bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2180: Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs
Authors: Ahmadibeni Yousef , Karim Kaleh , Boadi William
Published: July 2017

Leuprorelin (LEP) is a synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in 1985. The initial effect of administration LEP is to stimulate the pituitary secretion of FSH and LH. After a prolonged stimulation (constant concentration of LEP in the blood) pituitary becomes insensitive to the action of GnRH. This reduces the level of gonadotropin in the blood, resulting in decreased levels of sex hormones to postcastration or menopausal levels. In addition to the usual side effects of this agonist analogs of LH-RH, other reported adverse effects include transient hypertension, dry mouth, excessive salivation, paraesthesia and increased dysuria. Improving the biological activity of LEP by increasing the cellular uptake and retention is a remedy to this end.

In this study, a prodrug strategy has been introduced to optimize the hydrophobicity of LEP by using an appropriate hydrophobic linker attached to tris(4-methoxyphenyl)methanol (TPM) derivatives with the expectation to improve the cellular uptake. In this regard, several LEP conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. anisole, 2-fluoroanisole, 2-methylanisole 1,2-dimethoxybenzene or methyl 2-methoxybenzoate and 1,3,5-trioxane, followed by the conjugation with LEP and dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields.

Comparative antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of LEP.

Citation Format: Yousef Ahmadibeni, Kaleh Karim, William Boadi. Triphenylmethanol conjugates of leuprorelin asanti-cancer prodrugs [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 2180. doi:10.1158/1538-7445.AM2017-2180
Abstract 2187: A pro-nanodrug with intratumoral reconstitution and intracellular delivery beyond therapy-resistance molecular pumps
Authors: Xu Rong , Ferrari Mauro , Shen Haifa
Published: July 2017

Tumor metastases to distant organs pose a serious challenge to cancer treatment. The metastatic tumor lesions are less accessible to cancer drugs and the malignant cells often quickly develop therapy resistance. To address both biological and drug transport concerns in cancer treatment, we have developed a novel composite pro-nanodrug to provide sustained intra-tumoral assembly of nanotherapeutics, and tested its anti-cancer efficacy in murine models of breast cancer metastases to the lung and liver. Specifically, large payloads of polymeric doxorubicin (pDox) pro-drug were packaged as single molecules into a porous silicon microparticles that can be enriched in tumor tissue in the forms of vascular and cellular depots. Once inside the tumor, the pDox molecules self-assemble into nanoparticles that are released into the tissue where they are effectively internalized by tumor cells. The nanoparticulate prodrug is transported through the vesicular system, and doxorubicin is cleaved from the polymer and released in the immediate proximity of the nucleus beyond the reach of the drug efflux pumps. In vivo efficacy studies demonstrated that the pro-nanodrug was effective in treating metastatic tumors with or without expression of the multi-drug resistant genes.

Citation Format: Rong Xu, Mauro Ferrari, Haifa Shen. A pro-nanodrug with intratumoral reconstitution and intracellular delivery beyond therapy-resistance molecular pumps [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 2187. doi:10.1158/1538-7445.AM2017-2187
Abstract 2211: Characterization of monoclonal antibodies specific for HPV-positive head and neck cancer
Authors: Liu Hsuan-Chen , Parikh Falguni , Kraus Thomas , Moran Thomas , Sikora Andrew
Published: July 2017

HPV-driven head and neck squamous cell carcinoma (HNSCC) are among the fastest growing cancers. Although, HPV-HNSCC patients have an overall favorable prognosis, a significant number of patients relapse post-treatment, and currently there is no specific therapeutic approach targeting the unique biology of HPV-driven HNSCC. Our ongoing efforts to target HPV-HNSCC focus on the identification of cell surface antigens that are upregulated by HPV infection. We have developed an "antigen-agnostic" approach for generating HPV-HNSCC-targeting monoclonal antibodies for cancer diagnosis and treatment that does not rely on prior identification of target antigens. We used HPV-HNSCC membrane fractions to immunize recipient mice and generated HPV-specific hybridomas. We then screened five thousand hybridoma colonies by flow cytometry to test the specificity of binding to HPV-positive cancer cell lines (2HNSCC and 2 Cervical Cancer) and HPV-negative cancer cell lines (4 HNSCC and 1 CC). After primary screening, we narrowed down to forty-four clones; among these hybridoma clones, 6D8 and 6B3 bound preferentially to HPV-positive cancer cell lines. The binding targets of 6D8 and 6B3 were identified by immunoprecipitation and mass spectrometry; their targets are integrin alpha6 (ITGA6) and tissue factor (F3) respectively. Future work will validate the biological function of these mAbs in in vitro and in vivo models, and continue identifying more binding target of mAbs. We propose mAbs specifically targeting membrane-expressed antigens on HPV-related cancer cells as a potential approach for early diagnosis and targeted therapy.

Citation Format: Hsuan-Chen Liu, Falguni Parikh, Thomas Kraus, Thomas Moran, Andrew Sikora. Characterization of monoclonal antibodies specific for HPV-positive head and neck 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 2211. doi:10.1158/1538-7445.AM2017-2211
Abstract 2212: Protein engineering of the decapping enzyme NudT16 enhances its ability to hydrolyze protein-conjugated ADP-ribose for post-translational site identification via mass spectrometry
Authors: Thirawatananond Puchong , McPherson Robert L. , Malhi Jasmine K. , Leung Anthony K. , Gabelli Sandra B.
Published: July 2017

During nonhomologous end joining of DNA follow double-stranded breaks, one common signaling response is the adenosine diphosphate ribosylation (ADP-ribosylation) of recruiter scaffold proteins. ADP-ribosylation is a post-translational modification (PTM) that occurs on aspartate, glutamate, lysine, arginine and cysteine on proteins and is mediated chiefly by polyadenosine ribose polymerases (PARP). Using NAD+ as its substrate, PARP transfers an ADP-ribose onto another protein, releasing a nicotinamide ring in the process; this modification presents as a mono-ADP-ribosylation (MARylation) or poly-ADP-ribosylation (PARylation). While site identification of MARylated protein can be achieved through tandem MS/MS and searching for peptides whose spectra have been shifted by 541.0611 Da, a similar approach for PARylated protein is confounded by the variable length and branching of its PTM. To this end, ADP-ribosylated protein is normally incubated with a snake venom phosphodiesterase (SVP) to leave a standardized phosphoribose tag of 212.0086 Da. It has been shown that a recombinantly-expressed Nudix protein NudT16 provides a cost-effective alternative to SVP to process ADP-ribosylated protein. NudT16 in the cell normally decaps small nucleolar RNA. Our studies here sought to utilize the x-ray crystallographic structure of NudT16 in complex with ADP-ribose in guiding rational design mutations to enhance binding of our desired ADP-ribose substrate and to widen the hydrolase’s active site to better accommodate a protein-conjugated ADP-ribose. Mutants have demonstrated improved catalytic efficiency for ADP-ribose hydrolysis. Radiolabeled immunoassays of PARylated protein concur with these kinetic experiments by showing a reduction of radiolabeled PARP. Rational design of a ADP-ribose-hydrolyzing NudT16 with comparable catalytic efficiency to SVP eases lead discovery of biological mechanisms that are mediated through ADP-ribosylation such as DNA repair.

Citation Format: Puchong Thirawatananond, Robert L. McPherson, Jasmine K. Malhi, Anthony K. Leung, Sandra B. Gabelli. Protein engineering of the decapping enzyme NudT16 enhances its ability to hydrolyze protein-conjugated ADP-ribose for post-translational site identification via mass spectrometry [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 2212. doi:10.1158/1538-7445.AM2017-2212
Abstract 2224: Increased 15-lipoxygenase-1 activity limits tumor development in the azoxymethane mouse model of colon cancer: impact of omega-3-acid ethyl esters
Authors: Zuo Xiangsheng , Colby Jennifer K. , Liu Fuyao , Gao Shen , Wu Ling , Jaoude Jonathan C. , Moussalli Micheline J. , Tan Lin , Yang Peiying , Shureiqi Imad
Published: July 2017

Pro-inflammatory signaling has been shown to promote colorectal tumorigenesis and is a target for the development of effective chemopreventive approaches. The specialized pro-resolving lipid mediators (SPMs, e.g. resolvins), bioactive metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), actively terminate inflammation and have been proposed to possibly contribute to the anti-tumorigenic effects of DHA and EPA. The enzyme 15-lipoxygenase-1 (ALOX15) is a key biosynthetic enzyme in generation of resolvins. However, 15-LOX-1 expression is commonly lost during human CRC tumorigenesis starting in premalignant stages via transcriptional mechanisms independent of substrate availability. The impact of ALOX15 on DHA and EPA’s effects on tumorigenesis remain unknown. Mice with intestinal epithelium-specific expression of human ALOX15 (15-LOX-1-gut mice) and wild-type FVB controls were injected with azoxymethane (AOM, 7.5mg/kg) once weekly for 6w and followed for 20w. Mice were fed diet with 1% omega-3-acid ethyl esters (O3AEE, a pharmaceutical grade fish oil preparation of EPA and DHA ethyl esters) or control diet starting 3w before initiation with AOM. Colonic tumors developed in 10 of the 13 (77%) wild type (WT) mice fed control diet, 5 of the 10 (50%) WT mice fed O3AEE diet, 5 of the 12 (42%) 15-LOX-1-gut mice fed control diet, and 3 of the 10 (30%) 15-LOX-1-gut mice fed control diet. Lipid mediator levels were measured by liquid chromatography/ tandem mass spectrometry (LC-MS/MS). The SPMs resolvin E1 and D2 (RvE1, RvD2) as well as the pathway intermediates 18-HEPE and 17-HDHE were increased in ALOX15-gut mice on O3AEE (see Table; data are shown as ng/mg protein; mean ± SEM). Our results demonstrate that ALOX15 activity is important to DHA and EPA formation of resolvins and inhibition of colonic tumorigenesis. Supported by grants CPRIT RP150195 and NIH RO1 R01CA195686

SPMs in O3AEE or control diet fed miceWTWT15-LOX-1-gut15-LOX-1-gutControl dietO3AEE dietControl dietO3AEE diet18-HEPE00.46 + 0.500.82 + 0.3117-HDHE0.21 + 0.090.2 + 0.74.2 + 0.4113.35 + 3.1RvE10001.98 + 0.77RvD200.024 + 0.0240.17 + 0.0220.3 + 0.077

Citation Format: Xiangsheng Zuo, Jennifer K. Colby, Fuyao Liu, Shen Gao, Ling Wu, Jonathan C. Jaoude, Micheline J. Moussalli, Lin Tan, Peiying Yang, Imad Shureiqi. Increased 15-lipoxygenase-1 activity limits tumor development in the azoxymethane mouse model of colon cancer: impact of omega-3-acid ethyl esters [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 2224. doi:10.1158/1538-7445.AM2017-2224
Abstract 2228: Altering rictor with diosmetin reduces tumor progression in orthotopic prostate cancer model
Authors: Pakradooni Rebecca , Khalifa Ahmad , Patel Riddhi , Shukla Sanjeev
Published: July 2017

Rapamycin insensitive companion of mTOR (Rictor) is an essential subunit of mTOR complex 2, maintains the integrity of the complex and functions as full activator of Akt. Rictor has been implicated to be involved in growth and progression of malignancies. Reports suggested that overexpression of Rictor in prostate cancer tissues, which may have potential role in prostate cancer progression. We demonstrated silencing Rictor in PC-3 cells decreased p- Akt (Ser-473) expression; conversely p-Akt (Thr-308) and p-PKCα (Ser-657) expression was increasing. Additionally to observe the molecular mechanism of Rictor regulation, we took HAP1 cells (derived from male chronic myelogenous leukemia (CML) cell line KBM-7) were edited and silenced by CRISPR/Cas9 with 2 and 10 base pair Rictor in a coding exon 5. HAP1 haploid human cell line contains a single copy of all chromosomes except for a heterozygous 30-megabase fragment of Chromosome 15; these cells are instrumental for genetic screening, as gene inactivation is greatly facilitated by the absence of a second gene copy. In these cells we observed p-Akt (Ser-473) expression was significantly less with more pronounced in 10 base pair than 2 base pair. Further to determine potential role of diosmetin (5, 7-Trihydroxy-4′-methoxyflavone; a natural flavonoid present in citrus plant, has anti-mutagenic properties) on Rictor silenced 2 base pair and 10 base pair HAP1 cells, we treated these cells in concentration response fashion, and observed decrease in p-Akt (Ser-473) expression than control cells. Next, we determine invivo potential of Rictor silencing, we used luciferase tag PC-3 cells silenced with Rictor gene orthotopically implanted in ventral prostate of mice. After 8 weeks of Rictor silenced cells implanted mice, we observed less luciferase activity in prostate and occasional metastasis than control luciferase PC-3 cells. Moreover, diosmetin fed mice in dose dependent fashion (20 and 50µg/animal/day) represented decrease in tumor luciferase activity with reduced tumor volume and no metastasis than control mice. We observed metastasis only in control and rapamycin (8 mg/kg body weight intraperitoneally every alternate day) treated mice in spine, lung and kidney. Taken together, our studies demonstrate that diosmetin fed animals resulted in growth inhibition and induction of apoptosis by altering Rictor signaling cascade. We are demonstrating that diosmetin modulates molecular targets viz., Rictor and Akt to alter cellular events and elicit anticancer effects in prostate cancer cells.

Citation Format: Rebecca Pakradooni, Ahmad Khalifa, Riddhi Patel, Sanjeev Shukla. Altering rictor with diosmetin reduces tumor progression in orthotopic prostate cancer model [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 2228. doi:10.1158/1538-7445.AM2017-2228
Abstract 2230: Luteolin selectively inhibits EZH2 and blocks H3K27 methylation in prostate cancer cells
Authors: Kanwal Rajnee , Yang Xiaoping , Shankar Eswar , Gupta Sanjay
Published: July 2017

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex (PRC2) and is involved in chromatin remodeling and gene silencing through its methylation of histone H3 on lysine 27 (H3K27). Specifically, trimethylation of H3K27 is associated with gene silencing and plays critical role in cancer initiation and progression. Therefore, blocking EZH2 catalytic activity may present a valid preventive and/or therapeutic strategy for the treatment of cancers with EZH2 overexpression including prostate cancer. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone luteolin (3’, 4’, 5, 7-tetrahydroxyflavone) as a specific inhibitor of EZH2 with preferential blocking of its catalytic site. Here we report luteolin, in micro molar range, inhibits EZH2 catalytic activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays. Treatment of human prostate cancer DU145 and 22Rv1 cells, which possess high constitutive EZH2 expression, with 5-20 μM luteolin significantly inhibits EZH2 and SUZ12 protein expression in dose and time dependent manner, although luteolin treatment did not affect protein expression of EED and RbAp46/48 protein, other members of PRC2 complex. Treatment of both cell lines with luteolin also reduced H3K27me3 and H3K27me2 protein and its enzymatic activity in dose and time dependent manner without affecting total H3 protein. In addition, luteolin was also effective in suppressing in vitro methylation performed using recombinant PCR2 complex. These events led to increase in the expression of downstream tumor suppressor genes including E-cadherin, SLIT2 and TIMP3, respectively. Interestingly, treatment of cells with proteasome inhibitor, MG132 together with luteolin did not prevent EZH2 degradation indicating that proteasomal degradation might not contribute to EZH2 inhibition. Taken together, our study suggest that luteolin acts on the catalytic binding site of EZH2 to exhibit downregulation of histone H3 methylation and could be developed as a potential promising agent for the prevention and/or treatment of various human cancers including prostate cancer with EZH2 overexpression.

Citation Format: Rajnee Kanwal, Xiaoping Yang, Eswar Shankar, Sanjay Gupta. Luteolin selectively inhibits EZH2 and blocks H3K27 methylation in prostate cancer cells [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 2230. doi:10.1158/1538-7445.AM2017-2230
Abstract 2246: Anti-proliferative activities of lipid fraction of extract from the skin of the catfish Arius Bilineatus, Valenciennes
Authors: Yang Peiying , Ding Jibin , Pan Yong , Jiang Yan , Afzal Mohammad , Paul Bincy M. , George Sosamma O. , Al-Hassan Jassim M.
Published: July 2017

The catfish (Arius bilineatus, Val.) secretes a gelatinous substance composed of biochemically active lipids and proteins from its skin upon stress or injury. Preparations from the skin have previously been shown to affect blood clotting and accelerates healing of non-healing diabetic foot ulcers in man. We have reported previously fish skin preparation (CSP) derived from the skin of the Catfish and it’s lipid fraction exerted anti-inflammatory activity in the in vitro cells and in vivo animal models. Here anti-proliferative effect of a lipid fraction of fish skin preparation (CSP-L) derived from the skin of the catfish and its plausible mechanism were investigated in human hepatocellular carcinoma (HCC) Hep3B and human pancreatic cancer Panc-1 cells. Cells were treated with CSP-L (0 to 100 μg/ml) for 72 hrs and cell proliferation was measured by the MTT assay. The results showed much stronger inhibition by CSP-L in Panc-1 cells than that of Hep3B cells with IC50 of 5.5 ± 1.4 μg/ml and 19.5 ± 7.7 μg/ml, respectively. Cell cycle analysis with PI staining suggested that CSP-L (25 - 100 μg/ml) led to G1 phase arrest in Hep3B cells whereas S phase arrest was observed in Panc-1 cells, suggesting the differential molecular mechanisms responsible for CSP-L induced cell growth suppression in Hep3B and Panc-1 cells. The alteration of cell cycle was concentration dependent. Additionally, CSP-L concentration dependently suppressed the invasion of Hep3B and Panc-1 cells. The molecular mechanism associated with CSP-L’s anti-proliferative effect was examined by Western blotting in both Hep3B and Panc-1 cells. Intriguingly, CSP-L (50 and 100 μg/ml) notably decreased protein levels of cyclin D, Stat3, pRB and pERk in Hep3 B cells in a concentration dependent manner. In contrast, only pRB and pERK protein expression were reduced in CSP-L treated Panc-1 cells. These again suggest that CSP-L inhibited the proliferation of Hep3B and Panc-1 cells by different molecular mechanisms. Collectively, our preliminary data suggest that CSP-L has a great potential to be developed as an anticancer or preventive agent for both HCC or pancreatic cancer and warrants further investigation. This study was support by a grant from Kuwait Foundation for the Advancement of Science No. KFAS 2013-120701A-D, and Kuwait University Research Grant No. SL03/14.

Citation Format: Peiying Yang, Jibin Ding, Yong Pan, Yan Jiang, Mohammad Afzal, Bincy M. Paul, Sosamma O. George, Jassim M. Al-Hassan. Anti-proliferative activities of lipid fraction of extract from the skin of the catfish Arius Bilineatus, Valenciennes [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 2246. doi:10.1158/1538-7445.AM2017-2246
Abstract 225: Chemoproteomic evaluation of target engagement in clinical samples
Authors: Nomanbhoy Tyzoon K.
Published: July 2017

One of the challenges during the clinical development of kinase inhibitors is understanding whether or not a compound is actually binding the kinase of interest, in the appropriate tissue, during the course of compound treatment. While compound concentration in blood can be determined from pharmacodynamics, there are very few approaches that directly measure whether or not the compound is binding the target kinase. Herein, we apply a chemoproteomics platform (KiNativ®) using a desthiobiotin ATP acyl phosphate probe (ATP probe), to monitor target engagement in clinical samples. As a proof of concept, we demonstrate that compound can be added to whole blood, after which peripheral blood mononuclear cells (PBMCs) are isolated, lysed, labeled with the ATP probe, and analyzed by mass spectrometry to determine whether or not compound treatment blocks the probe-labeling of the target. We successfully applied this approach in the analysis of both the reversible JNK inhibitor CC-930, as well as the covalent BTK inhibitor Ibrutinib (Imbruvica®). We then extended the study to monitor the inhibition of BTK by Ibrutinib in PBMCs isolated from patients undergoing drug treatment. Finally, we demonstrate that in addition to profiling kinases in PBMCs isolated from whole blood, this method can also be used to profile kinases in solid tumors. Thus, the chemoproteomics approach described here could be applied as a general method to monitor target engagement for inhibitors developed against a variety of different kinases in clinical samples.

Citation Format: Tyzoon K. Nomanbhoy. Chemoproteomic evaluation of target engagement in clinical samples [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 225. doi:10.1158/1538-7445.AM2017-225
Abstract 2255: SMAD4 loss is associated with poor prognosis in Middle Eastern colorectal cancer
Authors: Ahmed Maqbool , Siraj Abdul K. , Masoodi Tariq , Bu Rong , Al-Dayel Fouad , Al-Kuraya Khawla S.
Published: July 2017

Background: Colorectal cancer (CRC) is major cause of morbidity and mortality in cancer patients worldwide and it ranks as the most common cancer in males and the third most common among females in Saudi Arabia. Alteration in TGF-β pathway has been reported in many cancers. So In search for new molecular targets we analyzed the role of SMAD4, critical TGF-β pathway mediator, in Saudi colorectal cancers

Methods: 426 CRC cases were analyzed for SMAD4 mutations by targeted capture sequencing and protein expression status by immunohistochemistry in a tissue microarray format. Results were analyzed for association with any clinico-pathological parameters and for prognostic significance.

Results: SMAD4 mutations were detected in 11.9 %( 50/418) cases of Saudi colorectal cancers. CRC with SMAD4 mutations were significantly associated with NRAS mutations (p=0.0481). SMAD4 complete loss of expression by immunohistochemistry was seen in 12.8% (52/404) cases and this loss was associated with young age (p=0.0236) and inversely with MSI-high tumors (p=0.0005). SMAD4 expression loss by immunohistochemistry and mutation were significantly associated with each other

(p=0.0028). In the multivariate analysis using the Cox proportional hazard model SMAD4 expression loss was an independent marker of poor prognosis (p=0.0119)

Conclusion: SMAD4 alteration was found to be associated with a poor overall survival in the Saudi colorectal cancer patients. With the advent of targeted anticancer therapy, this study confirms the findings of other investigators and highlights a potential target which can be exploited to improve the survival of CRC patients in the Kingdom of Saudi Arabia

Citation Format: Maqbool Ahmed, Abdul K. Siraj, Tariq Masoodi, Rong Bu, Fouad Al-Dayel, Khawla S. Al-Kuraya. SMAD4 loss is associated with poor prognosis in Middle Eastern colorectal 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 2255. doi:10.1158/1538-7445.AM2017-2255
Abstract 2260: Haplotypes of chromosome 17q21.31 affect liver metastasis by small intestinal neuroendocrine tumors
Authors: Kobayashi Shinta , Silva Edaise da , Contractor Tanupriya , Tang Laura , Harris Chris R.
Published: July 2017

Neuroendocrine tumors are the most common tumors of the small intestine. Very little is known about genetic changes that cause SI-NETs, which have a very low frequency of mutations. SI-NETs are highly metastatic to the liver, and patients with liver metastases have a five year survival rate of less than 50%. Caucasian patients are more likely to develop metastasis than patients of other races. We have studied a 900 kB inversion at chromosome 17q21.31, which is common to Caucasians but rare in other races. Within a collection of 117 Caucasian patients with ileal carcinoids, patients with the inversion haplotype were significantly less likely to have liver metastasis. A second Caucasian-specific haplotype in this region, beta2, was also tested for potential association with metastasis of ileal carcinoids. Unlike the inversion haplotype, beta2 associates with increased metastasis of ileal carcinoids. We suspect that the fact that the metastasis-promoting beta2 haplotype is more common among Caucasians than the metastasis-suppressing inversion haplotype (44% incidence vs. 33% incidence) is probably why Caucasians wind up with a higher frequency of metastasis than races that carry neither beta2 nor the inversion.

Citation Format: Shinta Kobayashi, Edaise da Silva, Tanupriya Contractor, Laura Tang, Chris R. Harris. Haplotypes of chromosome 17q21.31 affect liver metastasis by small intestinal neuroendocrine tumors [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 2260. doi:10.1158/1538-7445.AM2017-2260
Abstract 2262: Correlation between number and sites of metastases and differential pretreated EBV DNA load profiles and their effects on outcomes in patients with metastatic nasopharyngeal carcinoma
Authors: Hsu Cheng-Lung , Wang Hung-Ming , Lin Tung-Liang , Kuo Yung-Chia
Published: July 2017

Differential overall survival of different organ site metastases in nasopharyngeal carcinoma (NPC) had been reported but the underlying mechanism was unclear. We try to find out the possible mechanism from plasma and tumor tissue markers. Total 178 patients of metastatic NPC were enrolled. Their pre-treatment plasma EBV DNA concentrations and cytokines and tissue macrophage, proliferation and apoptosis markers were determined. The overall patient response rate after treatment was 51.7% and median overall survival (OS) was 19 months. Single organ site metastasis had better outcome than multiple organs involved (median OS: 26 months vs. 16 months) with statistical significance. Among single organ site involved, pure lung metastasis had longer survival than bone or liver involved (median OS: 50 months vs. 21 months vs. 18 months) with P<0.001. Pretreatment plasma EBV DNA concentrations were lower in patients with lung metastasis than bone or liver metastasis in single organ involved group. Plasma IP-10 and MCP-1 expression level correlated with the differential single organ site metastasis OS and EBV DNA load. Liver metastatic tissue had higher macrophage infiltration density and higher proliferation index than lung metastatic group. In single organ site metastasis of NPC, lung involved patients had better outcome than bone or liver metastasis. Low pretreatment plasma EBV DNA load, cytokines expression such as IP-10 and MCP-1, tissue macrophage infiltration, and proliferation index may contribute these results.

Citation Format: Cheng-Lung Hsu, Hung-Ming Wang, Tung-Liang Lin, Yung-Chia Kuo. Correlation between number and sites of metastases and differential pretreated EBV DNA load profiles and their effects on outcomes in patients with metastatic nasopharyngeal carcinoma [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 2262. doi:10.1158/1538-7445.AM2017-2262
Abstract 2263: Neonatal hormone levels and risk of testicular germ cell tumors (TGCT)
Authors: Morimoto Libby , Zava David , McGlynn Katherine , Stanczyk Frank , Wiemels Joseph , Ma Xiaomei , Metayer Catherine
Published: July 2017

Testicular germ cell tumors (TGCT) are the most commonly occurring cancers in adolescent and young adult males in the U.S. Steroid sex hormones play a central role in the development of the testis. As proposed by the testicular dysgenesis syndrome hypothesis, the origins of TGCT are likely to be in utero or early in life, and to be a manifestation of disturbed prenatal testis development. However, no studies have provided direct, empirical evidence to date. Using an innovative linkage between the California birth records and cancer registry data, we conducted a population-based case-control study of neonatal hormones levels and risk of TGCT diagnosed at 0-19 year of age. We obtained archived neonatal dried blood spot (DBS) specimens from 370 TGCT cases (276 adolescent and young adults [AYA] aged 15-19 yrs at diagnosis; 94 0-4 yrs at diagnosis), and 344 age- and race/ethnicity-matched controls, born between 1982 and 2009. Liquid chromatography with tandem mass spectrometry was used to measure a panel of 17 sex steroids, glucocorticoids, and mineralcorticoids; 12 were present at detectable levels in the newborn DBS samples, including estrone (E1), estradiol (E2), estriol (E3), testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for matching factors and age (in hours) of child at blood spot collection. A4, a precursor for T and E1, was positively associated with TGCT (OR: 1.71, 95% CI: 1.09-2.69). Analyses stratified by age group showed that this association was limited to AYA, and was of stronger magnitude in this group (OR: 2.33, 95% CI: 1.37-3.97). A similar, though weaker, trend was observed for T (ORoverall: 1.37, 95% CI: 0.86-2.19; ORAYA: 1.73. 95% CI: 1.00-3.00). There was no significant association of the other measured hormones with risk. In the first case-control study of TGCT with direct measures of neonatal hormone levels, we found that higher levels of T and A4 were associated with increased risk of TCGT, particularly among males diagnosed at 15-19 years of age. These results oppose the dominant theory in TGCT etiology, that TGCT is related to androgen insufficiency in utero, and provides an important link in the etiologic pathway of this increasingly common cancer.

Citation Format: Libby Morimoto, David Zava, Katherine McGlynn, Frank Stanczyk, Joseph Wiemels, Xiaomei Ma, Catherine Metayer. Neonatal hormone levels and risk of testicular germ cell tumors (TGCT) [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 2263. doi:10.1158/1538-7445.AM2017-2263
Abstract 2276: Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort
Authors: Jang Jieun , Hwang Yunji , Ahn Choonghyun , Ko Kwang-Pil , Shin Aesun , Yoo Keun-Young , Park Sue K.
Published: July 2017

Backgrounds: Attenuation by genistein, an isoflavone abundant in soybean, of gastric carcinogenesis induced by sodium chloride was reported in an animal study. Up to date, role of isoflavone as an effect modifier on the association between salt intake and gastric cancer risk is not clearly established.

Methods: We randomly selected 640 subcohort subjects without cancer history at enrollment from the Korean multi-center cancer cohort participants. Ninety-nine gastric cancer cases were identified from the inside (N=8) and the outside (N=91) of the subcohort after the 12.2 years of median follow-up time. To estimate individual’s salt intake, we measured 24-hour urinary sodium excretion from spot urine using the Tanaka’s equation. Three isoflavone plasma concentrations (Genistein, daidzein, and equol) of 167 subjects among case-cohort subjects had been measured using time-resolved fluoroimmunoassay. Cubic spline curve for gastric cancer risk according to urinary sodium level was used to define optimal cut-off points of urinary sodium excretion concentration. Weighted Cox proportional hazard regression was used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs). Stratified analysis by isoflavone level was conducted to assess effect modification by isoflavone on the association between salt intake and gastric cancer.

Results: Gastric cancer risk in the high salt intake group (urinary sodium excretion ≥6,000mg/day) was significantly increased (HR, 1.69; 95% CI, 0.99-2.90) compared to the reference group (urinary sodium excretion 4500-5,999mg/day). Magnitudes of gastric cancer risk by high salt intake were more strengthened in the group with low plasma isoflavone concentrations (One or no genistein, diadzein or equol levels over the median concentrations) (HR, 6.92; 95% CI, 1.80-26.56). Contrary to the low isoflavone group, no significant differences in gastric cancer risk according to salt intake levels were found in the group with high isoflavone concentration.

Conclusions: High salt intake is associated with gastric cancer risk, but this association can be attenuated by high concentration of isoflavones. We suggest that sufficient intake of soybean products, the rich sources of isoflavone, may give protection against gastric cancer in the population with high salt intake.

Citation Format: Jieun Jang, Yunji Hwang, Choonghyun Ahn, Kwang-Pil Ko, Aesun Shin, Keun-Young Yoo, Sue K. Park. Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort [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 2276. doi:10.1158/1538-7445.AM2017-2276
Abstract 2284: Effects of smoking on breast tumor pathology
Authors: Costantino Nicholas , Shriver Craig D. , Ellsworth Rachel E.
Published: July 2017

Background Although smoking is not a well-established breast cancer risk factor, proximity of lungs to the breasts and findings that tobacco smoke constituents serve as mammary carcinogens in animal models suggests that smoking may alter the breast microenvironment and affect breast tumorigenesis. To determine how smoking influences tumor pathogenesis, the relationships between smoking and pathological characteristics and outcome were evaluated in 1,707 women with invasive breast cancer.

Methods Patients enrolled in the Clinical Breast Care Project 2001-2013 filled out a questionnaire that included answers to current smoking status, current and previous pack use/day, number of years smoked, and length since last smoked. Patients were classified as never, former or current smokers. Pack years was calculated as years smoked x pack use/day. Logistic regression was performed to determine whether smoking was associated with any characteristics. Significance was defined as P<0.05

Results 55.7% of women never smoked, 31.5% were former smokers and 12.8% were current smokers. The average number or pack years was 14.5 in former smokers and 25.5 in current smokers. Current smoking status was associated with lymph node metastasis (OR 1.44; 95% CI 1.03-2.01), positive HER2 status (OR 1.54, 95% CI 1.04-2.25), larger tumor size (OR 1.55; 95% CI 1.14-2.11) and higher tumor stage (OR 1.54, 95% CI 1.16-2.04) when compared to never smokers. Former smokers were less likely to be diagnosed with later stage tumors (OR 0.77, 95% CI 0.62-0.96) compared to never smokers. No significant associations were detected when pack years were considered as a continuous variable; when categorized as 0, <20, 20-34 or >35 pack years, >35 pack years was associated with positive HER2 status (OR 1.80, 95% CI 1.06-3.03) and tumors of the ER+HER2+ subtype (OR 1.99, 95% CI 1.07-3.7). Overall survival was significantly lower for former and current smokers compared to never smokers (P=0.014); however, breast cancer specific survival did not differ significantly between groups (P=0.226).

Conclusions Current smokers are at increased risk for having larger and later stage tumors with positive lymph node and HER2 status. Tumor size, stage and lymph node status are temporal factors, thus suggest that current smokers may have delayed diagnosis compared to never and former smokers. In contrast, HER2 status reflects a biological phenomenon and the risk of HER2 positivity increases with pack years, suggesting that carcinogens found in tobacco smoke may promote overexpression of HER2.

Citation Format: Nicholas Costantino, Craig D. Shriver, Rachel E. Ellsworth. Effects of smoking on breast tumor pathology [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 2284. doi:10.1158/1538-7445.AM2017-2284
Abstract 2306: Sleep duration and risk of fatal prostate cancer in CPS-I and CPS-II
Authors: Gapstur Susan M. , Stevens Victoria L. , Carter Brian D. , Wang Ying , Jacobs Eric J.
Published: July 2017

There is growing evidence that factors associated with circadian rhythm disruption may be associated with prostate cancer risk. In a previous analysis focusing on shift-work in the Cancer Prevention Study (CPS)-II that included only employed men, we observed an association between short sleep duration and higher risk of prostate cancer death that was limited to the first eight years of follow-up of the cohort. To corroborate and expand on these results, we examined the association between sleep duration and death from prostate cancer in a combined analysis of men in CPS-II and men enrolled in an earlier cohort study, CPS-I, regardless of employment status. After excluding men with uninterpretable sleep information, prevalent cancer and prevalent prostate disease at baseline, the analysis included 407,649 men from CPS-I followed from 1950 through 1972, and 416,040 men from CPS-II followed from 1982 through 2012. During follow-up, 1,546 men in CPS-I and 8,704 men in CPS-II died of prostate cancer. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) and estimates were meta-analyzed using a fixed-effects model because the design and population of CPS-I and CPS-II were similar. Among men aged 65 years and younger, short sleep duration was associated with higher risk of death from prostate cancer during the first eight years of follow-up; compared to 7 hours/night, the RRs (95% CIs) for 3-5, and 6 hours/night were 1.61 (1.10-2.37), and 1.25 (0.99-1.58), respectively. Among men older than age 65 years, the corresponding RRs (95% CIs) were 0.97 (0.68, 1.38), and 1.02 (0.82, 1.27), respectively. There was no association between sleep duration and fatal prostate cancer during later follow-up. These findings support evidence that factors related to circadian rhythms may increase fatal prostate cancer risk. The observed association between short sleep duration and higher risk of fatal prostate cancer only during the first 8-years of follow-up suggests that short sleep duration could affect later stages of prostate carcinogenesis. Reasons for lack of an association in older men are unclear but may include the marked decline in nocturnal melatonin levels with age, which could reduce the relative biologic impact of melatonin inhibition by sleep-deprivation.

Citation Format: Susan M. Gapstur, Victoria L. Stevens, Brian D. Carter, Ying Wang, Eric J. Jacobs. Sleep duration and risk of fatal prostate cancer in CPS-I and CPS-II [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 2306. doi:10.1158/1538-7445.AM2017-2306
Abstract 2307: The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins
Authors: Kim Eun Mi , Um Hong-Duck
Published: July 2017

Although well known as a transcription factor, the p53 tumor suppressor also exists in the cytoplasm (including the mitochondria) of normal and cancer cells. Moreover, nuclear p53 is translocated to the mitochondria upon apoptotic stimulation of cells. The cytoplasmic/mitochondrial p53 can bind pro-survival Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, and Bcl-w), liberating Bax therefrom. Bax then exerts its pro-apoptotic or anti-invasive function depending on experimental conditions. Given the ability of p53 to interact with p21, we investigated the possible involvement of p21 in these functions. Here, we show that whereas p53 can bind to Bcl-w alone, it requires p21 to liberate Bax from Bcl-w and suppress/promote cell invasion/death, respectively. p21 consistently binds Bcl-w, forming a p53/p21/Bcl-w complex. Only this trifold complex, but not any of the pairings, facilitates the release of Bax from Bcl-w. Accordingly, a p53 derivative incapable of binding p21 fails to mediate radiotherapy-induced tumor retardation and cell death in mice. We further show that Bcl-2 and Bcl-XL also serves as a target of p53/p21 cooperative action. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple types of cellular components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21.

Citation Format: Eun Mi Kim, Hong-Duck Um. The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins [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 2307. doi:10.1158/1538-7445.AM2017-2307
Abstract 2309: Acetylation of survivin represses transactivation of STAT3 to induce sodium butyrate-induced apoptosis in human mucoepidermoid carcinoma cell lines
Authors: Cho Sung-Dae
Published: July 2017

Sodium butyrate (NaBu) is one of histone deacetylase inhibitors and possesses anticancer activity. Here, the aim of this study is to determine the molecular mechanism by which NaBu controls apoptosis in MC3 and YD15 human mucoepidermoid carcinoma (MEC) cell lines. NaBu caused growth inhibition and induced apoptosis in both cell lines accompanied by the acetylation of histone proteins H2A and H3. NaBu clearly increased survivin and cleaved caspase 3 evidenced by human apoptosis array and it regulated survivin molecule at a post-transcriptional level. NaBu caused nuclear translocation of survivin protein and increased survivin acetylation in both cell lines. In addition, STAT3 and survivin were co-localized in nucleus by NaBu resulting in the decrease in the expression level of Bcl-XL mRNA which is one of STAT3 downstream molecules. In addition, NaBu induced caspase-dependent apoptosis in human MEC cells. Taken together, these results suggest that NaBu is a potent apoptosis inducer in human MEC cell lines through survivin-STAT3 signaling cascades and these findings provide the basis of its clinical application for the treatment of human MEC.

This abstract is supported by SNU Invitation Program for Distinguished Scholar and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A12055874)

Citation Format: Sung-Dae Cho. Acetylation of survivin represses transactivation of STAT3 to induce sodium butyrate-induced apoptosis in human mucoepidermoid carcinoma cell lines [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 2309. doi:10.1158/1538-7445.AM2017-2309