bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 701: A novel class of Ras selective inhibitors
Authors: Canzoneri Joshua C. , Chen Xi , Keeton Adam B. , Lee Kevin , Gary Bernard , Butler Ethan B. , Grizzle William E. , Wilson Landon , Barnes Stephen , Boyd Michael R. , Piazza Gary A.
Published: August 2015

Despite the fact that activating mutations in the various forms of Ras were identified as driving factors in oncogenesis over thirty years ago, there are still no effective therapeutics which act on this target. We recently synthesized and characterized a novel class of compounds that show striking potency and selectivity to inhibit the growth of tumor cells with mutant Ras. Through iterative structure-activity studies, we selected for and optimized Ras selectivity to achieve high potency with IC50 values in the low nanomolar range and selectivity indices of nearly 100-fold. For example, ADT-062 inhibited the growth of human HCT116 colon tumor cells that harbor mutant K-Ras with an IC50 value of 8.4 + 3.6 nM,. In contrast, human HT29 colon tumor cells that have wild type Ras displayed an IC50 value of 521 + 253 nM in response to ADT-062 treatment. When surveying a larger panel of colon tumor cell lines, we observed a direct correlation between potency and Ras activation status. Further, ADT-062 induced cell cycle arrest only in the Ras-mutant cell line. To study the mechanism by which this class of compounds selectively inhibits the growth of tumor cells with mutant K-Ras, we profiled lysates from treated HCT116 and HT29 colon tumor cells using high resolution LC-MS/MS. Over 100 ions were identified that were differentially affected by treatment with ADT-062 at its IC50 value in the respective cell line. Among the ions of interest, a component of the purine biosynthetic pathway, 5′-phosphoribosyl-N-formylglycinamide (FGAR), was found to be induced 200-fold (p = .0031) in K-Ras mutant cells compared with Ras wild type cells. Together, these findings suggest that this compound may cause a Ras selective disruption of purine metabolism and cell cycle progression which contributes to the selectivity by which this novel class of compounds inhibit the growth of tumor cells with mutant Ras. These findings may enable us to develop this compound class as a novel therapeutic which targets Ras driven tumors and tumors which may become resistant to other targeted therapeutics through secondary Ras mutations.

Citation Format: Joshua C. Canzoneri, Xi Chen, Adam B. Keeton, Kevin Lee, Bernard Gary, Ethan B. Butler, William E. Grizzle, Landon Wilson, Stephen Barnes, Michael R. Boyd, Gary A. Piazza. A novel class of Ras selective inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 701. doi:10.1158/1538-7445.AM2015-701
Abstract 710: CRP induction in tamoxifen-resistant breast cancer cells
Authors: Choi Min Chang , Moon Aree , Kang Keon Wook
Published: August 2015

Breast cancer is one of the most common cancer types among post-menopausal women. Tamoxifen has been known as the most effective therapeutic option for estrogen receptor-positive breast cancer. One of the main issues of breast cancer is acquisition of tamoxifen resistance, and if it does, the way to treat tamoxifen-resistant breast cancer has not been discovered. It has been recently suggested that c-reactive protein (CRP), inflammatory marker found in many diseases may be related to breast cancer progression. Here, we found that tamoxifen-resistant breast cancer (TAMR-MCF-7) cells expresses much higher protein and mRNA level of CRP compared to parent breast cancer (MCF-7) cells. CRP knock-down by lentiviral shRNA did not affect cell proliferation rate of TAMR-MCF-7 cells. One of the main characteristics of tamoxifen-resistant breast cancer is higher migratory ability. Through trans-well migration assay, we have discovered that CRP alone increases migratory function of MCF-7 cells. Moreover, CRP knock-down significantly reduced cell migration of TAMR-MCF-7 cells. It has been recently reported that sphingosine-1-phosphate (S1P) induces CRP in mammary epithelial cells and ultimately causes cancer cell transformation. S1P treatment increased CRP expression in MCF-7 cells. Protein expression of sphingosine kinase (Sphk) 1 and 2, which catalyzes conversion of sphingosine to S1P, was also increased in TAMR-MCF-7 cells. Among five S1P receptors, we also discovered that S1P receptor 3 (S1Pr3) is related with CRP induction in TAMR-MCF-7 cells. Taken together, tamoxifen-resistant breast cancer expresses high level of CRP and S1P-S1Pr3 plays a key role in CRP induction in TAMR-MCF-7 cells. Higher levels of CRP increases migratory function of tamoxifen-resistant breast cancer cells. CRP may be an important therapeutic target for the treatment of tamoxifen-resistant breast cancer.

Citation Format: Min Chang Choi, Aree Moon, Keon Wook Kang. CRP induction in tamoxifen-resistant breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 710. doi:10.1158/1538-7445.AM2015-710
Abstract 714: Cbl-b Inhibits p-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers
Authors: Zhang Ye , Qu Xiujuan , Teng Yuee , Xu Ling , Liu Jing , Li Zhi , Hu Xuejun , Liu Yunpeng
Published: August 2015

Background The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown.

Methods Immunofluorescence microscopy and proximity ligation assays were used to analyze the translocation of P-gp into caveolae. Nude mice (n = 7 mice per group) were injected with SGC7901/Adr vector, SGC7901/Adr + Cbl-b cells and/or Dox and tumor growth was assessed. Immunoprecipitation and western blotting were used to examine the effects of Cbl-b mediated ubiquitination and degradation of c-Src. Immunochemistry was performed on primary tumor specimens from breast cancer patients (n = 319) to determine the relationship of Cbl-b with overall survival.

Results c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance (MDR) in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae, resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy.

Conclusions Our findings reveal a new regulatory mechanism of P-gp transport function.

Citation Format: Ye Zhang, Xiujuan Qu, Yuee Teng, Ling Xu, Jing Liu, Zhi Li, Xuejun Hu, Yunpeng Liu. Cbl-b Inhibits p-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 714. doi:10.1158/1538-7445.AM2015-714
Abstract 729: The role of skp2 in paclitaxel-resistant prostate cancer cells
Authors: Yang Yeguo , Song Qiong , Lu Yi , Zhang Jian , Fu Jiejun
Published: August 2015

Prostate cancer is the most common cancer and the second most frequent cause of cancer-related death of men in the United States. It has been shown that the F-box protein Skp2(S-phase kinase associated protein 2) plays an important role in the development and progression of prostate cancer. The molecular mechanism responsible for paclitaxel-resistant in prostate cancer cells remain unclear. Interestingly, we found that the expression of Skp2 is higher in the paclitaxel-resistant prostate cancer cells DU145-TXR or PC-3-TXR compared with their parental cells DU145 or PC-3 respectively.This study was aimed to investigate the role of Skp2 in prostate cancer cell resistance to paclitaxel and the progress of epithelial-to-mesenchymal transition(EMT). Skp2 encoding plasmid was stably transfected into PC-3 and DU145 cells. Meanwhile, Skp2 was silenced by shRNA in DU145-TXR or PC-3-TXR cells. MTS assay was used to measure the cytotoxicity effect of Skp2 overexpression or knockdown of Skp2 in cells after treatment with paclitaxel. We found that when downregulating Skp2 in DU145-TXR and PC-3-TXR, the cells showed a more sensitive response to paclitaxel. Moreover, Overexpression of Skp2 enhances prostate cancer cells resistance to paclitaxel. EMT markers E-cadherin was decreased while vimentin was increased in PC-3-TXR or DU145-TXR cells. The further study showed that when downregulating Skp2 in PC-3 or DU145, the expression of E-cadherin was increased. However, E-cadherin has no significant change when knockdown of Skp2 in PC-3-TXR or DU145-TXR cells. CyclinD1, P21 and P27 were found to increase while CyclinB1 and CyclinE2 to decrease when downregulating Skp2 in PC-3-TXR or DU145-TXR cells. These data provide evidence that Skp2 is associated with prostate cancer cell resistance to paclitaxel. Skp2 could be a potential therapeutic target for prostate cancer. This study is supported by NSFC key project 81130046, NSFC projects 81201669, 81171993 and 81272415.

Note: This abstract was not presented at the meeting.

Citation Format: Yeguo Yang, Qiong Song, Yi Lu, Jian Zhang, Jiejun Fu. The role of skp2 in paclitaxel-resistant prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 729. doi:10.1158/1538-7445.AM2015-729
Abstract 732: Using functional and chemical genomics to identify mechanisms of Enzalutamide resistance in prostate cancer
Authors: Jeganathan Sujeeve , Zoubeidi Amina , Gleave Martin , Wouters Brad G. , Joshua Anthony M.
Published: August 2015

Introduction: Enzalutamide is a recently approved potent androgen receptor antagonist for prostate cancer both in the pre- and post-docetaxel settings. Its action relies upon 3 defined mechanisms of action: 1) blocking testosterone binding to the androgen receptor (AR), 2) preventing nuclear translocation of AR, and 3) inhibiting AR-DNA binding. However, despite its utility in prolonged overall survival in both these settings, disease relapse is inevitable, suggesting that resistance to the drug is somehow being acquired and is of vital concern.

Methods: Using a combination of high-throughput functional genomic (kinome-shRNA) and chemical genomic (pharmacological inhibitor) screens, along with various in vitro / in vivo assays (proliferation, apoptosis, necrosis, soft agar growth, etc.) we have identified the IkB kinase (IKK) / IkB / NFkB signaling axis as important for acquisition of, and continued resistance to, Enzalutamide.

Results: Using a panel of Enzalutamide-resistant and -sensitive cell lines, we show that targeting this signaling axis will selectively kill Enzalutamide-resistant cells while not affecting the proliferation of sensitive cells. Moreover, our data shows that the pharmacological inhibitors and shRNAs are effective even without Enzalutamide administration, negating any potential drug-drug interaction issues. Finally, we have found that our cells are resistant to Enzalutamide in an AR-V7-independent manner, suggesting that NFkB signaling is acting in a novel manner to bring about the resistance phenotype.

Conclusions: Through in vitro and in vivo experiments, we provide evidence that targeting activators of NFκB signalling can be a strategy to help patients with Enzalutamide-resistant prostate cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Sujeeve Jeganathan, Amina Zoubeidi, Martin Gleave, Brad G. Wouters, Anthony M. Joshua. Using functional and chemical genomics to identify mechanisms of Enzalutamide resistance in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 732. doi:10.1158/1538-7445.AM2015-732
Abstract 739: Tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemoresistance that is reversed by Notch pathway inhibition in lung adenocarcinoma
Authors: Hassan Khaled A.
Published: August 2015

Background: Lung cancer is the leading cause of cancer death in the world, mainly due to complex genetic events that characterize lung cancer, tumor heterogeneity and resistance to traditional and targeted treatments. Resistance may be explained by passive clonal selectivity, however, the propensity and variability of resistance suggests an active process of tumor plasticity. We hypothesize that tumor cells undergo an epithelial to mesenchymal transition as a mechanism of resistance to chemotherapy.

Results: The lung adenocarcinoma cell lines NCI-H1299, NCI-H358, and NCI-H441 were exposed to gradually increasing doses of docetaxel over 12-16 weeks. Chemoresistance emerged with a 10-15X increase in IC50 as compared to parental cells. With each treatment dose increase more than 50% of cells remained alive, suggesting bulk cell transformation. This resistance has been maintained for more than 20 generations after withdrawal of docetaxel. Morphologically, NCI-H358 and NCI-H441 chemoresistant cell lines lost their cobblestone architecture becoming more spindle-shaped. Using RT-PCR assays, there was increased expression of mesenchymal-related genes, vimentin (2.5-3.5X), twist (2-4X) and decreased expression of epithelial-related genes such as E-CAD (2-5X). Our previous data suggested that Notch activity plays a significant role in the EMT process, thus we evaluated Notch downstream genes expression by RT-PCR. We detected increase expression of Hey2 (2.5-3.5X), in NCI-H358 and NCI-H441 resistant cell lines as compared to parental cells. When chemoresistant cell lines were exposed to gamma secretase inhibitor, a Notch inhibitor, they became less invasive, epithelial-like and sensitive to docetaxel.

Conclusion: These data suggest that tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemotherapy resistance that is controlled through the Notch pathway. Inhibiting Notch activity induces mesenchymal to epithelial transition and re-sensitizes cells to chemotherapy. Notch inhibition in combination with standard chemotherapy represents a potential approach to achieve better disease control.

Citation Format: Khaled A. Hassan. Tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemoresistance that is reversed by Notch pathway inhibition in lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 739. doi:10.1158/1538-7445.AM2015-739
Abstract 741: Anti-tumor activity and acquired resistance mechanism of dovitinib in RET-rearranged lung adenocarcinoma
Authors: Kang Chan Woo , Jang Kang Won , Cho Byoung Chul
Published: August 2015

Background:

RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib, a potent inhibitor of FGFR, VEGFR, and PDGFR, on RET-rearranged LADC is not known. This aims of the study are to explore anti-tumor effects and mechanism of acquired resistance of dovitinib in RET-rearranged LADC.

Results:

Dovitinib potently induced cell cycle arrest in G1 phase and dose-dependent suppression of phosphorylation of RET and ERK in LC-2/ad LADC cells harboring CCDC6-RET rearrangement. Selective inhibition of dovitinib on autophosphorylation of RET kinases was confirmed in HEK293 cells expressing KIF5B-RET or CCDC6-RET. In Human RTK array, dovitinib did not show significant inhibition of phosphorylation on FGFR or VEGFR in LC-2/ad cells. Dovitinib exhibited growth inhibition of LC-2/ad cells more efficiently than vandetanib, sunitinib, and sorafenib, which was confirmed in vivo xenograft models. To identify the acquired resistance mechanism, we established resistant cells to dovitinib (LC-2/ad DR) from LC-2/ad cell line. Knockdown of RET or dovitinib did not inhibit RET-induced ERK phosphorylation in LC-2/ad DR cells. Using microarray and immunoblotting, we confirmed aberrant focal adhesion kinase signaling, including c-Src. Dasatinib, a Src inhibitor, suppressed ERK phosphorylation and growth of LC-2/ad DR cells.

Conclusion:

Dovitinib can be a potential therapeutic option for RET-rearranged LADC. Acquired resistance to dovitinib can be overcome by targeting SRC.

Citation Format: Chan Woo Kang, Kang Won Jang, Byoung Chul Cho. Anti-tumor activity and acquired resistance mechanism of dovitinib in RET-rearranged lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 741. doi:10.1158/1538-7445.AM2015-741
Abstract 759: Metformin enhances the benefit of ALK inhibitors in ALK translocation-positive non-small cell lung cancer cells
Authors: Kim Mi Young , Kim Geum Ock , Shin Dong Hoon , Kim Tae Min , Kim Jin-Soo
Published: August 2015

Background: Crizotinib is an effective tyrosine kinase inhibitor (TKI) against non-small cell lung cancers (NSCLCs) with anaplastic lymphoma receptor tyrosine kinase (ALK) translocation. Recently, the second generation ALK inhibitors, including alectinib (CH5424802) and ceritinib (LDK378) are actively investigated in clinical trials and show strong anti-tumor effect both in crizotinib-naïve and refractory NSCLC patients with ALK translocation. Unfortunately, the efficacy of these ALK inhibiting TKIs is limited due to primary and acquired resistance to these agents. Metformin is a widely used antidiabetic drug and shows promising anti-tumor effect in several cancers. Here, we define a therapeutic synergism between ALK inhibitors and metformin.

Material and Methods: NSCLC cells with ALK translocation-positive (ALK+) and crizotinib-sensitive H2228 and H3122, and ALK+, crizotinib-resistant SNU2535 and ALK translocation-negative H226 were evaluated. We assessed response of these NSCLC cells to crizotinib, alectinib and ceritinib alone or in combination with metformin by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and anchorage independent growth in soft agar. Combination indices (Cis) were calculated by CalcusynTM (Biosoft, Cambridge, UK). Western blots were performed to assess biochemical changes, especially those related with ALK signaling components.

Results: The combination of ALK inhibitors with metformin induced a strong anti-proliferative effect only in ALK+ cell lines (CI of crizotinib and metformin: 0.31 - 0.79, CI of alectinib and metformin: 0.40 - 0.86, CI of ceritinib and metformin: 0.38 - 0.65). Alectinib and ceritinib effectively inhibited growth of crizotinib-resistant SNU2535, while crizotinib did not. Notably, synergistic effects of these ALK inhibitors and metformin were also shown in SNU2535 cells. Compared to ALK inhibitor alone, the combination of ALK inhibitor plus metformin resulted in decreased phosphorylation of ALK and downstream targets, such as AKT or ERK, both in crizotinib-sensitive and resistant ALK+ cells.

Conclusion: Collectively, these data support that ALK inhibitors and metformin are synergistic in ALK+ NSCLC cells. Resistance to crizotinib as well as alectinib and ceritinib might be overcome by addition of metformin.

Citation Format: Mi Young Kim, Geum Ock Kim, Dong Hoon Shin, Tae Min Kim, Jin-Soo Kim. Metformin enhances the benefit of ALK inhibitors in ALK translocation-positive non-small cell lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 759. doi:10.1158/1538-7445.AM2015-759
Abstract 772: Anti-tumor efficacy of the selective pan-FGFR Inhibitor BAY 1163877 in preclinical squamous cell carcinoma models of different origin
Authors: Héroult Mélanie , Ocker Matthias , Kopitz Charlotte , Zopf Dieter , Hägebarth Andrea , Ziegelbauer Karl , Ince Stuart , Ellinghaus Peter
Published: August 2015

Squamous cell carcinoma (SCC) is a common subtype of lung cancer and is strongly associated with smoking. In contrast to adenocarcinomas of the lung, SCCs do not significantly harbor epidermal growth factor (EGFR) mutations or ALK, ROS1 or RET translocations, which are therapeutically tractable. SCC of the lung and SCC of the head and neck region and esophagus not only share risk factors, morphologic features and mechanisms of tumorigenesis but also frequent fibroblast growth factor receptor 1 (FGFR1) gene alterations. In addition, we found that FGFR2 and FGFR3 expression were also altered in patient derived models of SCC of various origins. FGFRs may thus represent viable therapeutic targets for the treatment of SCC.

BAY 1163877, an orally available and potent inhibitor of FGFR1, FGFR2 and FGFR3, inhibited SCC cell proliferation as well as downstream FGFR signaling in vitro. When applied in vivo, BAY 1163877 was able to reduce growth of a FGFR1-overexpressing lung SCC xenograft model, a FGFR1-overexpressing esophageal SCC xenograft model, and a FGFR3-overexpressing head and neck SCC xenograft model, achieving reductions in tumor growth by 67 to 92% as compared to the vehicle control. BAY 1163877 was very well tolerated in all models performed.

These data suggest that selective inhibition of FGFR1 to 3 with BAY 1163877 might have therapeutic potential for the treatment of SCC malignancies. A phase I clinical trial (NCT01976741) to determine the safety, tolerability and recommended Phase 2 dose in advanced cancer patients is ongoing.

Citation Format: Mélanie Héroult, Matthias Ocker, Charlotte Kopitz, Dieter Zopf, Andrea Hägebarth, Karl Ziegelbauer, Stuart Ince, Peter Ellinghaus. Anti-tumor efficacy of the selective pan-FGFR Inhibitor BAY 1163877 in preclinical squamous cell carcinoma models of different origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 772. doi:10.1158/1538-7445.AM2015-772
Abstract 8: Differential roles of OCT3/4, SOX2 and NANOG for constitutive high NOXA expression levels in embryonal carcinoma (EC) cells
Authors: Bayha Christine , Gutekunst Matthias , Aulitzky Walter E. , van der Kuip Heiko
Published: August 2015

Recently we found that hypersensitivity of embryonal carcinoma (EC) to chemotherapy is mediated by high constitutive levels of NOXA protein. This pro-apoptotic BH3-only protein primes EC cells to undergo rapid and massive apoptosis in response to p53 activation. Both hypersensitivity as well as high NOXA protein levels were lost upon differentiation in these cells. We here investigated the role of three key regulators of pluripotency, namely OCT3/4, SOX2 and NANOG for NOXA protein and transcript (PMAIP1) expression in two EC cell lines, the pluripotent NTERA-2D1 and the nullipotent 2102EP. We found that siRNA-mediated silencing of POU5F1 (OCT3/4) led to a down-regulation of PMAIP1 mRNA by ∼80% and to an almost complete loss of NOXA protein (by >90%). On the other hand, silencing of SOX2 or NANOG only slightly reduced transcript levels (by ∼20% and ∼30%, respectively). At the same time, a distinct down-regulation of NOXA protein levels (by ∼75%) was observed in SOX2- and NANOG-deprived cells, respectively. These data indicate that the high constitutive levels of NOXA in EC cells depend on two independent mechanisms, (1) transcriptional regulation predominantly mediated by OCT3/4, and (2) post-transcriptional regulation mediated by either one of the stem cell factors. Indeed, we found that siRNA-mediated loss of one stem cell factor led to a ∼2fold reduction of NOXA protein stability in both cell lines reaching a NOXA half-life of approximately 2 hours, which was comparable to that observed in PHA stimulated lymphocytes from normal donors.

These data demonstrate that the high constitutive levels of NOXA protein in EC cells are due to OCT3/4 dependent induction of the PMAIP1 transcript and a prolonged NOXA protein stability mediated by either one of the stem cell factors.

Citation Format: Christine Bayha, Matthias Gutekunst, Walter E. Aulitzky, Heiko van der Kuip. Differential roles of OCT3/4, SOX2 and NANOG for constitutive high NOXA expression levels in embryonal carcinoma (EC) cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 8. doi:10.1158/1538-7445.AM2015-8
Abstract 807: Parental radiation elicits increased intestinal tumorigenesis in the F1 generation of APCMin/+ and APC1638N/+ mice
Authors: Suman Shubhankar , Kumar Santosh , Moon Bo-Hyun , Fan Ziling , Fornace Albert J. , Datta Kamal
Published: August 2015

The risk of colorectal cancer (CRC) has been reported to increase with radiation exposures as well as with a positive family history. Radiation exposure has also been implicated in inducing heritable changes in parental germline cells and thus increasing risk of cancer in the offspring. However, effects of parental radiation exposure on trans-generational colorectal carcinogenesis in offspring have not been explored yet. We employed two well-characterized mouse models (APCMin/+ and APC1638N/+) of human CRC to determine trans-generational effects of low dose radiation on colorectal carcinogenesis. Male APCMin/+ and APC1638N/+, and female C57BL/6J mice were exposed to whole body 25 cGy of x rays. Mating was initiated two days after radiation exposure, F1 offspring were genotyped, and male and female APCMin/+ and APC1638N/+ were grouped and housed separately. APCMin/+ mice were euthanized 150 days after birth, APC1638N/+ mice after 210 days, and tumor frequency and size in intestine and colon were noted. Significantly increased intestinal tumor frequency and increased numbers of larger tumors were observed in F1 mice of irradiated parents relative to F1 mice of sham-irradiated parents. Greater trans-generational tumorigenic effects of radiation were observed in male offspring relative to female offspring. In conclusion, here we present an early report for the first time that low dose radiation exposure has a trans-generational effect on intestinal tumorigenesis with potential implications for radiation exposure-related human health consequences.

Citation Format: Shubhankar Suman, Santosh Kumar, Bo-Hyun Moon, Ziling Fan, Albert J. Fornace, Kamal Datta. Parental radiation elicits increased intestinal tumorigenesis in the F1 generation of APCMin/+ and APC1638N/+ mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2015-807
Abstract 809: BrafV637E mutation as an early change in hepatocarcinogenesis induced by neonatal treatment with diethylnitrosamine in B6C3F1 mice
Authors: Yamamoto Masahiro , Tanaka Hiroki , Bing Xin , Nishikawa Yuji , Yamazaki Kohsuke , Shimizu Keiko , Ogawa Katsuhiro
Published: August 2015

Neonatal treatment of B6C3F1 mice with diethylnitrosamine (DEN) is often employed as an experimental model for hepatic tumors. In this model, microscopic preneoplastic foci emerge in the early stage and subsequently progress into adenomas, from which hepatocellular carcinoma (HCC) is finally developed. We detected the BrafV637E mutation, that is correspondent to the human BrafV600E mutation, in 4/4 DEN-induced hepatic tumors at 13 months after DEN treatment by whole exome analysis, and further in 16/17 (94.1%) late tumors by the PCR-direct sequencing method. By microdissection, the BrafV637E mutation was also detected in 16/18 (88.8%) and 22/28 (78.5%) microscopic lesions (preneoplastic foci and microadenomas) respectively at 5 and 8-9 months after DEN treatment. Meanwhile, although the BrafV637E mutation was detected in 5/7 (71.4%) hepatic tumors induced by neonatal DEN treatment followed by repeated CCl4 administration, it was not found in 24 hepatic tumors induced by CCl4 alone and 6 spontaneous hepatic tumors in B6C3F1 mice, indicating that the BrafV637E mutation is specific to the DEN-initiated hepatic tumors, presumably being derived from the genotoxic action of DEN. The DEN-induced tumors showed hyperphosphorylation of MEK and ERK1/2, indicating that the BrafV637E mutation activated the downstream MAPK pathway. Furthermore, the DEN-induced tumors overexpressed the pro-survival/pro-proliferative cytokines/chemokines such as complement C5/C5a, soluble intercellular adhesion molecule (sICAM-1), IL-1 receptor antagonist (IL-1ra) and chemokine CXCL9 as well as the oncogene-induced senescence (OIS) markers, p15Ink4b and p19Arf mRNAs, suggesting that the BrafV637E mutation might influence the gene expression that is involved either in cellular growth/survival or OIS. Transgenic mice expressing BrafV637E specifically in the liver under the control of albumin promoter showed enlarged hepatic mass as large as 4-5 times of normal liver, and whole liver was consisted of small basophilic hepatocytes resembling the cells in the early preneoplastic lesions induced by neonatal treatment with DEN. These results indicate that the BrafV637E mutation plays a pivotal role in the DEN-induced hepatocarcinogenesis.

Citation Format: Masahiro Yamamoto, Hiroki Tanaka, Xin Bing, Yuji Nishikawa, Kohsuke Yamazaki, Keiko Shimizu, Katsuhiro Ogawa. BrafV637E mutation as an early change in hepatocarcinogenesis induced by neonatal treatment with diethylnitrosamine in B6C3F1 mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 809. doi:10.1158/1538-7445.AM2015-809
Abstract 838: Household stove improvement and lung cancer mortality in Xuanwei, China: A 33-years’ follow-up study
Authors: Seow Wei Jie , Li Wen-Qing , Chapman Robert S. , Hu Wei , Vermeulen Roel , He Xingzhou , Bassig Bryan A. , Kim Christopher , Rothman Nathaniel , Lan Qing
Published: August 2015

Background: Household stove improvement from unvented stoves to stoves with chimney (vented stoves) and portable stoves has been shown to reduce lung cancer mortality in our prior cohort study in Xuanwei county, China (1976-1992). It remains unclear whether the protective effects against lung cancer mortality persist over time with extended follow-up (1993-2009). In our study, we examined the associations between vented stove and portable stove use with risk of lung cancer mortality based on a 33 years’ follow-up in Xuanwei.

Methods: A total of 42,422 individuals in Xuanwei were retrospectively followed from 1976 through 1992, and prospectively followed to 2009. Extensive information on household stove and fuel use at different age periods during the lifetime was collected in the 1992 and 2009 follow-up surveys. Lung cancer mortality data were obtained by integrating the information from hospital records and death certificates. Multivariable Cox regression models were used to estimate the hazard ratio (HR) of lung cancer mortality associated with stove improvement, adjusting for potential confounders.

Results: We observed a significant reduction in lung cancer mortality associated with improvement to vented stoves (multivariate-adjusted HR = 0.43, 95% confidence interval (CI) = 0.40-0.47) and portable stoves (multivariate-adjusted HR = 0.21, 95% CI = 0.19-0.24). There was a monotonic trend towards a decreased risk of lung cancer mortality with increasing years since stove improvement to vented stoves and portable stoves (P-trend for both <0.0001). Similar associations were observed for both men and women.

Conclusions: Household stove improvement to both vented stoves and portable stoves were inversely associated with risk of lung cancer mortality. These findings have important public health implications for nearly 3 million people who still use solid fuels for cooking and heating in homes, particularly in developing countries.

Citation Format: Wei Jie Seow, Wen-Qing Li, Robert S. Chapman, Wei Hu, Roel Vermeulen, Xingzhou He, Bryan A. Bassig, Christopher Kim, Nathaniel Rothman, Qing Lan. Household stove improvement and lung cancer mortality in Xuanwei, China: A 33-years’ follow-up study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 838. doi:10.1158/1538-7445.AM2015-838
Abstract 850: Hepatitis B virus genotype, mutations, human leukocyte antigen polymorphisms and their interactions in hepatocellular carcinoma: a multi-centre case-control study
Authors: Wen Juan , Song Ci , Jiang Deke , Jin Tianbo , Zhai Xiangjun , Xu Jianfeng , Shen Hongbing , Hu Zhibin
Published: August 2015

Objective:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Our aim was to evaluate the effects of the hepatitis B virus (HBV) genotype, mutations, HLA single nucleotide polymorphisms (SNPs) and their interactions on HCC risk.

Methods: A multi-centre case-control study of 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers as controls was performed. HBV genotype, mutations and genome-wide association studies (GWAS)-identified HLA-DQ/DR SNPs (rs9272105 and rs9275319) were detected.

Results: We found that the frequencies of the HBV genotypes B and BC (coinfection) were varied among the studied areas, but genotype C was consistently more frequent in HBV-related HCC (80.6% among HCC vs. 34.4% among the controls). Moreover, 11 HBV hotspot mutations in the EnhII/BCP/PC region were independently and significantly associated with HCC risk. We also detected significant interactions of HLA-DQ/DR rs9272105 with both the HBV genotype and mutations (P < 0.05 for each), but there were not significant interactions for rs9275319. Through a stepwise regression analysis, the HBV genotype, the 11 mutations, HLA-DQ/DR rs9272105 and rs9275319, and the interaction of the mutation A1752G with rs9272105 were all entered into the prediction model of HCC, and the area under the curve (AUC) for the panel including the HLA-DQ/DR SNPs, HBV genotype and mutations was 0.840 (sensitivity = 81.3%, specificity = 74.8%).

Conclusions: The HBV genotype, the mutations and the HLA-DQ/DR SNPs may serve as biomarkers for the surveillance of HBV persistent carriers. Large studies with prospective designs are warranted to further evaluate our results.

Note: This abstract was not presented at the meeting.

Citation Format: Juan Wen, Ci Song, Deke Jiang, Tianbo Jin, Xiangjun Zhai, Jianfeng Xu, Hongbing Shen, Zhibin Hu. Hepatitis B virus genotype, mutations, human leukocyte antigen polymorphisms and their interactions in hepatocellular carcinoma: a multi-centre case-control study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 850. doi:10.1158/1538-7445.AM2015-850
Abstract 862: Association of non-steroidal anti-inflammatory drugs with colorectal cancer by subgroups in the Vitamins and Lifestyle (VITAL) Study
Authors: Wang Xiaoliang , Peters Ulrike , Potter John D. , White Emily
Published: August 2015

Background: There is substantial evidence that use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colorectal cancer (CRC), but no subgroup has been identified for which the chemoprevention effect outweighs the risk of side effects. Methods: We tested the interaction between NSAID use and multiple risk factors on CRC risk in the VITAL cohort. A total of 73,458 individuals aged 50-76 completed a questionnaire between 2000 and 2002, and 674 incidental colorectal cancer cases were identified through 2010. Results: In stratified analysis, high use of any type of NSAIDs (4+days/week for 4+ years) was statistically significantly associated with a lower risk of CRC across all subgroups stratified by sex, BMI, physical activity, smoking, alcohol intake, screening and dietary factors, with a suggestion of stronger association among men, obese individuals, and heavier drinkers; however, none of these tests for interaction reached statistical significance. The associations were almost identical for subjects with higher overall CRC risk scores (HR: 0.62; 95% CI: 0.49-0.79) and those with lower risk scores (HR: 0.61; 95% CI: 0.42-0.88). Differential effects by cancer subsites and stages were tested. NSAID use was associated with a greater risk reduction of proximal colon cancer vs distal (p for difference = 0.06) and distant stage vs local (p for difference = 0.04). Conclusion: The association between high use of NSAIDs and CRC risk does not differ significantly among subgroups. Impact: Our results suggest that NSAIDs have a generally beneficial role in colorectal cancer prevention, largely unmodified by other exposures.

Citation Format: Xiaoliang Wang, Ulrike Peters, John D. Potter, Emily White. Association of non-steroidal anti-inflammatory drugs with colorectal cancer by subgroups in the Vitamins and Lifestyle (VITAL) Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 862. doi:10.1158/1538-7445.AM2015-862
Abstract 865: Physical inactivity increases the risk of endometrial cancer and premenopausal breast cancer
Authors: Johnsson Anna , Broberg Per , Johnsson Anders , Tornberg Åsa , Olsson Håkan
Published: August 2015

Background. Epidemiological studies indicate that physical activity reduces the risk of cancer. Physical inactivity or sedentary behavior, has recently been suggested as a risk factor independent of physical activity level. Breast and endometrial cancer incidence have both been associated with physical activity, and endometrial cancer incidence with physical inactivity/sedentary behavior. The purpose of the present study was to investigate physical inactivity as a risk factor for breast cancer, divided into pre- and postmenopausal subtypes, and for endometrial cancer, and to explore possible dose-response relations regarding the level of physical inactivity.

Methods. In a population-based prospective cohort study, 29 520 women in the southern part of Sweden, in ages between 25 and 64 years, participated. A questionnaire-based survey was performed 1990-92. Their reported professions were classified as sedentary or not which together with reported participation in competitive sports constituted the basis for classification into three activity-levels; (1) physical inactivity, defined as having sedentary occupation and no participation in competitive sports, (2) partly inactive, defined as either having a sedentary occupation or non- participation in competitive sports, (3) Physical active, defined as not having a sedentary occupation and participation in competitive sports. The association between physical inactivity and pre and postmenopausal breast and endometrial cancer incidence were analyzed by Cox regression, adjusted for hormonal factors, family history of cancer, body mass index (BMI) and age.

Results. Physical inactive women had a significantly increased risk of endometrial cancer (HR = 2.41, 95% CI 1.14-5.11) and premenopausal breast cancer (HR = 2.40, 95% CI 1.14-5.02), compared with women who were less physical inactive. No such association was found for postmenopausal breast cancer. Analysis of linear trend showed a significant dose-response relationship with increased risk of both premenopausal breast cancer (ptrend 0.02) and endometrial cancer (ptrend <0.01).

Conclusions. In the current study we found an increased incidence of premenopausal breast cancer and endometrial cancer in physical inactive women and a linear trend indicating dose-response relationship. Not only physical activity but also the avoidance of physical inactivity may reduce the risk of premenopausal breast cancer and endometrial cancer.

Citation Format: Anna Johnsson, Per Broberg, Anders Johnsson, Åsa Tornberg, Håkan Olsson. Physical inactivity increases the risk of endometrial cancer and premenopausal breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 865. doi:10.1158/1538-7445.AM2015-865
Abstract 87: Targeting androgen receptor acetylation as a treatment for castrate-resistant prostate cancer
Authors: Heine Erin , Merry Diane E. , Dehm Scott , Knudsen Karen E. , Montie Heather L.
Published: August 2015

The goal of our studies is to determine the potential of targeting androgen receptor (AR) acetylation as a means to counter androgen-independent prostate cancer (PCa). AR lysine residues 630/632/633 are acetylated in response to androgen-binding. This AR modification has been shown to enhance the transcriptional function of AR and to contribute to prostate tumorigenesis. These observations are supported by the discovery of an AR mutation that mimics this modification in a subset of prostate cancer patients (K630T), as well as increased levels of AR acetyltransferases in some advanced cases. We are specifically interested in the role of this modification in castrate-resistant prostate cancer, and we hypothesize that acetylation contributes to aberrant AR activation in castrate-resistant prostate cancer and possibly in androgen receptor antagonist resistant disease. We are utilizing genetic and pharmacological approaches to determine the function of AR acetylation in PCa, both in cell culture and in in vivo models. We have generated C4-2 cell lines within which we have stably knocked down endogenous AR (shRNA) and replaced it with acetylation-mutant AR (acetylation-null, acetylation-mimic, or lysine-intact controls). We have been performing growth and transcription assays to assess the effect of AR acetylation on these attributes of castrate-resistant PCa. Cells expressing acetylation-mimic AR have increased expression of select AR target gene transcripts, compared to cells expressing AR, null for acetylation. Enhanced AR transcriptional activity corresponds with a growth advantage of acetylation-mimic AR-expressing cells, whereas acetylation-null AR expressing cells undergo a substantial growth inhibition. Studies in mouse xenografts will further clarify whether AR acetylation is a driver of castrate-resistant disease and whether targeting AR acetylation is a rational strategy to treat this advanced disease state. Continued studies will also validate the potential of targeting AR acetylation as a means to combat AR antagonist resistant disease. The growth inhibition of cells expressing acetylation-null AR suggests that reducing AR acetylation may be a means to treat castrate-resistant PCa.

Citation Format: Erin Heine, Diane E. Merry, Scott Dehm, Karen E. Knudsen, Heather L. Montie. Targeting androgen receptor acetylation as a treatment for castrate-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 87. doi:10.1158/1538-7445.AM2015-87
Abstract 888: Reproductive and hormonal factors and mortality risk among women with colorectal cancer in the NIH-AARP Diet and Health Study
Authors: Arem Hannah , Park Yikyung , Felix Ashley , Zervoudakis Alice , Brinton Louise A. , Matthews Charles E. , Gunter Marc J.
Published: August 2015

Introduction

Women in the US have lower rates of colorectal cancer than men, which has prompted research into the role of estrogen in carcinogenesis. While use of menopausal hormone therapy (MHT) and other hormonally-related factors have been associated with lower risk of colorectal cancer (CRC), associations between these factors and colorectal cancer survival are not well defined.

Methods

The NIH-AARP cohort includes 566,398 AARP members (aged 50-71 years) who resided in one of six US states or two metropolitan areas and completed a mailed baseline questionnaire in 1995-1996. Among 2,053 women with incident colorectal cancer in the NIH-AARP Diet and Health Study, we examined associations of age at menarche, age at menopause, age at first birth, parity, oral contraceptive use, and menopausal hormone therapy use with overall and disease-specific mortality. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and disease-specific mortality, adjusting for tumor stage and grade, treatment, years since diagnosis, body mass index, marital status, smoking status, diabetes, and physical activity.

Results

There were 759 deaths (332 due to CRC) over a median 7.7 years of follow-up. We observed a suggestive, but not statistically significant, lower risk of all-cause mortality among women who were 13 years or older at menarche compared to those 12 or younger (HR = 0.89, 95% CI 0.77-1.03), but no associations for age at menopause, age at first live birth, parity, or oral contraceptive use. Compared to never MHT use former MHT use was not associated with mortality risk, but we found an inverse association among current users at study entry for both all-cause mortality (HR = 0.80, 95% CI 0.67-0.94) and colorectal cancer-specific mortality (HR = 0.72, 95% CI 0.56-0.93). These associations were stronger among those who reported fewer than five years of MHT use at baseline than among those with a longer duration of use.

Conclusion

We found evidence of an inverse association between MHT use at study entry and all-cause and colorectal cancer-specific mortality risk. Future studies should focus on how varying usage patterns, including types of preparation used, affect tumor progression and colorectal cancer survival.

Citation Format: Hannah Arem, Yikyung Park, Ashley Felix, Alice Zervoudakis, Louise A. Brinton, Charles E. Matthews, Marc J. Gunter. Reproductive and hormonal factors and mortality risk among women with colorectal cancer in the NIH-AARP Diet and Health Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 888. doi:10.1158/1538-7445.AM2015-888