bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 925: Single nucleotide polypmorphisms in the estrogen receptor gene as a determining factor in Tamoxifen-treated ovarian cancer
Authors: Mojica Wilfrido , Mojica Paul , Sykes Don
Published: May 2015

Epithelial Ovarian Carcinomas (EOC) frequently present as late stage malignancies. Because of this lengthy, clinically silent period, a significant number of mutations may accumulate with each emerging clonal population. After surgical removal and chemotherapy, recurrent disease may still occur. Opting for hormonal therapy is a treatment consideration for those patients who have asymptomatic recurrence or, if they are not tolerating treatment well, may require a break from chemotherapy. However, because of the aggressive nature of EOC, hormonal treatment should be administered only if it will provide some efficacious benefit. The active metabolite of Tamoxifen (OH-tamoxifen) can function as a hormonal antagonistic agent to estrogen driven EOCs. However, single nucleotide variations and/or mutations in the ligand binding domain (LBD) of the estrogen receptor alpha (ESR1) gene may negatively affect the ability of OH-tamoxifen to bind and effect its desired action, resulting in wasted time and treatment. Identification of nucleotide variants/ mutations in the ESR1 LBD may be of clinical importance by identifying patients with EOC who may be better suited for treatment with other agents. In this study we identified twelve cases of ESR1(+) EOC in which the treating clinician had requested immunohistochemical confirmation of ESR1 expression. Four separate primer pairs were designed to encompass the amino acids responsible for OH-tamoxifen binding identified from a previous crystallography study. These same regions responsible for binding OH-tamoxifen were also queried in the dbSNP database for nucleotide variations. Representative tissue blocks with >80% tumor content were selected from each case. DNA was extracted from formalin fixed, paraffin embedded tissue sections and subjected to the polymerase chain reaction creating 48 different samples. The resulting amplicons were purified and sequenced, followed by basic local alignment analysis to the most recent NCBI homo sapien gene annotation for the ESR1 gene. No variants were identified in the dbSNP database for the regions of interest. Our results found only one silent nucleotide variation which was located in exon 10. Prior to this study the justification for using tamoxifen in EOC was empiric. Our results indicate that the absence of nucleotide variations in the critical ESR1 LBD for OH-tamoxifen provide scientific evidence and support for its’ continued usage as an optional treatment modality in ESR1(+)EOC.

Citation Format: Wilfrido Mojica, Paul Mojica, Don Sykes. Single nucleotide polypmorphisms in the estrogen receptor gene as a determining factor in Tamoxifen-treated ovarian cancer. [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 925. doi:10.1158/1538-7445.AM2014-925
Abstract 929: Identification of ZBTB20 as a novel oncogene associated with the gender bias occurrence of hepatocellular carcinoma
Authors: Keng Vincent W. , Tschida Barbara R. , Kuka Timothy P. , Moriarity Branden S. , Bell Jason B. , Largaespada David A.
Published: May 2015

The role of zinc finger and BTB domain containing 20 (ZBTB20) in hepatocellular carcinoma (HCC) is not well defined, as there are many discrepancies in the literature regarding its role in liver tumorigenesis. ZBTB20 has been implicated to play a role in liver cancer as a potential oncogene where increased expression is associated with poor survival. Conversely, it has been shown to be a transcriptional repressor of the alpha-fetoprotein (Afp) gene in adult liver using knockout studies, and reduced levels of ZBTB20 allow for upregulation of AFP with increased tumor severity in certain cases of HCC. Zbtb20 was initially identified as a candidate liver cancer gene in a forward genetic screen using the Sleeping Beauty (SB) insertional mutagenesis system in mice. In order to determine the role of ZBTB20 in liver cancer, the SB transposon system was used as a genetic tool to randomly integrate ZBTB20-expression vectors into the genome of fumarylacetoacetate hydrolase (Fah)-deficient mouse hepatocytes by hydrodynamic injection. This method of reverse genetics is a powerful tool for in vivo validation of novel oncogenes and tumor suppressor genes. Hepatocytes transgenic for ZBTB20 and in the context of tumor protein p53 (TP53) inactivation developed liver tumors in a male gender bias manner. Although ZBTB20 induced hepatic hypertrophy in both genders, hepatomegaly was observed exclusively in male animals. Interestingly, activation of the ß-catenin (Ctnnb1) dependent Wnt signaling pathway was observed in all male experimental injected animals, indicating the role of Zbtb20 in this important pathway for liver tumorigenesis. Taken together, these results implicate the role of ZBTB20 as a novel oncogene involved in the gender bias occurrence of HCC.

Citation Format: Vincent W. Keng, Barbara R. Tschida, Timothy P. Kuka, Branden S. Moriarity, Jason B. Bell, David A. Largaespada. Identification of ZBTB20 as a novel oncogene associated with the gender bias occurrence of hepatocellular carcinoma. [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 929. doi:10.1158/1538-7445.AM2014-929
Abstract 94: The role of Pik3ca in uterine gland morphogenesis and fertility in mice
Authors: Shin Heesung , Kim Tae Hoon , Yoo Jung-Yoon , Zhao Jean J. , Lydon John P. , Ha Un-Hwan , Jeong Jae-Wook
Published: May 2015

Pik3ca mutations are frequently observed in endometrial carcinomas. Inappropriate activation of PI3Kα-mediated signaling results in increased AKT-dependent or AKT-independent signaling. The PI3K/AKT signaling pathway plays a critical role in the maintenance of equilibrium between cell survival and apoptosis. In order to investigate the role of Pik3ca in uterine function and tumorigenesis, we generated a mouse model in which Pik3ca gene expression is ablated specifically in the PR-expressing cells (PRcre/+ Pik3caf/f). Ablation of Pik3ca was confirmed by real time PCR, western blot, and immunohistochemical analysis of the uteri. PRcre/+ Pik3caf/f mice were subfertile due to defective uterine development. PRcre/+ Pik3caf/f mice showed significantly decreased uterine weight compared Pik3caf/f mice at 2 months of age. Interestingly, PRcre/+ Pik3caf/f mice exhibited a defect of endometrial gland development. Number of glandular epithelia were significantly decreased in PRcre/+ Pik3caf/f mice compared to control Pik3caf/f mice. The expression of Foxa2, a specific glandular epithelial marker, was significantly decreased in PRcre/+ Pik3caf/f mice and apoptosis was significantly increased in the luminal epithelium of PRcre/+ Pik3caf/f mice. These results indicate that Pik3ca plays a role in female fertility and uterine development.

(This work was supported by NIH U54 HD007495 to J.P.L, Basic Science Research Program (2010-0009047) funded by the MEST, Korea to U-H.H., and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG to J.W.J.)

Citation Format: Heesung Shin, Tae Hoon Kim, Jung-Yoon Yoo, Jean J. Zhao, John P. Lydon, Un-Hwan Ha, Jae-Wook Jeong. The role of Pik3ca in uterine gland morphogenesis and fertility in mice. [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 94. doi:10.1158/1538-7445.AM2014-94
Abstract 958: Activation of COL11A1 by anticancer drugs through IGF-1R/PI3K pathway confers chemoresistance in ovarian cancer via activating NF-κB-mediated Twist1 expression
Authors: Wu Yi-Hui , Huang Yu-Fang , Chou Cheng-Yang
Published: May 2015

Epithelial ovarian carcinoma remains the most lethal gynecologic malignancy. While initial response to first-line therapy (consisting of surgical cytoreduction and combination platinum/taxane therapy) is usually effective, the majority of patients will ultimately recur with chemotherapy-resistant cancer and succumb to disease. Biomarkers that predict patient's responsiveness to chemotherapy might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the molecular mechanisms of collagen type XI alpha 1 (COL11A1) in chemo-resistance of ovarian cancer. We analyzed the expression profiles of 60 epithelial ovarian cancer tissue samples obtained at first cytoreductive surgery to identify genes linked with chemotherapy response. Among the 47 selected genes, collagen type XI alpha 1 (COL11A1) was the most highly elevated in chemo-resistance tumors. Small interference RNA-mediated specific reduction in COL11A1 protein levels increased the sensitivity to cisplatin and taxol in ovarian cancer cells. A combination of experimental approaches, including real-time RT-PCR, western blotting, luciferase assay and chromatin immunoprecipitation (ChIP) assays, showed that COL11A1 knockdown attenuated Twist1 expression and suppressed binding of NF-κB to its putative Twist1 promoter binding site, suggesting that the NF-κB/Twist1 axis is upregulated by COL11A1. Cisplatin and taxol treatment triggers the activation of IGF-1R/PI3K signaling cascades, leading to activation of COL11A1 and Twist1. Pharmacological inhibition of PI3K abrogated the cisplatin and taxol-triggered, COL11A1-dependent chemo-resistance. Furthermore, the c/EBPβ binding site on the COL11A1 promoter was identified as the major determinant of cisplatin and taxol-dependent COL11A1 activation. Analysis of 88 ovarian cancer patients indicated that high COL11A1 mRNA levels are significantly associated with high Twist1 mRNA levels and poor clinical outcome. We conclude that activation of COL11A1 by anti-cancer drugs through IGF-1R/PI3K pathway confers chemo-resistance in ovarian cancer cells via activating NF-κB-mediated Twist1 expression.

Citation Format: Yi-Hui Wu, Yu-Fang Huang, Cheng-Yang Chou. Activation of COL11A1 by anticancer drugs through IGF-1R/PI3K pathway confers chemoresistance in ovarian cancer via activating NF-κB-mediated Twist1 expression. [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 958. doi:10.1158/1538-7445.AM2014-958
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

Lymphomas are common (1/30 Canadians), but responses to chemotherapy depend on the tumour biology. We sequenced > 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

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

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

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

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

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

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

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

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

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.
Abstract ES8-1: Spatial and temporal evolution of breast cancer
Authors: Yates Lucy
Published: May 2015

Cancers are ecosystems of genetically related clones, competing across space and time for limited resources. To understand the clonal structure of breast cancers we applied a combination of high depth targeted capture and whole genome sequencing to multiple samples from individual primary breast cancers and metastases. Our work has identified that the extent of subclonal diversification within the primary tumor varies considerably among patients and encompasses many spatial patterns, including local growth, intraductal dissemination and clonal intermixture. Landmarks of disease progression, such as acquiring invasive or metastatic potential are frequently associated with the emergence of distinct driver events and sometimes arise within detectable subclones of antecedent lesions, suggesting that subclonal mutations in the primary tumor could be relevant if actionable. The impact of structural variation on the breast cancer driver landscape is relatively understudied, but our work indicates that structural variation frequently makes a major contribution to the somatic mutational landscape late in disease evolution. Thus, the interplay of mutation, growth and competition drives clonal structures of breast cancer that are complex, variable across patients and clinically relevant.

Citation Format: Lucy Yates. Spatial and temporal evolution of breast cancer [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 ES8-1.
Abstract ES8-3: Epigenetic heterogeneity in cancer
Authors: Polyak Kornelia
Published: May 2015

Heterogeneity of cancer cells within tumors is a major challenge in clinical oncology as it underlies tumor progression and therapeutic resistance. Cancer cells can have varying genotypes, epigenetic states such as DNA methylation and chromatin patterns, and phenotypes. The high frequency of somatic mutations in genes encoding for epigenetic regulators and transcription factors in breast cancer highlight the importance of perturbed epigenetic programs in breast tumorigenesis. Some forms of epigenetic heterogeneity within tumors is due to variability for cellular differentiation states such as luminal and basal features, whereas other forms reflect transient cellular states sometimes triggered by microenvironmental signals. Cellular epigenetic heterogeneity within tumors thought to play key roles in metastatic progression and therapeutic resistance. Thus, its better understanding and our ability to modulate it are critical for the design of more effective cancer treatment strategies. In contrast to genetic alterations, epigenetic states are reversible and due to intense research in this area, the number of compounds for their modulation is rapidly increasing. Because epigenetic modulators likely to work best in combination with other agents, the design of clinical trials testing their efficacy requires novel approaches.

Citation Format: Kornelia Polyak. Epigenetic heterogeneity in cancer [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 ES8-3.
Abstract ES9-3: Adjuvant and neoadjuvant therapy: Current practice and future approaches
Authors: Winer Eric P.
Published: May 2015

Triple negative breast cancer (TNBC) is accounts for approximately 10-15% of all breast cancer and is associated with a higher risk of disease recurrence, particularly early recurrence, than the other breast cancer subtypes. From a genomic standpoint, TNBC is heterogeneous, though we do not know how to incorporate this heterogeneity in treatment decisions. At the present time, there are no targeted systemic therapies for TNBC, and standard/neoadjuvant treatment consists of chemotherapy. Most treatment regimens include both an anthracyline and a taxane and involve 6-8 cycles of therapy, though simpler regimens such as AC x 4, TC x 4, or CMF x 6 remain an option for patients with a stage I disease. Neoadjuvant chemotherapy is often administered to decrease the extent of breast or axillary surgery. Outside of a clinical trial, anthracycline/taxane-based regimens remain the standard of care in the neoadjuvant setting. The addition of the platinum salts to standard therapy increases the proportion of patients who achieve a pathologic complete response, but it is unclear if these agents extend disease-free or overall survival. It is also unknown which patients benefit from the platinum salts and whether these agents should be added to or substituted for some portion of the standard regimen. Other investigational regimens, such as those including the PARP inhibitors, are also being studied in the neoadjuvant setting. On an individual patient level, response to neoadjuvant therapy is closely tied to outcome. Patients with a pathologic complete response have a far better outcome than those with residual disease, particularly those with extensive residual disease. However, it is unknown if the achievement of a higher pathologic complete response within a comparative trial leads to an improvement in disease-free or overall survival. Similarly, it is unknown if the addition of agents such as the platinum salts or other investigational treatmens can reduce the risk of recurrence in patients with residual disease after standard therapy. Ultimately, improved outcomes will be achieved through carefully controlled adjuvant and neoadjuvant trials conducted in close collaboration with laboratory investigators. It is likely that our understanding of the underlying biology of triple negative disease as well as our treatment approaches will evolve significantly in the next decade.

Citation Format: Eric P. Winer. Adjuvant and neoadjuvant therapy: Current practice and future approaches [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 ES9-3.
Abstract MS1-1: Characterising cancer risks for carriers of mutations in BRCA1, BRCA2, PALB2, and RAD51C genes
Authors: Antoniou Antonis C.
Published: May 2015

The presentation will provide an overview of the latest developments and challenges in understanding the penetrance of mutations in the BRCA1, BRCA2, PALB2 and RAD51C genes. Genetic counselling currently relies on average cancer risk estimates obtained from retrospective penetrance studies involving large numbers of families segregating mutations in these genes. The talk will present penetrance estimates from ongoing prospective analyses, based on data from the International BRCA1/2 Carrier Cohort Study, the largest cohort of BRCA1/2 mutation carriers worldwide that includes >10,000 mutation carriers at baseline with prospective follow-up information. Several common alleles and other risk factors have now been shown to modify breast cancer risk for BRCA1 and BRCA2 mutation carriers. The talk will review the latest efforts and results from the Consortium of Investigators of Modifiers of BRCA1/2 to identify genetic modifiers of risk and provide individualised cancer risks for BRCA1 and BRCA2 mutation carriers on the basis of polygenic risk scores. We will also present penetrance estimates based on analyses of combined data from families segregating mutations in PALB2 and RAD51C, the largest efforts of their kind. Finally the presentation will demonstrate how the effects of common and rare breast cancer susceptibility variants are incorporated into the BOADICEA model to provide comprehensive risks of developing breast cancer in the future.

Citation Format: Antonis C. Antoniou. Characterising cancer risks for carriers of mutations in BRCA1, BRCA2, PALB2, and RAD51C genes [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 MS1-1.
Abstract OT1-1-06: A phase I study of LDE225 in combination with docetaxel in patients with triple negative (TN) advanced breast cancer (ABC): GEICAM/2012-12 (EDALINE study)
Authors: Martin Miguel , Ruiz-Borrego Manuel , Trigo José M , Antolin Silvia , Garcia-Saenz Jose A , Hernando Andres , Ocaña Alberto , Rojo Federico , Lopez-Tarruella Sara , Corral Jesus , Ribelles Nuria , Calvo Lourdes , Moreno Fernando , Caballero Rosalia , Carrasco Eva
Published: May 2015

Background: LDE225 is a potent and selective oral inhibitor of Smo, a key component of the hedgehog (Hh) signaling pathway. Up-regulation of the Hh pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer. Here we report an ongoing phase I study exploring the combination of LDE225 with docetaxel in TN ABC patients to identify the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D) (ClinicalTrials.gov Identifier: NCT02027376).

Trial Design: Eligibility criteria include patients with TN ABC candidates to receive treatment with docetaxel that have received a maximum of 3 prior chemotherapy regimens. Those patients with CNS involvement are also candidates if treated and clinically stable. Treatment consists of 21-day cycles with docetaxel 75mg/m2 on day 1, every 21 day and LDE225 once daily. We use a standard 3+3 design in sequential cohorts (3 dose levels (DL) of LDE225: 400mg once daily (DL1), 600mg once daily (DL2), 800mg once daily (DL3); and a DL-1: LDE225 400mg once daily and docetaxel 60mg/m2 every three weeks). The primary endpoint is the MTD and RP2D of the combination; secondary endpoints include evaluation of safety and tolerability, in addition to pharmacodynamic (PD) and pharmacokinetic (PK) studies. Patients are treated until radiologic or symptomatic progression or unacceptable toxicity occurs. PK will be performed to evaluate whether LDE225 influences the pharmacology of docetaxel. PD assessments include Hg gene expression signature associated to pathway activation in tumor samples and changes in Smo related biomarkers in skin and blood correlative samples. Efficacy will be measured in terms of time to progression and objective response rate. A minimum of 9 and a maximum of 18 patients will be included in this phase I. The study is approved by ERBs and Competent Authority and already recruiting patients (two patients included in DL1).

Citation Format: Miguel Martin, Manuel Ruiz-Borrego, José M Trigo, Silvia Antolin, Jose A Garcia-Saenz, Andres Hernando, Alberto Ocaña, Federico Rojo, Sara Lopez-Tarruella, Jesus Corral, Nuria Ribelles, Lourdes Calvo, Fernando Moreno, Rosalia Caballero, Eva Carrasco. A phase I study of LDE225 in combination with docetaxel in patients with triple negative (TN) advanced breast cancer (ABC): GEICAM/2012-12 (EDALINE study) [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 OT1-1-06.
Abstract OT2-4-02: Testing BRCA 1/2 mutation using next generation sequencing (BRCANGS)
Authors: Park Hyung Seok , Park Seo Jin , Kim Sanghwa , Ryu Jegyu , Kim Jee Ye , Park Seho , Kim Seung Il , Sohn Joo Hyuk , Choi Jong Rak
Published: May 2015

Testing BRCA 1/2 mutation is important for patients with breast cancer, and Sanger sequencing is a standard method to identify BRCA 1/2 mutation. Next generation sequencing (NGS) is a high-throughput parallel sequencing that can provide genetic information with high accuracy. NGS is a faster and cost-effective method to detect gene mutations compared to Sanger sequencing. This study is a prospective non-randomized obsevational study which evaluates the clinical role of NGS testing for BRCA 1/2 compared to Sanger sequencing. Eligibility criteria are wome aged 19 to 80 years, patients with breast or ovarian cancer history in 2nd degree family members, male breast cancer, bilateral breast cancer, patient with breast cancer under 40 year of age, simultaneous breast and ovarian cancer, patients with epithelial ovarian cancer, and breast cancer with other simultaneous extramammary malignancy. Primary endopont of the study is the overall accuracy of NGS compared to Sanger sequencing. Seconary endponts are sensitivity, specifcity, false negative, and false positive rates of NGS compared to Sanger method. Target accrual of the pilot study is 12 patients, and futher extension of patients accrual is scheduled after the anlaysis of the pilot study. This study is approved by institutial review board of Severance Hospital. The study is conducted and planned by Prof. HS Park, Yonsei University College of Medicine, Seoul, Korea and supported by Korea Breast Cancer Foundation. ClinicalTrials.gov identifier is NCT02151747.

Citation Format: Hyung Seok Park, Seo Jin Park, Sanghwa Kim, Jegyu Ryu, Jee Ye Kim, Seho Park, Seung Il Kim, Joo Hyuk Sohn, Jong Rak Choi. Testing BRCA 1/2 mutation using next generation sequencing (BRCANGS) [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 OT2-4-02.