bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1204: Enhanced efficacy of selumetinib by pretreatment of 5-FU in preclinical Ras/Raf-mutant colorectal cancer models
Authors: Jang Hye Yeon , Lee Haeng Jung , Nam Yeo Jin , Kim Won Dong , Bae Yong Ju , Jung Jin Hwang , Lee Seung Jin , Moon Dae Hyuk
Published: July 2017

Optimal strategy for the application of MEK inhibitor as combination therapy has not been established in Ras/Raf-mutant colorectal cancer (CRC). As we preliminary observed that 5-FU-induced pharmacodynamic changes were restored by ERK inhibition, we hypothesized that post-treatment of MEK inhibitor would enhance antitumor activity of 5-FU. Treatment of 5-FU for 2 days followed by selumetinib for another 2 days (FS schedule) exhibited synergism for cell viability, whereas reverse or concomitant combination showed antagonism or inconsistent response, respectively, in 8 kinds of CRC cell lines including BRAFV600E colo205, BRAFV600E RKO, or KRASG13D HCT8 cells. Combination as FS schedule persistently down-regulated the phosphorylation of ERK and pS6 throughout treatment period, whereas selumininib alone or reverse combination transiently decreased within 24 hr. The cells treated as FS schedule exhibited higher apoptosis and lower capacity of anchorage-independent cell growth than the cells under single or reverse combination. Microarray analysis revealed the distinct groups of genes underlying different efficacy by schedule-dependent treatment. Tumor growth in mice administered 5-FU at 10 mg/kg/day for colo205 and at 30 mg/kg/day for HCT8 for 7 days followed by selumetinib at 10 mg/kg/day for colo205 and 25 mg/kg/day for HCT8 for another 7 days was significantly retarded than that in mice treated with single agents. But the combination in reverse sequence induced comparable tumor growth to single agents. Decreased expression of Ki67 was observed in tumors from mice treated as FS scheduling. Our results suggest that the schedule-dependent combination of 5-FU and selumetinib may be benefit in patients having CRC with hyper-activation of Ras/RAF pathway.

Citation Format: Hye Yeon Jang, Haeng Jung Lee, Yeo Jin Nam, Won Dong Kim, Yong Ju Bae, Jin Hwang Jung, Seung Jin Lee, Dae Hyuk Moon. Enhanced efficacy of selumetinib by pretreatment of 5-FU in preclinical Ras/Raf-mutant colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1204. doi:10.1158/1538-7445.AM2017-1204
Abstract 1210: Hederagenin overcomes the cisplatin resistance of head and neck cancer by targeting the antioxidant defense mechanisms
Authors: Shin Daiha , Kim Eun Hye , Jang Hyejin , Lee Jaewang , Kim Ji Won , Lee Jae Ryung , Kwon Minsu , Baek Seungho , Roh Jong-Lyel
Published: July 2017

Background: Cisplatin is a first-line chemotherapeutic agent for head and neck cancer (HNC). Acquired resistance to cisplatin is the most common reason for the failure of cisplatin chemotherapy. Hederagenin is extracted from the leaves of Cyclocarya paliurus, also known as sweet tea, which is one of the most popular teas utilized in traditional Chinese medicine. There is accumulating evidence it exhibited significant cytotoxicity against several types of cancers, however, which has been rarely tested in HNC cells. Herein, we examined the potential utility of hederagenin for overcoming cisplatin resistance in HNC cells and further clarified its molecular mechanisms of action.

Methods: Parental and cisplatin-resistant HNC cells, and Nrf2 or SLC7A11 gene overexpressed HNC cell lines and other human HNC cells were used. The cells were used to examine the effects of hederagenin treatment in HNC cell lines by measuring cell viability, cell cycle, cell death, reactive oxygen species (ROS) production, glutathione level, mitochondrial membrane potential (ΔΨm), and protein expression. The anti-tumor effect of hederagenin in mouse tumor xenograft models was also tested.

Results: Hederagenin induced cell death in both cisplatin-sensitive and -resistant HNC cells. Hederagenin treatment resulted in effective death of cisplatin-resistant HNC cells in a form of apoptotic cell death with the ΔΨm change. Hederagenin inhibited Nrf2 and SLC7A11 resulting in an increased ROS accumulation in HNC cells, of which effects were reversed by the pretreatment of antioxidant trolox. In addition, hederagenin caused the apoptosis effectively induced by targeting the antioxidant defense mechanisms in HNC cells. Subsequently, hederagenin activated signaling pathways of cell death involving caspase-3, PUMA, and PARP in the cells. The growth inhibitory effects of hedragenin were also confirmed in the tumor xenograft model implanted with cisplatin-resistant HNC cells.

Conclusions: Our data suggests that hederagenin can overcome the resistance of cisplatin in resistant HNC cells via targeting antioxidant systems.

Citation Format: Daiha Shin, Eun Hye Kim, Hyejin Jang, Jaewang Lee, Ji Won Kim, Jae Ryung Lee, Minsu Kwon, Seungho Baek, Jong-Lyel Roh. Hederagenin overcomes the cisplatin resistance of head and neck cancer by targeting the antioxidant defense mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1210. doi:10.1158/1538-7445.AM2017-1210
Abstract 1215: Apigenin overcomes drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer
Authors: Seo Hye-Sook , Ku Jin Mo , Hong Se Hyang , Choi Hyeong Sim , Woo Jong-Kyu , Jang Bo-Hyoung , Shin Yong Cheol , Ko Seong-Gyu
Published: July 2017

Drug resistance in chemotherapy is a major obstacle for successful treatment of cancer. Drug resistance is caused by various reasons including the overexpression of P-glycoprotein (P-gp, MDR1). Development of new useful compound which overcomes drug resistance is urgent. Apigenin, a dietary flavonoid, is reported as an anti-cancer drug in vivo and in vitro. In the present study, we investigated whether apigenin is able to reverse drug resistance using adriamycin-resistant breast cancer cells (MCF-7/ADR) and xenograft mouse model. As a result, apigenin significantly decreased cell growth and colony formation in MCF-7/ADR and its parental MCF-7 cells. This growth inhibition was related with accumulation of subG0/G1 apoptotic population and increase of apoptosis cell number. Apigenin reduced the mRNA expressions of multi-drug resistance 1 (MDR1) and multi-drug resistance associated proteins (MRPs) in MCF-7/ADR cells. Apigenin also down-regulated the expression of P-gp. Apigenin reversed drug efflux from MCF-7/ADR cells resulting in Rho123 accumulation. Inhibition of drug resistance by apigenin is related with suppression of STAT3 signaling pathway. Apigenin decreased STAT-3 activation (p-STAT3) and its nuclear translocation, and inhibited the secretion of VEGF and MMP-9 which are STAT3 target genes. STAT3 inhibitor, JAK inhibitor I and HIF-1α inhibitor decreased cell growth in MCF-7 and MCF-7/ADR cells. In conclusion, apigenin overcomes drug resistance, and this study advances human health.

Note: This abstract was not presented at the meeting.

Citation Format: Hye-Sook Seo, Jin Mo Ku, Se Hyang Hong, Hyeong Sim Choi, Jong-Kyu Woo, Bo-Hyoung Jang, Yong Cheol Shin, Seong-Gyu Ko. Apigenin overcomes drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1215. doi:10.1158/1538-7445.AM2017-1215
Abstract 1216: Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric cancer
Authors: Kim Hyun Myong , Jeong Inhye , Park Kyu Hyun , Kim Tae Soo , Kwon Woo Sun , Jeung Hei-Cheul , Jung Minkyu , Rha Sun Young
Published: July 2017

Platinum-based antineoplastic drugs are chemotherapeutic agents to usually treat gastric cancer (GC) include cisplatin. However, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Especially, increased DNA repair is drug targetable mechanism and useful in the treatment strategy of cisplatin-resistant cancer. Casein kinase 2 (CK2) has critical role of multiple cellular processes with DNA repair. For this reason, research for CK2 expression correlated with DNA repair mechanism is important in gastric cancer. Combination of cisplatin and CK2 inhibitor (CX-4945, also known as Silmitasertib, Senhwa Biosciences, USA) may improve cisplatin-induced DNA damage for GC treatment. In this study, we screened sensitivity of cisplatin and CX-4945 in 49 GC cell lines by MTT assay. For molecular profiling, we analyzed variants and gene expression using whole exome sequencing and RNA sequencing. RNA and protein expression of CK2 subunits (α/α’) using real-time RT-PCR and Western blot. Also, activity of CK2α was measured by ELISA. Combination treatment performed different schedules including concurrent and sequential. Synergistic effect was analyzed by Bliss Independence model. As CK2 profiling, CK2α’ mRNA expression was a tendency to correlated with CX-4945 sensitivity(p=0.0504). Moreover, CK2α’ protein expression was a correlated with CX-4945 sensitivity(p=0.0252). Other molecular profiling did not reveal any clear correlations. Twenty one (Group1: cisplatin extremely resistant and CK2 high, Group2: cisplatin intermediate resistant regardless of CK2 expression) cell lines were performed combination treatment. Both YCC-21 and YCC-28 cell lines show synergistic effect (+20% and +22%, respectively) in concurrent schedule. Only MKN-74 cell line show synergistic effect (+11%) in Pre-addition. The 4 cell lines (YCC-18, YCC-38, SNU-1 and -216) were show synergistic effect (+10%, +37%, +11% and +19%, respectively) in Post-addition. In conclusion, early inhibition of CK2 shows synergistic effect in group 1, because CK2 is high expression. In group 2, late inhibition of CK2 demonstrated synergistic effect. It means CK2-related DNA repair is up-regulating for repair to cisplatin-induced DNA damage. Personalized the treatment schedule for inhibit CK2-induced DNA repair is a new strategy to restore cisplatin resistant in GC.

Citation Format: Hyun Myong Kim, Inhye Jeong, Kyu Hyun Park, Tae Soo Kim, Woo Sun Kwon, Hei-Cheul Jeung, Minkyu Jung, Sun Young Rha. Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2017-1216
Abstract 1229: RNAi-based β-catenin inhibition in combination with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance
Authors: Ganesh Shanthi , Shui Serena , Chopda Girish , Koser Martin , Craig Kevin , Dutta Chaitali , Lai Cheng , Dudek Hank , Wang Weimin , Brown Bob D. , Abrams Marc
Published: July 2017

Despite recent advances in early detection and therapeutic intervention, colorectal cancer (CRC) remains one of the most deadly cancers in the United States. The Wnt/β-catenin and KRAS/BRAF-driven MAPK pathways were reported to cooperate in inducing CRC initiation and progression. Several studies have also identified Wnt signaling as a resistance mechanism in MAPK pathway-activated CRCs. Thus far, independent targeting of these single oncogenic events in CRC has yielded limited therapeutic success. RNA interference (RNAi) triggers are capable of silencing any expressed mRNA with high potency and specificity, including previously un-druggable targets such as β-catenin, an oncogene frequently dysregulated in CRC. DCR-BCAT is a chemically-optimized DsiRNA targeting CTNNB1, the gene which encodes β-catenin, formulated in a second-generation EnCore lipid nanoparticle. We have previously reported extensive preclinical pharmacology for DCR-BCAT in mouse tumor models of diverse origin. (Ganesh et al, Mol Cancer Ther 2016). Here we demonstrate that the dual inhibition of β-catenin and MEK demonstrates synergistic efficacy in not only primary CRC, but also in aggressive liver metastases of CRC in preclinical models. This combination of DCR-BCAT and the MEK inhibitor trametinib was also efficacious in tumors which are known to be resistant to trametinib, as well as tumors which acquire resistance due to drug exposure. These data support clinical development of these combination approaches for this first-in-class RNAi therapeutic.

Citation Format: Shanthi Ganesh, Serena Shui, Girish Chopda, Martin Koser, Kevin Craig, Chaitali Dutta, Cheng Lai, Hank Dudek, Weimin Wang, Bob D. Brown, Marc Abrams. RNAi-based β-catenin inhibition in combination with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance with MEK inhibition promotes synergistic anti-tumor efficacy and overcomes resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2017-1229
Abstract 1230: Talazoparib, a second generation PARP inhibitor, is a novel therapy for PTEN mutants in prostate cancer
Authors: Reinstein Zachary Z. , Vatapalli Rajita , Anker Jonathan , Pamarthy Sahithi , Carneiro Benedito , Abdulkadir Sarki
Published: July 2017

Prostate cancer is the most common cancer among men, other than skin cancer, in the United States. When the cancer enters into the metastatic castration resistant stage (mCRPC), few treatment options are currently available and the disease is considered incurable. The purpose of this study is to investigate a new, targeted therapy against prostate cancers, including mCRPC. Talazoparib is a novel PARP inhibitor with up to 100-fold higher potency and PARP affinity when compared to PARP inhibitors such as olaparib, veliparib, and rucaparib. Current literature suggests that PTEN mutants have high sensitivity to talazoparib. PTEN is a tumor suppressor gene that is commonly lost in prostate cancers. A murine prostate cancer cell line, Myc-CaP, which has been modified to overexpress the oncogene Myc, was edited by the CRISPR-Cas9 system to knock out the PTEN gene. Myc-CaP and Myc-CaP PTEN KO cells were treated with olaparib, an FDA approved, first generation PARP inhibitor, and talazoparib. Talazoparib decreased cell viability significantly more in PTEN KO cells versus PTEN wild-type (WT) cells. No such trend was observed when these cells were treated with olaparib. In addition, IC50 values in prostate cancer cell lines with heterozygous or homozygous deletion of PTEN were up to 20 times lower with the talazoparib treatment when compared to olaparib. Not only does this indicate that talazoparib is much more potent than olaparib, but also preferentially impairs cell growth in PTEN mutants. PTEN’s signal transduction prevents the phosphorylation of AKT, which is necessary for cell proliferation. When cells were treated with an AKT inhibitor, MK2206, alone or in combination with talazoparib, pAKT protein levels decreased, but the greatest effect was seen when MK2206 was used in combination with a low dose of talazoparib in the Myc-Cap cell line with wt PTEN. Western blot analysis showed that PTEN was upregulated following talazoparib treatment. These results indicate synergy of talazoparib and MK2206 in reducing the phosphorylation of AKT in a dose-dependent manner. Talazoparib is by far the most potent PARP inhibitor developed to date. With talazoparib potentially acting on prostate cancer with PTEN mutations, talazoparib treatment may expand current PARP inhibitor treatment in advanced prostate cancers and thereby elicit a response in as many as 80% of patients. Thus, talazoparib has vast therapeutic potential in prostate cancer.

Citation Format: Zachary Z. Reinstein, Rajita Vatapalli, Jonathan Anker, Sahithi Pamarthy, Benedito Carneiro, Sarki Abdulkadir. Talazoparib, a second generation PARP inhibitor, is a novel therapy for PTEN mutants in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1230. doi:10.1158/1538-7445.AM2017-1230
Abstract 1231: Restoration of tumor suppression in vivo by systemic delivery of PTEN mRNA nanoparticles
Authors: Xu Yingjie , Islam Mohammad Ariful , Zope Harshal , Mahmoudi Morteza , Langer Robert S. , Shi Jinjun , Zetter Bruce R. , Farokhzad Omid C.
Published: July 2017

PTEN (phosphatase and tensin homolog on chromosome ten) is one of the most common lost or mutated tumor suppressor genes in human cancers, including ~50% of metastatic castration-resistant prostate cancer (mCRPC). By catalyzing PIP3 dephosphorylation, PTEN negatively regulates the PI3K-AKT-mTOR pathway, which is frequently altered in mCRPC. Reintroduction of functional PTEN for mCRPC treatment has proven difficult. By employing self-assembled lipid-polymer hybrid nanoparticle platforms, we successfully reintroduced PTEN mRNA to PTEN-null prostate cancer cells both in vitro and in vivo. These mRNA-loaded nanoparticles demonstrate high protein expression efficiency, low toxicity and good stability in serum and tumor accumulation. We confirmed that restoration of PTEN in PTEN-null prostate cancer cells inhibits the PI3k-AKT pathway, reduces cell viability and enhances apoptosis in vitro. Systemic delivery of PTEN mRNA-loaded nanoparticles in prostate xenograft tumors results in ~85% inhibition of tumor growth and leads to tumor cell death without toxic side effects in vivo. In summary, this work provides proof of concept of mRNA-based gene therapy for systemic restoration of functional PTEN for tumor suppression in vivo. It represents a novel approach to PI3K-AKT pathway inhibition, with the potential to specifically target cancers with loss of PTEN function.

Citation Format: Yingjie Xu, Mohammad Ariful Islam, Harshal Zope, Morteza Mahmoudi, Robert S. Langer, Jinjun Shi, Bruce R. Zetter, Omid C. Farokhzad. Restoration of tumor suppression in vivo by systemic delivery of PTEN mRNA nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1231. doi:10.1158/1538-7445.AM2017-1231
Abstract 1237: PDGF induces cell growth and changes in glucose metabolism in colon cancer in the absence of PDGF receptors
Authors: Moench Romana , Grimmig Tanja , Germer Christoph-Thomas , Waaga-Gasser Ana Maria , Gasser Martin
Published: July 2017

Background: The Platelet derived growth factor (PDGF) and its receptors play a major role in inducing proliferation, migration, and angiogenesis by activating intracellular PI3K/Akt/mTOR signaling events in different solid tumors and therefore represent attractive targets in tumor therapy. Recently we showed a PDGF-induced activation of metabolism and proliferation in HT29 colon cancer cells in the absence of specific PDGF receptors. The aim of this study was to analyze PDGFR and VEGFR expression and possible alternative PDGF binding partners in colorectal cancer (CRC).

Methods: Human HT29 colon cancer cells were cultured and stimulated with PDGF in a time-dependent manner. Additionally, VEGFR2 and EGFR inhibition was performed to analyze alternative PDGF signaling events. Whole cell or RNA extracts were analyzed by Western Blot and RT-q-PCR for receptors and PI3K/Akt/mTOR signaling. To investigate the effects of specific receptor inhibition on proliferation, MTS proliferation assays were performed. Moreover, mRNA levels of PDGFR and VEGFR in tumors from patients with CRC were analyzed by RT-qPCR.

Results: Human UICC stage I-IV tumors exhibited a significantly increased PDGFRβ and VEGFR1,2 gene expression. As observed previously, HT29 colon cancer cells showed only positivity for VEGFR1,2, but no PDGFR protein expression. Despite that, stimulation with PDGF resulted in increased proliferation and metabolic changes. In contrast, Caco-2 and SW480 colon cancer cells showed PDGFR and VEGFR expression on protein level. Interestingly, PDGF stimulation increased VEGFR1 and 2 gene expression in HT29 colon cancer cells and secondly inhibition of VEGFR2 and EGFR showed alterations in proliferation and Akt signaling in PDGF stimulated cancer cells.

Conclusion: Despite the absence of PDGF receptors in HT29 colon cancer cells, PDGF induced proliferating and metabolic effects in the tumor cells, suggesting an alternative binding partner on the tumor cell surface. Further investigation of the alternative PDGF binding partners could be of clinical relevance in CRC.

Note: This abstract was not presented at the meeting.

Citation Format: Romana Moench, Tanja Grimmig, Christoph-Thomas Germer, Ana Maria Waaga-Gasser, Martin Gasser. PDGF induces cell growth and changes in glucose metabolism in colon cancer in the absence of PDGF receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1237. doi:10.1158/1538-7445.AM2017-1237
Abstract 1247: Identifying novel regulators of the Unfolded Protein Response (UPR) by genome-scale CRISPR-Cas9 knockout screens
Authors: Leli Nektaria Maria , Dey Souvik , Brady Lauren , Koumenis Constantinos
Published: July 2017

Development and growth of a tumor as well as its ability to metastasize involves a complex relationship with its tissue microenvironment. A proliferating tumor encounters several microenvironmental stress conditions such as hypoxia, lack of nutrients and acidosis. To cope with these conditions, cancer cells have developed elaborate cytoprotective mechanisms which provide them with distinct advantages to thrive. Thus, deciphering the signaling pathways which get activated in the tumor microenvironment has been paramount to develop new therapeutic strategies for treatment. The Unfolded Protein Response (UPR) is an adaptive prosurvival pathway elicited by stresses in the tumor microenvironment (e.g., hypoxia, low glucose) and involves translational and transcriptional activation of effector genes which act to relieve cellular stress and block cancer cell death. We developed a strategy to comprehensively analyze critical mediators of cell fate in response to UPR activation. We have delivered a lentiviral genome-scale CRISPR Cas9 knockout (GeCKOv2) library to Sq20B cells (human squamous head and neck carcinoma) and A375 (human melanoma) cells. The library is targeting 19,050 genes with 123,411 unique guide sequences and enables both negative and positive selection screening. We used the GeCKO v2 library to identify genes essential for triggering the UPR in response to thapsigargin and tunicamycin, known specific activators of ER stress. Our highest-ranking candidates include BIRC5/Survivin, a well-studied molecule that acts as an inhibitor of apoptosis and is highly expressed in cancer cells and eukaryotic translation initiation factor eIF6, whose overexpression increases motility and invasiveness of cancer cells. Our preliminary results indicate that loss of Survivin and eIF6 dramatically enhance sensitization of cells to various ER stress conditions. Moreover, this synergistic outcome is observed when cells are treated with YM155, a small molecule that selectively suppresses Survivin and is used in phase I/II clinical trials. Lastly, morphological changes like endoreduplication are observed after long term absence of Survivin indicating its endogenous ER stress inducing role. Taken together, Survivin and eIF6 are important mediators of survival following ER stress and characterizing the pathways involved can lead to the development of novel targeted agents and therapeutic approaches.

Citation Format: Nektaria Maria Leli, Souvik Dey, Lauren Brady, Constantinos Koumenis. Identifying novel regulators of the Unfolded Protein Response (UPR) by genome-scale CRISPR-Cas9 knockout screens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1247. doi:10.1158/1538-7445.AM2017-1247
Abstract 1251: Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice
Authors: Miyazawa Miki , Subbaramaiah Kotha , Bhardwaj Priya , Zhou Xi Kathy , Wang Hanhan , Falcone Domenick J. , Giri Dilip D. , Dannenberg Andrew J.
Published: July 2017

Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and poor prognosis for PC patients. Recently, we showed that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade PC in men. It’s possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the natural history of PC. Pioglitazone, a ligand of PPARγ, is used to treat diabetes and possesses anti-inflammatory properties. Here our main objectives were to determine if pioglitazone inhibited obesity-related periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Mice were fed either a high fat (HF) diet or low fat (LF) diet to determine if obesity caused periprostatic WAT inflammation as defined by the presence of CLS. To determine if pioglitazone inhibited obesity-associated periprostatic WAT inflammation, obese HF diet fed mice were either continued on HF diet alone or treated with HF diet containing two doses (0.005% or 0.05% w/w) of pioglitazone. Treatment with pioglitazone reduced the density of CLS in periprostatic WAT, and suppressed levels of TNF-α, TGF-β and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knock out mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obese mice. Pioglitazone blocked TNF-α-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone-mediated induction of adiponectin suppressed the elevation in MCP-1 levels thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPARγ-adiponectin-MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade PC or improve outcomes for men with PC.

Citation Format: Miki Miyazawa, Kotha Subbaramaiah, Priya Bhardwaj, Xi Kathy Zhou, Hanhan Wang, Domenick J. Falcone, Dilip D. Giri, Andrew J. Dannenberg. Pioglitazone inhibits periprostatic white adipose tissue inflammation in obese mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1251. doi:10.1158/1538-7445.AM2017-1251
Abstract 1262: Aspirin inhibits the carcinogenesis of esophageal squamous cell carcinoma and enhances its responses to cisplatin
Authors: Zou Zhigeng , Fan Hongjun , Yu Xiying , Zhang Shuming , Guo Liping , Jiang Wei , Lu Shih-Hsin
Published: July 2017

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Over 70% of ESCC cases occur in China. Unfortunately, the treatment of ESCC has hardly been improved all these years. Several studies suggested that aspirin (ASA) might decrease the risk of ESCC and prolonged the survival of patients with ESCC. However, it is unclear if ASA could prevent ESCC and/or enhance ESCC treatment by chemotherapy. In this study, a N-nitroso-N-methylbenzylamine (NMBzA) - induced ESCC model was employed to prove that aspirin could prevent the growth of esophageal tumor. F344 rats were treated with NMBzA by subcutaneous injection with or without ASA in drinking water (2mg/ml). After 35 week ASA-NMBzA or NMBzA alone treatment, rats were killed and esophageal tumor development were examined. The results showed that F344 rats treated with NMBzA and receiving a daily intake of ASA developed much less tumors than F344 rats treated with NMBA alone both in amount and in size (Tumor count: 2.40 ± 1.57 vs 10.85 ± 3.86 , P < 0.001; Tumor volume: 11.10 ± 13.38 mm3 vs 70.79 ± 41.65 mm3, P < 0.001). Immunohistochemical analysis indicated that a higher rate of apoptosis was observed in the basal layer of esophageal epithelium in ASA-NMBzA treated rats than in NMBzA alone treated rats. These results indicated that ASA prevented development of esophageal tumors in rats induced by NMBzA. Moreover, using in vitro human ESCC cell culture and in vivo xenograft models, we showed that ASA has strong beneficial effects on inhibition of ESCC cell proliferation and colony formation, reduction of ESCC cancer stem cells and enhance of ESCC cell cytotoxicity induced by cisplatin treatment. Biochemical analysis revealed that these effects of ASA on human ESCC cells in vitro and in vivo were due to inhibiting the repairing of DNA damage, decreasing the efflux activity and ALDH1 activity of the tumor cells, and blockades of PI3K/Akt pathway. Thus, our results demonstrated a positive role of aspirin in the prevention and treatment of ESCC.

Note: This abstract was not presented at the meeting.

Citation Format: Zhigeng Zou, Hongjun Fan, Xiying Yu, Shuming Zhang, Liping Guo, Wei Jiang, Shih-Hsin Lu. Aspirin inhibits the carcinogenesis of esophageal squamous cell carcinoma and enhances its responses to cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1262. doi:10.1158/1538-7445.AM2017-1262
Abstract 1266: Metformin represses esophageal carcinogenesis in NMBzA-treated rat model through inhibiting AMPK/mTOR and Stat3 signaling pathways
Authors: Fan Hongjun , Zou Zhigeng , Yu Xiying , Guo Liping , Jiang Wei , Lu Shih-Hsin
Published: July 2017

Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Metformin is one of the most used diabetic drugs for the management of type 2 diabetes mellitus in the world. The role of metformin in prevention of the development and progression of a variety of human tumors has been studied. However, the detailed mechanisms have not yet been fully understood. In the present study, we investigated the effects of metformin on the suppression of esophageal carcinogenesis in a rat model, in which F344 rats were treated with N-nitroso-N-methylbenzylamine (NMBzA 0.30 mg/kg s.c.) three times per week for 35 weeks to induce esophageal tumors. To monitor the effects of metformin in this model, one group of rats were administered with metformin (3 g/L) in the drinking water at the first NMBzA injection. Our results showed that although there was no significant difference in body weight in rats of different groups, rats treated with NMBzA and metformin together significantly reduced the tumor formation and tumor volume when compared with rats treated with NMBzA alone. Statistic analyses demonstrated that the tumor numbers was reduced in NMBzA-treated rats received metformin to an average of 1.85 ± 1.09 tumors per rat when compared with 10.85 ± 3.86 (P < 0.001) in rats without metformin, while the tumor volume was decreased from 70.79 ± 41.65 mm3 per rat without metformin administration to 8.64 ± 13.45 mm3 (P < 0.001) with metformin administration. In addition, 7 out of 24 rats in the NMBzA-treated group died before week 35 but no rats died in the other groups. Furthermore, immunoblotting analysis indicated that p-mTORSer2448, p-Stat3Tyr705, and Cyclin D1 protein levels significantly decreased, while p-AMPKThr172 significantly increased in tumors obtained from rats treated with NMBzA and metformin when compared with tumors obtained from rats treated with NMBzA alone. Thus, our results indicated that metformin suppressed NMBzA-induced esophageal carcinogenesis via inhibition of the AMPK/mTOR and Stat3 signaling pathways. Together, our study suggested that metformin might have a potential use for treatment and prevention of esophageal cancer.

Citation Format: Hongjun Fan, Zhigeng Zou, Xiying Yu, Liping Guo, Wei Jiang, Shih-Hsin Lu. Metformin represses esophageal carcinogenesis in NMBzA-treated rat model through inhibiting AMPK/mTOR and Stat3 signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2017-1266
Abstract 1277: Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with obesity and lifestyle factors on postmenopausal breast cancer risk
Authors: Jung Su Yon , Ho Gloria , Rohan Thomas , Strickler Howard , Bea Jennifer , Papp Jeanette , Sobel Eric , Zhang Zuo-Feng , Crandall Carolyn
Published: July 2017

Objectives: Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. Stratifying via obesity and lifestyle modifiers, we evaluated the effects of insulin-like growth factor-I (IGF-I)/insulin resistance (IR)–related traits on breast cancer risk as a mediator or influencing factor in this case-cohort study.

Method: Using 75 single-nucleotide polymorphisms (SNPs) in genes related to IGF-I/IR traits and signaling pathways, and data from 1,003 postmenopausal women in Women’s Health Initiative Observation ancillary studies, we assessed the effects of IGF-I/IR-traits (fasting total and free IGF-I, IGF binding protein-3, glucose, insulin, and homeostatic model assessment–insulin resistance) by proportional change estimation. Using traits as mediators of the IGF-I/IR–traits genetic variants-cancer relationship, we partitioned total effect of these genetic variants on cancer risk into two putative mechanisms: 1) indirect (mediated by traits) and 2) direct (through pathways other than traits). For the effects of IGF-I/IR traits on IGF-I/IR signaling pathways–relevant genetic variants–cancer risk, we used the same algorithm as that for mediator, but interpreted as an influential factor.

Results: Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E nonusers and users. The mediation effects of IGF-I/IR traits on these SNPs–cancer relationship differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by IGF-I/IR traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways–related genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP–cancer relationship explained by IGF-I/IR traits varied 45-50% between the strata.

Conclusions: Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits.

Citation Format: Su Yon Jung, Gloria Ho, Thomas Rohan, Howard Strickler, Jennifer Bea, Jeanette Papp, Eric Sobel, Zuo-Feng Zhang, Carolyn Crandall. Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with obesity and lifestyle factors on postmenopausal breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1277. doi:10.1158/1538-7445.AM2017-1277
Abstract 1279: A polymorphism of VEGF -2489C/T is associated with prostate cancer susceptibility in Mexicans
Authors: Martínez-Rizo Abril , Casillas-Rangel Xavi ,   Cuerpo Académico Investigación Bioquímica (UAN-CA-266), Andrade-Madrid Hilda , Benites-Godinez Veronica , Rodríguez-Ocampo Nallhely
Published: July 2017

Introduction: Prostate cancer (CaP) encompasses a range of malignant prostate tissue dysplasias that primarily affects men over 50 years, is the second leading cause of cancer mortality in males. VEGF expression is associated with tumor progression and metastasis in patients with CaP. The SNP -1154 G/A is associated with the severity of CaP populations in Tunisia and the United Kingdom while -634 G/C alone has been associated in Tunisian population. It is unknown whether these polymorphisms could serve as biomarkers in the Mexican population.

Aim: To associate VEGF polymorphisms -1154 G/A and - 634 G/C with the severity of prostate cancer in patients of western Mexico.

Materials and methods: The gDNA was analyzed a total of 525 men of whom 301 are presented HBP and 224 patients with clinical diagnosis of prostate cancer. For association with severity they were subclassified into high (≥7) and low grade (≤6) following the Gleason scale. Genotyping was performed by Real Time PCR using TaqMan probes system.

Results. When we compare the allelic frequencies in the control group, they are in Hardy-Weinberg equilibrium. However, no significant association of the disease with polymorphisms or severity or progression was found.

Conclusions: There is no association between prostate cancer and genetic polymorphisms at -634 and -1154 position of the promoter region of VEGF.

Note: This abstract was not presented at the meeting.

Citation Format: Abril Martínez-Rizo, Xavi Casillas-Rangel, Cuerpo Académico Investigación Bioquímica (UAN-CA-266), Hilda Andrade-Madrid, Veronica Benites-Godinez, Nallhely Rodríguez-Ocampo. A polymorphism of VEGF -2489C/T is associated with prostate cancer susceptibility in Mexicans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1279. doi:10.1158/1538-7445.AM2017-1279
Abstract 1293: ABO blood type and cancer risk: preliminary findings from a phenome analysis
Authors: Beeghly-Fadiel Alicia , Giri Ayush , Bastarache Lisa , Pulley Jill , Warner Jeremy , Denny Josh
Published: July 2017

Introduction: ABO blood type has long been implicated in disease susceptibility, including cancer. However, evidence for associations with many malignancies is mixed. We applied a novel phenome approach to test to cancer codes from electronic medical records (EMR) in relation to ABO blood type in a large predominantly Caucasian study population.

Approach: Among adults aged 18-100, cancer case and control status were assigned using 58 general neoplasm related phenome codes to de-identified EMR at the Vanderbilt University Medical Center. Blood type from serologic assays was ascertained from EMR-linked laboratory reports. Associations between blood type and cancer phenomes were quantified with Odds Ratios (OR) and corresponding 95% Confidence Intervals (CI) from logistic regression in models adjusted for sex and stratified by race/ethnicity. Only analyses with at least 100 cases per strata were conducted.

Results: Among 221,015 Non-Hispanic Caucasians, 37,841 Blacks, 7,714 Hispanic Caucasians, and 3,616 Asian subjects with ABO blood type available in linked EMR, we evaluated 56, 37, 4, and 3 general cancer phenome codes, respectively. After employing Bonferroni corrections, ABO blood type was significantly associated with cancers of the pancreas, ovary, cervix, skin, and hematopoietic system. Caucasians with blood type O were less likely to have ovarian cancer (OR: 0.82, 95% CI 0.73-0.91) and pancreatic cancer (OR: 0.83, 95% CI: 0.74-0.92), and more likely to have squamous cell or other skin cancer (OR: 1.08, 95% CI: 1.04-1.13) and myeloid leukemia (OR: 1.15, 95% CI: 1.06-1.25) than those with other blood types (A, B, or AB). Hispanic Caucasians with blood type O were less likely to have cervical cancer (OR: 0.56, 95% CI: 0.38-0.82) than those with other blood types. No associations surpassed correction for multiple comparisons among Blacks or Asians.

Conclusions: Our phenome approach confirmed known associations between blood type and risk of pancreatic and ovarian cancer, and adds to accumulating evidence supporting associations with skin cancer and leukemia. Our novel cervical cancer association among Hispanic Caucasians and other nominally significant findings, especially in understudied non-Caucasians, should be further evaluated in large and diverse populations. In addition, research to determine how ABO blood type may influence cancer development and progression, and if such associations can be exploited for risk prediction or cancer prevention is warranted.

Citation Format: Alicia Beeghly-Fadiel, Ayush Giri, Lisa Bastarache, Jill Pulley, Jeremy Warner, Josh Denny. ABO blood type and cancer risk: preliminary findings from a phenome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1293. doi:10.1158/1538-7445.AM2017-1293
Abstract 131: Chemotherapeutic effects of naturally occurring colossolactones against solid tumor cells in-vitro
Authors: Baghdadi Mohammed A. , Al-Abbasi Fahad A. , El-Halawany Ali M. , Al-Abd Ahmed M.
Published: July 2017

Colossolactones were isolated previously from the Vietnamese mushroom ganoderma colossum, such triterpenoids. The different colossolactone compounds (schisanalactonoe a, colossolactone I, ergosterol, colossolactone III, colossolactone II, colossolactone IV, colossolactone E) characterized by the presence of a six-membered lactone ring (ring D) with or without a seven-membered lactone rings (ring A) were isolated. In the current study, using DPPH free radical scavenging assay, all colossolactone compounds showed weak antioxidant activity with EC50’s of 99.46, 220.32, 219.65, 100.81, 238.54, 116.57 and 131.94 µM, respectively. Isolated compounds were examined for their potential anticancer activity against breast (MCF-7), cervix (HeLa), colorectal (HCT-116) and liver (HepG2) cancer cells. Cytotoxicity of the isolated compounds was assessed in the aforementioned cell lines using SRB assay after 72 h of exposure and fitted using Emax model. Amongst colossolactones, schisanalactonoe-A and colossolactone-IV showed the best cytotoxic profile in all cell lines under investigation with IC50’s ranged from 4.9 to 64.2 µM; and R-fraction less than 47.5%. Further mechanistic studies for the detailed mechanism of cytotoxicity of schisanalactonoe-A and colossolactone-IV are currently carried out.

Citation Format: Mohammed A. Baghdadi, Fahad A. Al-Abbasi, Ali M. El-Halawany, Ahmed M. Al-Abd. Chemotherapeutic effects of naturally occurring colossolactones against solid tumor cells in-vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 131. doi:10.1158/1538-7445.AM2017-131
Abstract 1311: Germline variation at 8q24 and prostate cancer risk
Authors: Wang Kan , Olama Ali Amin Al , Eeles Rosalind , Conti David , Kote-Jarai Zsofia , Haiman Christopher A.
Published: July 2017

The 8q24 region harbors multiple risk variants for distinct cancers including 7 for prostate cancer, the majority of which lie in separate linkage disequilbrium blocks. It is not known whether a common biological mechanism underlies the association of genetic variation with cancer risk at 8q24, or whether there are site-specific functions of regulatory elements that are affected in this region. Given the proximity, the MYC oncogene is a likely candidate as are multiple long non-coding RNAs in the region. To further understand the contribution of germline variation to prostate cancer risk we performed a comprehensive fine-mapping analysis of the region in men of European ancestry from the PRACTICAL/ELLIPSE Consortium. More specifically, we tested 1,731 genotype tag SNPs and 12,221 imputed variants spanning the risk region (127.3-129.0Mb) in 56,363 prostate cancer cases and 37,386 controls of European ancestry that were genotyped with the Illumina OncoArray. We performed stepwise logistic regression and identified 13 variants with risk allele frequencies between 0.006 and 0.998 that surpassed genome-wide statistical significance (p-values between 3.2x10-8 and 8.0 x10-78) and with per allele odds ratios ranging from 1.11(rs5013678) to 2.68(rs183373024). Ongoing analyses that will be presented include incorporating existing GWAS and fine-mapping data (iCOGs) for men of European and African ancestry (35,000 cases and 35,000 controls) using JAM, a Bayesian approach that investigates multi-SNP models using marginal meta-analysis statistics. Leveraging the power from the overall multiethnic meta-analysis (>93,000 cases and >72,000 controls) will provide further insight into the number of independent signals in the region and their contribution to prostate cancer risk in these populations.

Citation Format: Kan Wang, Ali Amin Al Olama, Rosalind Eeles, David Conti, Zsofia Kote-Jarai, Christopher A. Haiman. Germline variation at 8q24 and prostate cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1311. doi:10.1158/1538-7445.AM2017-1311