chemotherapy may induce an anti-tumour immune response mediated by FAS-FASL interactions, and that FAS mutations cause therapeutic resistance by blocking the chemotherapy-induced immune response. We will extend this work by evaluating the role of the immune response in chemotherapy-induced lymphoma apoptosis and by identifying therapies that will target FAS mutant lymphomas.
Citation Format: Nathalie Johnson, Denis Gaucher, Ryan Morin, Randy Gascoyne, Joseph Connors, Marco Marra, Jerry Pelletier, Hawley Rigsby, Koren Mann. FAS mutations induce therapeutic resistance in non-Hodgkin lymphomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 959. doi:10.1158/1538-7445.AM2014-959
Abstract 961: 6-phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumor growth by inhibiting LKB1-AMPK signaling
Authors: Shan Changliang , Elf Shannon E. , Gu Ting-Lei , Khoury Hanna J. , Boggon Titus , Kang Sumin , Chen Jing 
Published: May 2015

Abstract
6-phosphogluconate dehydrogenase (6PGD) in the oxidative pentose phosphate pathway (PPP) is upregulated in many cancers. However, how 6PGD is activated and provides a metabolic advantage to tumor growth is unknown. Here we show that 6PGD is commonly activated in human cancers by acetylation at K76 and K294,We found that 6PGD is commonly activated in human cancers by lysine acetylation. Acetylation at K76 and K294 promotes NADP+-binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we found that lysine acetylation of 6PGD is important for cancer cell metabolism, proliferation and tumor growth. We also performed systematic RNAi screens and identified DLAT and ACAT2 as 6PGD acetyltransferases and HDAC4 as 6PGD deacetylase, using two novel “targeted” shRNA libraries that target the majority of acetyltransferases and deacetylases in the human genome, respectively. In addition, we found that 6PGD controls intracellular levels of its product ribulose-5-phosphate (Ru-5-P) to regulate lipogenesis. Ru-5-P inhibits LKB1 by disrupting active LKB1 complex, leading to inhibition of AMPK and subsequent activation of acetyl-CoA carboxylase 1 and lipogenesis. Furthermore, we screened out Physcion and its derivative S3 as novel 6PGD inhibitors, which are efficacious in treatment of xenograft nude mice and primary leukemia cells from human patients with minimal toxicity and no off-target effect.
Our findings for the first time decipher the molecular mechanisms underlying 6PGD upregulation in cancer cells and suggest that 6PGD provides an additional and novel link between oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signaling. Moreover, identification and characterization of 6PGD inhibitors in translational/pre-clinical studies for the first time provide “proof of principle” to suggest 6PGD as an attractive anti-cancer target.
Citation Format: Changliang Shan, Shannon E. Elf, Ting-Lei Gu, Hanna J. Khoury, Titus Boggon, Sumin Kang, Jing Chen. 6-phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumor growth by inhibiting LKB1-AMPK signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 961. doi:10.1158/1538-7445.AM2014-961
Abstract 962: Identification of a PFKFB3 inhibitor suitable for phase I trial testing that synergizes with the B-Raf inhibitor vemurafenib
Authors: O'Neal Julie , Tapolsky Gilles , Clem Brian , Telang Sucheta , Chesney Jason 
Published: May 2015

Abstract
In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). This enzyme synthesizes fructose-2,6-bisphosphate, which is an activator of 6-phosphofructo-1-kinase, a key step of glycolysis that is tightly controlled by multiple metabolic feedback mechanisms. We recently identified the first competitive small molecule inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), and demonstrated that this agent is selectively cytotoxic to Ras-transformed epithelial cells and displays broad anti-tumor activity. We now report the discovery of a novel 3PO-derivative, PFK158, that is markedly more potent than 3PO, has excellent pharmacokinetic properties and causes ∼80% growth inhibition in several mouse models of human-derived tumors. Importantly, IND-enabling safety and toxicity studies have demonstrated that PFK158 is well tolerated in rats and dogs, providing support for a phase 1 trial in cancer patients planned for early 2014. Once the maximum tolerated dose is identified, we intend to conduct multiple phase 1/2 trials of PFK158 in combination with targeted agents given the ability of PFK158 to suppress glucose metabolism and multiple survival mechanisms. One such targeted agent, vemurafenib, is a mutant B-Raf inhibitor that was recently FDA-approved for BRAFV600E-positive melanoma patients. Unfortunately, a multitude of resistance mechanisms have resulted in disease progression in less than one year for the majority of melanoma patients treated with vemurafenib. We hypothesized that PFK158 would sensitize vemurafenib-resistant melanoma cells and found that the addition of PFK158 to vemurafenib caused a marked increase in the apoptotic death of several melanoma cell lines in vitro. These data provide rationale for the conduct of pre-clinical studies of PFK158 combined with vemurafenib in transgenic BRAFV600E melanoma mouse models which are in turn expected to justify a phase I/II trial of the combination in BRAFV600E-positive melanoma patients. In conclusion, PFK158 is the first PFKFB3 inhibitor to be examined in a phase I trial and may have significant clinical utility when combined with agents that target driver oncogenes.
Citation Format: Julie O'Neal, Gilles Tapolsky, Brian Clem, Sucheta Telang, Jason Chesney. Identification of a PFKFB3 inhibitor suitable for phase I trial testing that synergizes with the B-Raf inhibitor vemurafenib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 962. doi:10.1158/1538-7445.AM2014-962
Abstract 964: Inhibiting glycolysis with an LDHA inhibitor: A new solution to an old problem
Authors: O'Brien Thomas , Purkey Hans , Hitz Anna , Peterson Dave , Boudreau Aaron , Delnagro Christopher , Kwong Mandy , Hong Rebecca , Gao Min , Pang Jodi , Vanderbilt Alex , Williams Simon , Salphati Laurent , Sampath Deepak , Hatzivassiliou Georgia , Evangelista Marie 
Published: May 2015

Abstract
Tumors exhibit altered metabolic profiles compared to normal, non-transformed tissues. In the presence of oxygen, most differentiated cells convert glucose to ATP by oxidative phosphorylation (OX-PHOS), whereas tumor cells consume glucose and convert it to lactate, a phenomenon known as “aerobic glycolysis” or the “Warburg effect”. There is increased interest in targeting glycolysis as a therapeutic strategy in oncology, and one of the key enzymes in this pathway is lactate dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactate in the last step of glycolysis. A small molecule LDHA inhibitor that was identified by high throughput screening was optimized to generate GNE-140, which has a biochemical EC50 of 0.005 μM and inhibits MiaPaCa-2 pancreatic cell proliferation with an EC50 of 0.25 μM. We show that inhibition of LDHA reduces carbon flux from pyruvate to lactate, impairs glycolysis, and leads to global effects in cell metabolism. Cells cease proliferation within 24 hours of LDHA inhibition, yet only undergo cell death following sustained pathway inhibition. Finally, we show that pancreatic cell lines that are resistant to LDHA inhibition can be re-sensitized to LDHA inhibition by inhibiting OX-PHOS. In conclusion, we describe a potent cell active LDHA inhibitor that modulates glycolysis, induces cell death, and that can be used to help evaluate the importance of LDHA in tumor growth.
Citation Format: Thomas O'Brien, Hans Purkey, Anna Hitz, Dave Peterson, Aaron Boudreau, Christopher Delnagro, Mandy Kwong, Rebecca Hong, Min Gao, Jodi Pang, Alex Vanderbilt, Simon Williams, Laurent Salphati, Deepak Sampath, Georgia Hatzivassiliou, Marie Evangelista. Inhibiting glycolysis with an LDHA inhibitor: A new solution to an old problem. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 964. doi:10.1158/1538-7445.AM2014-964
Abstract 969: TGF-beta cross-talks with the EGF receptor family to promote proliferation of pancreatic cancer cells with dysfunctional RB
Authors: Gore Jesse , Deitz Samantha L. , Wilson Julie L. , Korc Murray 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, associated with a high frequency of KRAS mutations (95%) and loss of negative growth constraints, due, in part, to frequent CDKN2A (85%), TP53 (75%) and SMAD4 (55%) mutations. PDACs also overexpress all three TGF-β isoforms, and high levels of TGF-βs correlates with decreased survival. Recently, we showed that in human PDAC and in murine PDAC (mPDAC) arising in biologically aggressive, oncogenic Kras-driven genetically engineered mouse models (GEMMs), proliferating pancreatic cancer cells (PCCs) often exhibit abundant phosphorylated Smad2 and RB indicating that in these PCCs, canonical TGF-β signaling pathways are active, whereas RB is inactive. Using PCCs derived from a GEMM that expresses oncogenic Kras, but lacks RB (KRC cells), we showed that TGF-β1 activates canonical and non-canonical (MEK, Src, PI3K) pathways, and enhances growth in 3-dimensional (3D) culture. This mitogenic effect is abrogated by type I TGF-β receptor (TβRI) kinase inhibition with SB505124, combined inhibition by MEK/Src or MEK/PI3K, or re-expression of wild-type, but not mutant RB. Thus, loss of RB function enables TGF-β to directly enhance PCC growth. Given that the EGF receptor (EGFR) family can activate these non-canonical pathways and that TGF-β cross-talks with EGFR, we investigated the role of EGFR family members in mediating the mitogenic effects of TGF-β on RB-deficient PCCs. In 3D culture, TGF-β1-enhanced proliferation was inhibited by targeting EGFR with erlotinib and completely suppressed by EGFR/HER2 inhibition with lapatinib. Moreover, lentiviral-mediated silencing of HER2 markedly attenuated TGF-β1-stimulated KRC growth, and this inhibitory effect was potentiated by erlotinib. Thus, TGF-β1's mitogenic effects are mediated, in part, through transactivation of EGFR/HER2, raising the possibility that concomitant use of TβRI inhibitors and lapatinib to inhibit EGFR/HER2 and may represent a novel therapeutic approach in PDAC.
Citation Format: Jesse Gore, Samantha L. Deitz, Julie L. Wilson, Murray Korc. TGF-beta cross-talks with the EGF receptor family to promote proliferation of pancreatic cancer cells with dysfunctional RB. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 969. doi:10.1158/1538-7445.AM2014-969
Abstract 978: microRNA-211 modulates energy metabolism in human melanoma cells by destabilizing HIF1-α and downregulating PDK4
Authors: Mazar Joseph , Richardson Adam , Qi Feng , Lee Bongyong , Duran Angeles , Govindarajan Subramaniam , Shelley John , Brill Laurence M. , Li Jian-Liang , Han Xianlin , Moscat Jorge , Perera Ranjan Joseph 
Published: May 2015

Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in cellular physiology and tumorigenesis. We have previously reported that the expression of the melanocyte-specific miRNA miR-211 is significantly reduced or absent in non-pigmented melanoma cells and clinical melanoma samples. Here we report that ectopic expression of miR-211 in non-pigmented melanoma cells increases mitochondrial number, NADP to NADPH ratio, oxygen consumption, and fatty acid synthesis. Ectopic expression of miR-211 destabilizes hypoxia inducible factor 1α (HIF-1α) and downregulates pyruvate dehydrogenase kinase 4 (PDK4), which is known to convert cellular pyruvate to acetyl co-enzyme A. miR-211-expressing cells were characterized by uptake of glutamine, rather than glucose, as a source of cellular energy. Global proteomic, transcriptomic, lipidomic, and metabolomic profiling with integrated analysis revealed that miR-211 modulates several “-omics” signatures associated with oxidative phosphorylation. Here we show for the first time that a microRNA and its target genes play a key role in regulating mitochondrial energy metabolism in melanomas.
Citation Format: Joseph Mazar, Adam Richardson, Feng Qi, Bongyong Lee, Angeles Duran, Subramaniam Govindarajan, John Shelley, Laurence M. Brill, Jian-Liang Li, Xianlin Han, Jorge Moscat, Ranjan Joseph Perera. microRNA-211 modulates energy metabolism in human melanoma cells by destabilizing HIF1-α and downregulating PDK4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 978. doi:10.1158/1538-7445.AM2014-978
Abstract 980: Small molecule inhibitor of miR-155, SMM155I, inhibits epithelial-mesenchymal transition and tumor growth in cancer cells overexpressing miR-155
Authors: Xu Cheng-Xiong , Kong William , Kim Donghwa , Richards Edward , Yan Fei , Li Yueling , Coppola Domenico , Cheng Jin Q. 
Published: May 2015

Abstract
Accumulating studies have shown that miR-155 is frequently up-regulated in a various types of human malignancy. Expression of miR-155 induces epithelial-mesenchymal transition (EMT), transformation, tumor growth and metastasis as well as chemoresistance, whereas inhibition of miR-155 reverses these processes. Here we report the discovery of a small molecule miR-155 inhibitor, SMM155I, by screening the National Cancer Institute Diversity Set. SMM155I directly binds to miR-155 and inhibits miR-155 interaction with its targeted mRNAs without effect on expression of miR-155 and other miRs. The inhibition of miR-155 by SMM155I resulted in suppression of cell migration, invasion and EMT in human cancer cells that harbor elevated miR-155. Furthermore, SMM155I potently inhibited tumor growth in nude mice of human cancer cells in which miR-155 is aberrantly expressed but not of those cancer cells in which it is not. These findings provide strong evidence for pharmacologically targeting miR-155 for anticancer drug discovery.
Citation Format: Cheng-Xiong Xu, William Kong, Donghwa Kim, Edward Richards, Fei Yan, Yueling Li, Domenico Coppola, Jin Q. Cheng. Small molecule inhibitor of miR-155, SMM155I, inhibits epithelial-mesenchymal transition and tumor growth in cancer cells overexpressing miR-155. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 980. doi:10.1158/1538-7445.AM2014-980
Abstract 985: The mutational landscape of LN metastasis and recurrence in HNSCC
Authors: Hedberg Matthew Louis , Goh Gerald , Freilino Maria , Zeng Yan , Lui Vivian W. , Herbst Roy S. , Lifton Richard P. , Grandis Jennifer R. 
Published: May 2015

Abstract
Recent whole exome sequencing (WES) studies have reported the mutations that characterize primary head and neck squamous cell carcinomas (HNSCC). While exposure to tobacco, alcohol and HPV infection are known to contribute to HNSCC development and prognosis, the largest obstacle to long term survival is recurrent and metastatic disease. Approximately 50% of patients present with synchronous lymph node metastases (SLNM), where 5-year adjusted survival is ≈85% for patients without SLNM compared with 30-60% in patients with SLNM. 20-30% of patients cured of their primary HNSCC go on to develop recurrent disease, which is usually refractory to standard therapies. Here, we report the first WES study of paired primary tumor and SLNM from 14 HNSCC patients, and paired primary tumor and metachronous loco-regional metastases (MLRM) from 11 HNSCC patients. Primary tumors averaged 67 nonsynonymous mutations per tumor (n=21), SLNM averaged 89.3 (n=12), and MLRM averaged 41.7 (n=9). TP53 was the only gene mutated in a majority (57%) of primary tumors in our cohort. We observed similar rates of mutation in several of the TCGA-defined “HNSCC signature” genes in our primary cohort, including FAT1 (14.3%) and CASP8 (4.8%), among others. While the size of our cohort does not allow for appropriately powered statistical analyses; 206 and 204 genes, were mutated in metastatic tumors, but not the respective paired primary tumors, in the SLNM and MLRM cohorts, respectively. AP2B1 and ITPR3 mutations were enriched in SLNM, as newly acquired mutations were seen in multiple (2 and 2/12) SLNM samples. GLUL and DDR2 mutations were enriched in MLRM, as newly acquired mutations were seen in multiple (2 and 2/9) MLRM samples. All 4 genes have previously been implicated in the metastatic process in other cancers. The potential enrichment of DDR2 mutations in HNSCC metastases is especially intriguing, as mutations in this gene have been shown to confer sensitivity to the SRC-family kinase inhibitor, dasatinib, in lung and breast cancer. Here we report exquisite sensitivity to dasatinib in our HNSCC preclinical models harboring DDR2 mutations, suggesting further investigation of this drug is warranted in recurrent HNSCC.
Citation Format: Matthew Louis Hedberg, Gerald Goh, Maria Freilino, Yan Zeng, Vivian WY Lui, Roy S. Herbst, Richard P. Lifton, Jennifer R. Grandis. The mutational landscape of LN metastasis and recurrence in HNSCC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 985. doi:10.1158/1538-7445.AM2014-985
Abstract BL-2: What relevance have hormones for breast cancer in the genomic era?
Authors: Dowsett Mitchell 
Published: May 2015

Abstract
Neoadjuvant treatment of primary breast cancer provides an excellent scenario for integrating biomarker, clinical and pharmacological studies as well as being a valued treatment option for patients with primary breast cancer. ER+ breast cancer may be treated with either cytotoxic or endocrine therapy. Measurements of changes in proliferation and apoptosis have provided insights into the mechanisms of response to these agents. In both settings decreases in proliferation as measured using Ki67 as a biomarker occur in patients responding to treatment. In endocrine treatment the reduced proliferation occurs early and persists for many weeks appearing to be the main driver of response. Apoptosis is not increased but continues at a slightly reduced rate and leads to tumour shrinkage in a scenario in which cell replacement is now markedly attenuated. Changes in Ki67 induced by endocrine therapy have been validated as intermediate end-points reflecting long term benefit from treatment. In contrast the changes in Ki67 with cytotoxic therapy are best explained by a selective loss of more proliferative cells due to increased apoptotic death. Prognosis of patients is strongly influenced by the Ki67 in the residual disease at surgery. The integration of Ki67 with Residual Cancer Burden to form a Residual Proliferative Cancer Burden provides an attractive new end-point which may have generalisable applicability across different treatments. In all of these studies as well as others on multiple other biomarkers it is critical to understand the degree of reproducibility in tissue biopsies that most often sample less than 1% of the sometimes heterogenous tumour bed. Examples of the impact of this on expression profiles and exomic analyses will be shown.
Citation Format: Mitchell Dowsett. What relevance have hormones for breast cancer in the genomic era? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr BL-2.
Abstract ES5-1: Adherence and persistence with adjuvant aromatase inhibitor therapy
Authors: Henry Norah Lynn 
Published: May 2015

Abstract
Aromatase inhibitors (AI) are medications that inhibit the aromatase enzyme, which converts androgens to estrogens, resulting in suppression of estrogen production in postmenopausal women. Treatment of postmenopausal women diagnosed with hormone receptor positive breast cancer with adjuvant AI therapy for 5 years has resulted in significant improvements in disease free and overall survival. Despite their proven benefit, however, adherence to and persistence with AI therapy is poor. A key reason for non-persistence with therapy is the development of bothersome side effects that can have a negative impact on quality of life. Retrospective analyses have identified possible predictors of poor tolerance of therapy. Studies have also suggested that development of toxicity may be associated with better response to therapy. Because of the concern about non-persistence with therapy, especially in the setting of prescription of an oral medication for many years, there has been considerable research into understanding the mechanism underlying development of toxicity as well as treatment of these side effects. Ultimately the goal is to improve breast cancer survival outcomes while minimizing the negative impact of therapy on quality of life.
Citation Format: Norah Lynn Henry. Adherence and persistence with adjuvant aromatase inhibitor therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES5-1.