bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1048: Targeted BRAF therapy attenuates the promotional activity of estrogen in thyroid cancer.
Authors: Hanly Elyse K. , Rajoria Shilpi , George Andrea L. , Suriano Robert , Geliebter Jan , Pantelides Harry , Shin Edward J. , Tiwari Raj K. 
Published: August 2014

Abstract
Thyroid cancer, which is three to four times more prevalent in women than men, is the most common endocrine-related cancer in the United States and its incidence has increased in the past three decades. Among various genetic lesions identified in thyroid cancer, the BRAF V600E mutation is found in 50% of papillary thyroid cancers and affords an opportunity for targeted drug therapy. Our laboratory identified estrogen as a promotional factor in thyroid cancer, as estrogen enhances proliferation, migration, and invasion of thyroid cancer cells in vitro. Since the mitotic activity of estrogen is partially mediated by the mitogen-activated protein kinase (MAPK) pathway, we hypothesized that a targeted BRAF V600E inhibitor, PLX4032, would inhibit estrogen-mediated tumor-promoting activity. Results demonstrate that PLX4032 abrogates estrogen-induced increases in proliferation and invasion of BRAF V600E-mutated BCPAP papillary thyroid cancer cells in a dose-dependent manner. In contrast, this phenomenon was not observed in Nthy-ori 3-1 thyroid cells, which are wild-type immortalized thyroid cells without the BRAF V600E mutation. Expression of estrogen receptor is not modulated by PLX4032 treatment, indicating that PLX4032 targets signal transduction pathways in estrogen-responsive thyroid cells. PLX4032 down-regulates the expression of key signaling molecules of the BRAF pathway, including mitogen-activated protein kinase kinase (p-MEK), extracellular-signal regulated kinases (p-ERK), and mammalian target of rapamycin (p-mTOR) in BRAF-mutated BCPAP cells and does not alter the expression of these signaling molecules in wild-type Nthy-ori 3-1 cells. These results demonstrate a direct interlinking of a genetic lesion amenable to drug therapy with the promotional activity of estrogen. These findings will lead to an evaluation of combinational therapy including anti-estrogens and PLX4032 in preclinical animal models and a subset of patients harboring the BRAF V600E mutation. Targeting growth-promoting signal transduction pathways constitutively activated by genetic lesions will ultimately aid in overcoming resistance to traditional radioactive iodine therapy in patients with specific mutations such as BRAF V600E.
Citation Format: Elyse K. Hanly, Shilpi Rajoria, Andrea L. George, Robert Suriano, Jan Geliebter, Harry Pantelides, Edward J. Shin, Raj K. Tiwari. Targeted BRAF therapy attenuates the promotional activity of estrogen in thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2013-1048
Abstract 1051: EGFR inhibitors attenuate caspase-independent cell death and confer negative effects on cisplatin .
Authors: Yamaguchi Hirohito , Hsu Jennifer L. , Chen Chun-Te , Wang Ying-Nai , Hsu Ming-Chuan , Chang Shih-Shin , Du Yi , Ko How-Wen , Herbst Roy S. , Hung Mien-Chie 
Published: August 2014

Abstract
EGFR tyrosine kinase inhibitors (TKIs) have demonstrated exciting results and led to advanced therapy trials in combination with chemotherapy. However, clinical studies have raised an important question why the antagonism between TKI and chemotherapy occurs in lung cancer patients only with wildtype but not mutant EGFR. In this study, we further explored the mechanism through which gefitinib gives rise to the negative effects when combined with cisplatin in wildtype EGFR lung cancer cells. We found that gefitinib inhibited cisplatin-induced caspase-independent cell death (CID) but not caspase-dependent cell death (apoptosis). In wildtype EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis and therefore compromising the efficacy of cisplatin. Moreover, inhibition of the EGFR/ERK/AKT pathway by gefinitib activated FOXO3a and subsequently reduced reactive oxygen species (ROS) induced by cisplatin treatment and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, which are known to induce ROS-mediated CID, strongly enhanced the effect of cisplatin in wildtype EGFR cells. Taken together, our findings provide a possible explanation for the previously failed clinical trials as well as a novel insight into future cancer therapy.
Citation Format: Hirohito Yamaguchi, Jennifer L. Hsu, Chun-Te Chen, Ying-Nai Wang, Ming-Chuan Hsu, Shih-Shin Chang, Yi Du, How-Wen Ko, Roy S. Herbst, Mien-Chie Hung. EGFR inhibitors attenuate caspase-independent cell death and confer negative effects on cisplatin . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1051. doi:10.1158/1538-7445.AM2013-1051
Abstract 1052: Refametinib (BAY 86-9766): An allosteric inhibitor of MEK1/2, potently inhibits tumor growth in patient-derived xenograft models of gastric cancer.
Authors: Hung Huynh T. , Ong Richard , Soo Khee Chee , Puehler Florian , Scholz Arne , Mumberg Dominik , Zopf Dieter , Ziegelbauer Karl 
Published: August 2014

Abstract
Background: Gastric cancer (GC) is a prevalent and deadly disease. Because the Ras/Raf/MEK/ERK signaling cascade plays a critical role in signal transduction pathways that regulate growth factor response, angiogenesis, tumor cell proliferation, and apoptosis, blocking this signaling pathway could thus have therapeutic efficacy. This study aims to target this pathway in preclinical models of GC with refametinib (BAY 86-9766, RDEA119), an orally available, allosteric inhibitor of MEK1/2.
Methods: Eight patient-derived GC xenograft models with different histotypes were treated orally with refametinib or vehicle and tumor growth was monitored using caliper measurements. Tissue sections of vehicle- or refametinib-treated xenografts were analyzed by immunohistochemistry for cell proliferation, apoptosis and microvessel area, using antibodies against p-Histone H3Ser10, cleaved PARP and CD31, respectively. Tumor lysates were analyzed by Western Blotting with antibodies for effects on marker proteins for proliferation, apoptosis and angiogenesis.Results: Refametinib demonstrated significant tumor growth inhibition ranging from 66-87% in eight GC models at a dose of 15 mg/kg/d. Refametinib inhibited cell proliferation by 2-4 fold as observed by reduced staining for p-Histone H3Ser10. Increased staining for caspase-cleaved p85 PARP by 1.5 to 9 fold was detected, indicating that refametinib induced apoptosis. Furthermore the compound significantly inhibited angiogenesis in 2 of 8 models by 3-fold compared to the vehicle-treated group as indicated by reduced CD31 staining. Reduced cell proliferation and induction of apoptosis were associated with decreased levels of p-ERK1/2, p-cdk2Thr14/Tyr15, p-p90RSKSer359/363, p-p70S6KThr421/Ser424, p-4EBP1Thr70, p-S6RSer235/236 and p-eIF4ESer209 and elevation of p-AktSer473, Bim and cleaved PARP. Conclusion: We show that single-agent refametinib has significant anti-tumor activity in patient-derived gastric cancer preclinical models. Our findings support further investigation of refametinib either in monotherapy or in combination with inhibitors of the PI3K-AKT-mTOR pathway in the treatment of GC.
Citation Format: Huynh T. Hung, Richard Ong, Khee Chee Soo, Florian Puehler, Arne Scholz, Dominik Mumberg, Dieter Zopf, Karl Ziegelbauer. Refametinib (BAY 86-9766): An allosteric inhibitor of MEK1/2, potently inhibits tumor growth in patient-derived xenograft models of gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1052. doi:10.1158/1538-7445.AM2013-1052
Abstract 1055: Regorafenib-mediated potent and reversible inhibition of human hepatocellular carcinoma (HCC) cell growth, migration and AFP.
Authors: Carr Brian I. , D'Alessandro Rosalba , Refolo Maria Grazie , Iacovazzi Minna , Lippolis Catia , Messa Caterina , Cavallini Aldo 
Published: August 2014

Abstract
Background: Most HCC presents at an advanced stage, for which there are few effective treatments. Sorafenib enhanced survival by 10 weeks in a randomized trial and was approved by FDA. Sorafenib is a base for building better treatments. Regorafenib (Fluoro-Sorafenib, BAY 73-4506 or Stivarga) is a more potent analog in current clinical trials.
Methods: HCC cell lines were grown in culture. Growth was assessed using MTT, migration by scratch assay, medium AFP by clinical chemoluminescent immunometric method, cell AFP and kinases by western blot and cell AFP mRNA by real-time PCR.
Results: HCC growth in different cell lines was inhibited by Regorafenib 1-5 μM IC50. Removal of drug from the medium resulted in resumption of normal cell growth even after subsequent sub-culture. This recovery could be partially blocked by low concentrations of vitamin K1 or doxorubicin that were not growth inhibitory when used alone. Regorafenib 1 μM pre-treatment for 2 weeks resulted in very slow recovery. Cell treatment in culture with Regorafenib resulted in early decreases in phospho-ERK levels, followed by return to baseline levels within hours, despite continuous drug exposure. Cell growth recovery after Regorafenib was associated with induction of high phospho-JNK levels and the recovery was blocked by the actions of a JNK inhibitor. Regorafenib also inhibited cell migration and both AFP mRNA by PCR and cellular AFP on WB, and cell culture medium levels of AFP, but at much lower concentrations than needed (0.1-1 μM) for growth inhibition. Removal of drug also resulted in recovery of cell migration, but this recovery could be partially blocked by addition of vitamin K1 or doxorubicin, at drug concentrations that were not themselves inhibitory of cell migration. Even at 1 μM, Regorafenib slowed cell growth and migration after prolonged cell exposure and sub-culture. Pre-treated and recovering cells were much more sensitive to inhibition of migration by low concentration vitamin K1 6.25 μM or doxorubicin 0.01 μM. Conclusions: Regorafenib is a potent inhibitor of HCC cell line growth and works even at very low drug concentrations when cells are exposed for prolonged times. The effects are reversible and JNK could be a critical player in this process. Very low concentrations inhibit HCC cell migration and AFP. Regorafenib appears to be a promising new agent.
Citation Format: Brian I. Carr, Rosalba D'Alessandro, Maria Grazie Refolo, Minna Iacovazzi, Catia Lippolis, Caterina Messa, Aldo Cavallini. Regorafenib-mediated potent and reversible inhibition of human hepatocellular carcinoma (HCC) cell growth, migration and AFP. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1055. doi:10.1158/1538-7445.AM2013-1055
Abstract 1062: Imaging DNA damage response (DDR) during oncogenesis.
Authors: Cornelissen Bart , Able Sarah , Kersemans Veerle , Vallis Katherine A. 
Published: August 2014

Abstract
Introduction: DNA damage repair (DDR) signalling is upregulated during tumorigenesis and acts as a p53-mediated block on proliferation. Expression of the DNA double strand break (DSB) repair protein, γH2AX, is induced by the activated kinases pATM or pATR during oncogenesis. Previously, we showed that γH2AX presents an abundant epitope for non-invasive in vivo imaging of DSBs. We used 111In-labelled anti-γH2AX antibodies, conjugated to the cell penetrating peptide, TAT, to non-invasively image DDR during oncogenesis in a genetically engineered mouse model of HER2/neu-overexpression driven breast cancer.
Methods: Balb/neuT mice, genetically modified to express mutated rat neuT under MMTV promotor control, form multiple palpable carcinomas in mammary fat pads when animals are 130 days old. SPECT images were acquired weekly from balb/neuT mice (age 40-140 days; n=23) 24 h after i.v. injection of 111In-labelled anti-γH2AX-Tat or the non-selective agent, 111In-rIgG-Tat using a small animal SPECT/CT scanner. 111In uptake in fat pads was determined using volume of interest analysis. 111In uptake of &gt;5%ID/g was deemed positive. Anatomical and histological changes were assessed at different ages using DCE-MRI imaging and immunohistochemistry.
Results: Balb/neuT mice that were 80 days old developed multiple hyperplastic and dysplastic lesions in mammary fat pads. γH2AX foci were observed in these regions in balb/neuT mice that were 80-100 days old (10-15 foci/cell), but were less numerous in overt tumor tissue in 130-day-old mice (4-5 foci/cell). γH2AX foci were not observed in normal tissues in older mice (0 foci/cell), in mammary fat pads in younger mice (0 foci/cell), or in wild type mice (0 foci/cell). Serial SPECT imaging revealed a 7-fold increase in 111In-anti-γH2AX-Tat accumulation in mammary fat pads in mice 80-110 days old (up to 8.5 %ID/g), compared to non-specific control (P=0.0007), but not in younger or older mice (P&gt;0.05). Repeated SPECT imaging itself did not influence tumor occurrence (P&gt;0.05). The median time to detection of positive tissue was 96 days, much sooner than detection of lesions &gt;150 μm by DCE-MRI (117 days), or palpation (130 days) (P&lt;0.0001).
Conclusion: Using a γH2AX-targeted radiopharmaceutical, we were able to image the DNA damage response during neuT-mediated oncogenesis in balb/neuT mice. DDR imaging identified neoplastic tissue significantly earlier than anatomical imaging. These results suggest that γH2AX imaging has potential as a screening tool for cancer-prone individuals.
Citation Format: Bart Cornelissen, Sarah Able, Veerle Kersemans, Katherine A. Vallis. Imaging DNA damage response (DDR) during oncogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1062. doi:10.1158/1538-7445.AM2013-1062
Abstract 1069: Vav3 enhances androgen receptor splice variant activity and is critical for castration resistant prostate cancer growth and survival.
Authors: Peacock Stephanie , Fahrenholtz Cale D. , Burnstein Kerry L. 
Published: August 2014

Abstract
Advanced or metastatic prostate cancer is treated by androgen deprivation; however, patients inevitably relapse with castration resistant prostate cancer (CRPC) that grows independently of androgen. However, CRPC remains dependent on androgen receptor (AR) signaling, which includes constitutive, ligand–independent action of naturally occurring AR splice variants. For example, the AR splice variant AR3 (also termed AR–V7) is expressed in CRPC and is linked to poor prognosis. Vav3, a Rho GTPase guanine nucleotide exchange factor, is an AR coactivator that is up–regulated in human prostate cancer as compared to benign tissue as well as in pre–clinical models of CRPC. Vav3 confers castration–resistant growth to androgen–dependent human prostate cancer cells and increased expression has been linked to increased clinical biochemical relapse. Despite the importance of AR coactivators in promoting CRPC, the potential role of these regulatory proteins in modulating AR splice variant activity is unknown. We examined the contributions of Vav3 to AR activity in two CRPC cell lines that naturally express relatively high levels of Vav3 and AR3. Vav3 or AR3 knockdown greatly attenuated cell proliferation, soft agar growth and ligand–independent AR activity. Vav3 potently enhanced the transcriptional activity of AR3 and another clinically relevant AR splice variant ARv567es. Furthermore, Vav3 enhanced AR splice variant activity through a distinctly different mechanism than Vav3 coactivation of full length AR. Vav3 knockdown resulted in lowered nuclear AR3 levels while total AR3 protein and mRNA levels remained static. Conversely, overexpression of Vav3 resulted in increased nuclear AR3. Co–immunoprecipitation revealed that AR3 and Vav3 interact. These novel data demonstrating physical and functional interactions between Vav3, a unique AR coactivator, and an AR splice variant provide insights into the mechanisms by which Vav3 exploits and enhances AR signaling in the progression to CRPC.
Citation Format: Stephanie Peacock, Cale D. Fahrenholtz, Kerry L. Burnstein. Vav3 enhances androgen receptor splice variant activity and is critical for castration resistant prostate cancer growth and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2013-1069
Abstract 107: Pre-diagnostic levels of serum one-carbon metabolism biomarkers and risk of hepatocellular carcinoma.
Authors: Butler Lesley M. , Wang Renwei , Bottiglieri Teodoro , Gao Yu-Tang , Yuan Jian-Min 
Published: August 2014

Abstract
Pre-diagnostic levels of serum one-carbon metabolism biomarkers and risk of hepatocellular carcinoma
BACKGROUND. It is well established that rats fed diets deficient in choline and methionine spontaneously develop hepatocellular carcinoma (HCC). Tumor DNA from these animals show a characteristic hypomethylation pattern, suggesting that disruption of the one-carbon metabolism (1CM) pathway may be an underlying mechanism for hepatocarcinogenesis. Prospective epidemiological data on circulating levels of 1CM biomarkers in relation to HCC risk have been lacking.
METHODS. We prospectively examined the association between prediagnostic serum concentrations of betain, choline, cystathionine, homocysteine (Hcy), methionine, 5-methyltetrahydrofolate (5-MTHF), pyridoxal-5-phosphate (PLP, the bioactive form of vitamin B6), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), and risk of developing HCC among 297 incident HCC cases and 631 matched controls from a cohort of 18,244 men in Shanghai, China. Conditional logistic regression method was used to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for smoking, alcohol use, hepatitis B surface antigen (HBsAg) seropositivity and chronic liver disease.
RESULTS. Higher serum levels of PLP were associated with statistically significantly reduced risk of HCC. The ORs (95% CIs) for the 2nd, 3rd, and 4th quartiles of serum PLP were 0.52 (0.32, 0.85), 0.57 (0.35, 0.93) and 0.35 (0.20, 0.60), respectively, compared with the 1st quartile (Ptrend&lt;0.01). Among men with positive HBsAg, doubling serum choline concentration was associated with a statistically significant 58% decrease in HCC risk (OR=0.42; 95% CI: 0.19, 0.92) and doubling serum methionine concentration was positively associated with HCC risk (OR=2.94; 95% CI: 1.27, 6.82). Serum levels of cystathionine were associated with increased risk of HCC among all subjects (OR=1.92; 95% CI: 1.14, 3.21; Ptrend=0.01, comparing the 4th to 1st quartile). There was no association for HCC risk with circulating levels of 5-MTHF, Hcy, SAM, or SAH.
CONCLUSION. Choline and PLP may be protective against the development of HCC whereas circulating methionine may be a risk factor for developing HCC, especially among high-risk individuals. Future investigation is warranted to test whether diets high in vitamin B6 are effective in preventing HCC development in high-risk populations.
Citation Format: Lesley M. Butler, Renwei Wang, Teodoro Bottiglieri, Yu-Tang Gao, Jian-Min Yuan. Pre-diagnostic levels of serum one-carbon metabolism biomarkers and risk of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 107. doi:10.1158/1538-7445.AM2013-107
Abstract 1071: Impact of AR activation status on the DNA damage response.
Authors: Goodwin Jonathan F. , Schiewer Matthew J. , Feng Felix Y. , Knudsen Karen E. 
Published: August 2014

Abstract
Recent evidence implicates the androgen receptor (AR) as a critical modulator of the DNA damage response in prostate cancer. Treatment for locally advanced disease depends on combined radiation therapy and ablation of AR function, and clinical evidence strongly supports the contention that active AR reduces the response to radiotherapy. Moreover, it was reported in vitro that AR activation can induce DNA damage at sites of active transcription, thus providing additional evidence for crosstalk between the DNA damage response and AR pathways. Despite these observations, the underpinning mechanism by which AR alters the response to DNA damage remains unknown.
Several lines of evidence will be discussed which illuminate a role for AR in the response to DNA damage. First, investigation in a battery of hormone-therapy sensitive prostate cancer cells (in which AR activity remains dependent on ligand binding) and in castrate resistant tumor cells (reflecting advanced disease wherein AR activity is enhanced) showed that androgen depletion enhances the response to ionizing radiation. Restoration of dihydrotestosterone reduced the response to radiation, thus demonstrating that ligand-induced AR activity promotes a resistance to radiation. Second, the mechanism by which AR promotes radioresistance was addressed. Preliminary findings indicate that in the presence of DNA damage, AR dramatically alters the rate of DNA damage repair independent of significant effects on cell cycle. Moreover, these studies uncovered an unexpected role for androgen-activated AR to alter expression and subsequent activity of genes critical for the DNA damage response, possibly through differential recruitment of AR to loci of key players in the response to damage. Finally, a series radioresistant prostate cancer model systems were developed, wherein the impact of AR on acquired radioresistance is under investigation; early studies in these models indicate that altered AR output is associated with acquired radioresistance. Combined, the studies to be presented reveal novel functions of androgen and AR in controlling the molecular and cellular response to DNA damage, and provide the basis for future studies directed at targeting DNA-damage specific AR activity in the course of human disease.
Citation Format: Jonathan F. Goodwin, Matthew J. Schiewer, Felix Y. Feng, Karen E. Knudsen. Impact of AR activation status on the DNA damage response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1071. doi:10.1158/1538-7445.AM2013-1071