bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 972: Direct activation of pro-apoptotic BAX as a novel strategy for cancer therapy
Authors: Gavathiotis Evripidis , LaBelle James L. , Reyna Denis , Bellairs Joseph , Walensky Loren D. 
Published: August 2012

Abstract
BCL-2 family proteins are essential regulators of cellular life and death and, when deregulated, contribute to the development, maintenance, and chemoresistance of human cancer. Anti-apoptotic members contribute to cancer pathogenesis by sequestering the α-helical BH3 death domains of their pro-apoptotic counterparts such as BAX. The anti-apoptotic groove that binds and neutralizes BH3 helices has been successfully targeted by small molecules and stapled peptides in an effort to “inhibit the inhibitors” of apoptosis. Using a Stabilized Alpha-Helix of BCL-2 domain (SAHB) modeled after the BIM BH3 helix, we previously identified a geographically distinct BH3-binding groove that mediates the direct activation of BAX, suggesting a new strategy for inducing apoptosis by flipping BAX's “on switch”. Engagement of the novel site by BIM SAHB directly activates BAX (Gavathiotis et al. Nature, 2008), unleashing a succession of key conformational changes that culminates in the formation of toxic mitochondrial pores (Gavathiotis et al. Mol Cell, 2010). Here, we demonstrate that BIM SAHB effectively overcomes the apoptotic blockades of a series of diverse hematologic cancer cells by broadly targeting inhibitory anti-apoptotic complexes and directly activating BAX. Importantly, BIM SAHB induces dose-responsive caspase 3/7 activation and the morphologic features of apoptosis. To identify a BAX-selective agent, we further performed a computational screen to identify BAX activator molecules (BAMs) capable of directly engaging the BAX trigger site. We demonstrate by competitive fluorescence polarization binding assays and NMR analyses that BAM7 engages the BAX trigger site and, as a result, promotes the functional oligomerization of BAX. Strikingly, the molecule does not interact with the canonical BH3 binding pocket of anti-apoptotic proteins and induces cell death in a BAX-selective fashion. These first stapled peptide and small molecule gain-of-function modulators of a BCL-2 family protein highlight a new pharmacologic paradigm for induction of cancer cell apoptosis through direct activation of BAX.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 972. doi:1538-7445.AM2012-972
Abstract 977: Elevated MDM2 protein contributes to activity of MDM2 antagonists by enabling p53 induction of antitumor microRNAs
Authors: Xia Mingxuan , Huang Baoying , Chu Wei , Vassilev Lyubomir T. 
Published: August 2012

Abstract
Small-molecule inhibitors of p53-MDM2 binding, the nutlins, can free p53 from MDM2 control and effectively activate its growth suppressive and pro-apoptotic activity in cancer cells (Vassilev et al., Science, 2004, 303, 844). Optimized members of this family of molecules are currently under clinical investigation as novel therapeutic modality for cancers expressing wild-type p53. We have shown previously that MDM2 antagonists are most effective in cancer cells that overproduce MDM2 as a result of mdm2 gene amplification (Tovar et al., PNAS, 2006, 103, 1888). Here, we show that reduction of MDM2 protein by RNA interference decreases the effectiveness of nutlin-3a in osteosarcoma cells with mdm2 gene amplification, suggesting that MDM2 protein contributes to antitumor activity of MDM2 antagonists. In search of the mechanism behind this phenomenon, we found that nutlin-induced p53 activates the transcription of a specific subset of microRNAs in cancer cells with mdm2 amplification but not in cells expressing normal levels of MDM2 protein. Five specific members of the class (miR1, miR133, miR141, miR184, miR375) were studied and showed that their p53-dependent transcription is also dependent on the presence of high levels of MDM2 protein, generated by continuous p53 activation of MDM2 in the presence of nutlin. Weak p53 response elements were found in the promoter regions of all five miRs and p53 binding was conformed by ChIP analysis of cell lysates and p53 reporters in experiments with miR375. Transcriptional cofactor p300 was found elevated in cancer cells with mdm2 gene amplification and dependent on the presence of high MDM2 protein levels. Our experimental data suggests that in the presence of high p300, and high MDM2, generated by nutlin treatment, p53 acquires the ability to activate weak p53-responsive miR promoters in MDM2-amplified cells. Interestingly, miR mimics of two of the five p53-induced miRs showed growth suppressive effects in cancer cells and enhanced the activity of low dose nutlin-3a. These findings reveal a novel mechanism for modulation of p53 transcriptional activity and indicate that the high levels of MDM2, generated in mdm2-amplified cancer cells in the presence of nutlin, contribute to its antitumor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 977. doi:1538-7445.AM2012-977
Abstract 987: Overexpression of 14-3-3α in cancer cells activates PI3K via binding the p85 regulatory subunit
Authors: Xu Jia , Neal Christopher L. , Li Ping , Mori Seiji , Yang Jun , Neal Nina N. , Zhou Xiaoyan , Wyszomierski Shannon L. , Yu Dihua 
Published: August 2012

Abstract
The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3α overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3α overexpression-mediated Akt phosphorylation and the potential impact on breast cancer progression. We found that 14-3-3α overexpression was significantly (P = 0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3α overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3α expression by siRNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3α enhanced Akt phosphorylation through activation of PI3K. Mechanistically, 14-3-3α bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3 binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3α-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3α binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage independent growth and enhanced stress induced apoptosis. These findings revealed a novel mechanism by which 14-3-3α overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 987. doi:1538-7445.AM2012-987
Abstract CT-04: A phase II study of neoadjuvant metformin in prostatic carcinoma
Authors: Joshua Anthony M. , Zannella Vanessa , Bowes Barbara , Koritzinsky Marianne , Sweet Joan , Evans Andrew , Trachtenberg John , Jewett Michael , Finelli Antonio , Fleshner Neil , Pollak Michael 
Published: August 2012

Abstract
Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. We conducted a phase II single centre study of neoadjuvant metformin in localised prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who on initial assessment are found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that begin treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 22 evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported, all patients underwent subsequent radical prostatectomy with adverse effects related to metformin. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p&lt;0.01) and waist/hip ratio (p&lt;0.01). There was a trend for a PSA reduction (p=0.08). There were no correlations between any metabolic, morphometric or cancer-related serum indices. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicates promising effects on metabolic parameters, tissue results will be presented including proliferation indices and signaling pathway assessments.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr CT-04. doi:1538-7445.AM2012-CT-04
Abstract CT-05: A phase II trial of selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum
Authors: Farley John H. , Brady William E. , Birrer Michael J. , Lankes Heather , Coleman Robert , Morgan Mark , Mannel Robert , Yamada Diane , Mutch David , Rodgers William H. , Gershenson David M. 
Published: August 2012

Abstract
Background: This study evaluated selumetinib (AZD6244, ARRY-142866), an inhibitor of MEK-1/2, and explored associations between RAS/RAF mutations with clinical outcome. Methods: Women with recurrent low-grade serous ovarian or peritoneal carcinoma were eligible and received selumetinib at 100 mg orally BID until progression or toxicity. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST v 1.0. BRAF, KRAS, and NRAS mutational analysis was performed. Results: Between December 2007 and November 2009, 52 patients were enrolled. Fifty-eight percent of patients had received at least 3 prior chemotherapy regimens. Eight patients (15.4%) had complete (1) or partial (7) responses, and 34 (65%) had stable disease. The median PFS was 11.0 months. The median number of cycles received was 4.5, and 33% of patients received at least 12 cycles of selumetinib. Sixty-three percent of patients (33/52) had PFS&gt; 6 months. Grade 4 toxicities included cardiac (1 patient), pulmonary (1), and pain (1). The most common grade 3 toxicities were gastrointestinal (13), and dermatologic (9). Thirty-four patients had sufficient DNA for mutational analysis: 6% BRAF, 41% KRAS, 15% NRAS mutations were found, and 38% had no detectable mutation. There were no statistically significant differences in the proportion of responses by any mutation. Conclusions: Selumetinib is well tolerated and is active in the treatment of recurrent low-grade serous carcinoma. In exploratory analyses, response to selumetinib did not appear to be related to RAS/RAF mutational status, however the sample size was small. The 81% disease control rate is encouraging and worthy of further evaluation of MEK inhibitors in this population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr CT-05. doi:1538-7445.AM2012-CT-05
Abstract LB-102: Role of HOX genes in regulation of stem cell populations in normal and malignant colon tissue
Authors: Bhatlekar Seema , Czymmek Kirk , Viswanathan Vignesh , Gonye Greg , Boman Bruce 
Published: August 2012

Abstract
HOX genes are thought to play a role in regulating stem cells (SCs) during embryological development. Aberrant expression of HOX genes is seen in many cancers, including colorectal cancer (CRC). However, the mechanisms leading to aberrant HOX gene expression in CRC are not known. Because SCs are key to colon tumorigenesis, we hypothesized that (i) expression of specific HOX genes is different in malignant colonic SCs than in normal SCs and (ii) aberrant expression of these HOX genes is necessary for the tumor initiating ability of colon cancer SCs. Using real time PCR-based array analysis, we found that expression of many HOX genes are upregulated in colon carcinomas relative to normal colonic epithelium. We previously reported a ‘unique HOX gene signature’ for the SC enriched population; two-color microarray analysis showed that two HOX genes, HOXA4 and HOXD10 are expressed in the bottom part of the colonic crypt where SCs reside. Here, we confirmed this finding, and then, using immunohistochemistry, we validated it. HOXA4 and HOX D10 were expressed at the bottom part of the normal colonic crypt. Increased expression of these genes was also seen in colon carcinoma tissues. The results for colon carcinoma tissues were validated using real time PCR. As an independent method to validate the differential expression of HOX genes, we used flow cytometry and ALDEFLUOR to isolate, from a colon cancer cell line, SCs and non-SCs. HOXA4 and HOXD10 expression was then studied using real time PCR. HOXA4 was upregulated in SCs vs non-SCs. To determine whether these genes are differentially expressed in carcinomas relative to normal tissue, we co-stained tissues with antibodies against HOXA4 or HOXD10, and with SC markers, ALDH1 or CD166. We found that SCs express these HOX genes in the bottom part of the colonic crypt compared to non-SCs. In colon carcinoma tissues, not only was there co-staining, but also, the co-staining was increased relative to normal colonic epithelium. Our results implicate expression of HOXA4 and HOXD10 genes not only in the functioning of normal SCs, but also in the contribution of colon SCs to colon tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-102. doi:1538-7445.AM2012-LB-102
Abstract LB-104: Prostate-specific inactivation of Atbf1 causes mouse prostatic intraepithelial neoplasia
Authors: Sun Xiaodong , Fu Xiaoying , Li Jie , Xing Changsheng , Frierson Henry F. , Cardiff Robert D. , Wu Hao , Dong Jin-Tang 
Published: August 2012

Abstract
Cancer initiation and progression is triggered by loss of function of tumor suppressor genes. Previously, we have identified the AT-motif Binding Factor 1 (ATBF1) as a candidate tumor suppressor gene at 16q22 in the prostate. It undergoes frequent somatic mutations, reduced expression, or mislocalization in human cancers. However, its tumor suppressor role has not been examined in vivo. In the current study, we generated a conditional Atbf1 knockout mouse line using the Cre-loxP system. Tissue-specific inactivation of Atbf1 in prostatic epithelial cells caused hyperplasia in the dorsal lobes at as early as 4 months of age, which further progressed to mouse prostatic intraepithelial neoplasia (mPIN) in all four lobes. These precancerous lesions harbored molecular aspects similar to human PIN and prostate cancer, including increased cell proliferation, attenuated the basal cell layer, loss of the cell junction protein E-cadherin, and loss of an intact smooth muscle layer. Meanwhile, we observed elevated levels of Muc1 and p-Erk 1/2 in mPIN lesions. In addition, we identified and validated a number of genes that were disregulated in the Atbf1 knockout mice, and many of those genes encode secretory proteins. Supportively, an altered secretory protein profile was observed in the dorsal lobes. Taken together, our data demonstrated that loss of Atbf1 caused precancerous lesions in the prostate, thus providing in vivo evidence to a tumor suppressor role of the ATBF1 gene.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-104. doi:1538-7445.AM2012-LB-104
Abstract LB-105: Gli-IKBKE interactions in pancreatic tumorigenesis
Authors: Rajurkar Mihir , De Jesus-Monge Wilfredo E. , Driscoll David , Cotton Jennifer L. , Lewis Brian C. , Mao Junhao 
Published: August 2012

Abstract
Oncogenic mutations in KRAS are detected in a majority of human pancreatic malignancies, and are considered an initiating event in pancreatic ductal adenocarcinoma (PDAC). The downstream mechanisms through which KRAS drives tumorigenesis remain elusive. While recent in vitro studies have suggested that Gli proteins, the transcriptional effectors of Hedgehog signaling, may mediate KRAS oncogenic activity in PDAC cell lines, a requirement for Gli activation in pancreatic tumorigenesis has not been demonstrated in vivo. Here, we use genetically modified mouse models, and human PDAC cell lines to establish a requirement for Gli activation in KRAS initiation of pancreatic tumorigenesis, and identify IKBKE as a novel oncogenic target gene of Gli in PDAC. We show for the first time that inhibition of Gli transcription in the pancreatic epithelium suppressed the ability of activated KRAS to initiate tumorigenesis in vivo. Also, we find that expression of Gli1 along with oncogenic KRAS led to a dramatic acceleration in the formation of pancreatic intraepithelial neoplasia (PanIN) lesions, and increased mortality. Importantly, we identify IKBKE as a novel transcriptional target of Gli in PDAC cells, and also in the pancreatic epithelium in vivo. We also demonstrate that IKBKE is required for the survival and tumorigenicity of PDAC cells, thus implicating IKBKE as a novel pancreatic cancer oncogene. We have found that IKBKE activates the NF-kB pathway, and also activates Akt by phosphorylation in PDAC cells as part of its tumorigenic activity. Our studies demonstrate for the first time a requirement for Gli transcriptional activity in KRAS induced pancreatic tumorigenesis in vivo, and establish IKBKE as a novel Gli target and pancreatic cancer oncogene.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-105. doi:1538-7445.AM2012-LB-105
Abstract LB-11: Reduced cardiotoxicity and improved antitumor effect of the epirubicin-incorporating micelle NC-6300 in a hepatocellular carcinoma model
Authors: Yamamoto Yoshiyuki , Hyodo Ichinosuke , Takahashi Amane , Yasunaga Masahiro , Koga Yoshikatsu , Harada Mitsunori , Saito Hiroyuki , Tanaka Ryosuke , Hayashi Tatsuyuki , Kato Yasuki , Matsumura Yasuhiro 
Published: August 2012

Abstract
Background: Epirubicin, an anthracycline antitumor drug, has been approved for the treatment of various human tumors. However, epirubicin has significant dose-limiting cardiotoxicity, and there are no effective therapies to prevent or reduce this cardiotoxicity. Therefore, we investigated whether the epirubicin-incorporating micelle NC-6300 was more effective than epirubicin alone in reducing cardiotoxicity and improving the antitumor effect. Method: NC-6300 comprises epirubicin covalently bound to the polyaspartate chain of the polyethylene glycol-polyaspartate block copolymer via an acid-labile hydrazone bond. The conjugate spontaneously forms a micellar structure in an aqueous milieu. The diameter of NC-6300 is 60-70 nm, and the micellar formulation is stable under physiological condition. For evaluating the antitumor effects, NC-6300 (10 or 15 mg/kg) and epirubicin (10 mg/kg) were intravenously administered once a week for 3 weeks to C57BL/6 mice bearing human hepatocellular carcinoma (HCC) Hep3B xenografts implanted subcutaneously or orthotopically (n = 6-10). Cardiotoxicity was evaluated by using echocardiography to the mice that were given NC-6300 (10 or 15 mg/kg) or epirubicin (10 mg/kg) on days 1, 8, and 15 every 4 weeks, to a total of 9 administrations for 12 weeks (n = 6 for each evaluation point). Results: Compared to epirubicin, NC-6300 showed significant antitumor activity against Hep3B. Moreover, the survival rate in the orthotopic tumor model of Hep3B was significantly higher with NC-6300 treatment than with epirubicin treatment. With respect to cardiotoxicity, epirubicin-treated mice showed significantly deteriorated fractional shortening (FS) and ejection fraction (EF) 21 days after the beginning of administration. In contrast, no mice treated with NC-6300 experienced cardiotoxicity in terms of EF or FS during the observation period. Conclusion: The findings of this study imply that NC-6300 has a strong antitumor effect against HCC. Furthermore, NC-6300 significantly reduces the cardiotoxicity of epirubicin and warrants a clinical evaluation in patients with advanced solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-11. doi:1538-7445.AM2012-LB-11