bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3549: Synthetic triterpenoid CDDO-Me induces apoptosis in pancreatic cancer cells by inducing oxidative stress
Authors: Deeb Dorrah , Gao Xiaohua , Dulchavsky Scott A. , Gautam Subhash C. 
Published: June 2012

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy for pancreatic cancer has not been investigated. We have found that methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid exhibits potent anticancer activity against human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2) and wild-type K-ras (BxPC3) pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was due to the induction of apoptosis characterized by increased annexin-V-FITC and cleavage of PARP-1 and procaspases-3, -8 and-9. Killing of PDA cells by CCDO-Me involved the generation of reactive oxygen species (ROS) as determined from the oxidation of H2DCFD by flow cytometry and its inhibition by general purpose antioxidant NAC. CDDO-Me was also highly active against gemcitabine resistant MiaPaCa2 cells expressing markers of tumor-initiating cells (cancer stem-like cells?). An ongoing pilot experiment has shown the antitumor activity of CDDO-Me against BxPC3 xenograft in vivo. Together, these data demonstrated potential of CDDO-Me for treating pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3549. doi:10.1158/1538-7445.AM2011-3549
Abstract 355: Genetic alterations in 17β-hydroxysteroid dehydrogenase type 2 and 7 correlates with mRNA-expression but not estrogen levels in breast cancer
Authors: Straume Anne Hege , Knappskog Stian , Lønning Per Eystein 
Published: June 2012

Abstract
Background: Estrogens are believed to play an important role in both development and sustained growth of breast cancer. Estradiol (E2), the most biologically active estrogen, is often elevated in breast cancer tissue, and high plasma levels of E2 are correlated to increased breast cancer risk in postmenopausal women. Previously, we have shown that uptake of estrogen due to binding to the estrogen receptor (ER), is a probable determinant of intratumoral E2. Furthermore, we reported that increased expression of 17β-hydroxysteroid dehydrogenase type 7 (HSD17B7) might explain the increased ratio of E2 to estrone (E1) in breast tumors compared to non-tumorous breast tissue. Here we explored whether genetic alterations in HSD17B-isoforms might predict estrogen disposition in breast cancer.
Materials and methods: Tumor and normal breast tissue specimens were collected from 50 patients (37 postmenopausal and 13 premenopausal women) undergoing mastectomy. Samples were snap-frozen in the theatre. To evaluate potential mechanisms regulating intra-tumor and plasma estradiol levels, HSD17B2 and HSD17B7 were evaluated for mutation status, promoter hypermethylation and gene copy number. In addition, we quantified the transcription level of two HSD17B7 isoforms (HSD17B7_I and HSD17B7_II).
Results: We identified a novel single nucleotide polymorphism (SNP) in the HSD17B7 promoter region (transcription start + 56: T&gt;C) and found it correlated to increased enzyme expression level (p = 0.016). Also, we observed a novel SNP in the HSD17B2 promoter region (transcription start + 35: C&gt;T) associated with a lower expression level (p = 0.019). Nineteen patients were found to harbour HSD17B7-duplications predicting elevated mRNA-expression levels (p = 0.056). While some tumors revealed promoter hypermethylation in both HSD17B2 and 7, hypermethylation status was not associated with low mRNA-levels. None of these genetic alterations correlated to plasma or tissue estrogen levels.
Conclusion: Genetic alterations in HSD17B2 and 7 were found to influence the transcription level of these genes, but not estradiol levels in plasma or breast cancer tissue.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2011-355
Abstract 3571: Exploratory biomarker discovery for clinical development of ARQ 087, a potent pan-FGFR kinase inhibitor
Authors: Yu Yi , Gu Xiubin , Nakuci Enkelada , Zhao Xiaolan , Chang Edward , Szwaya Jeff , Castro Jenn , Cousens Laura , Bull Cathy , Wang Yunxia , Savage Ron , Waghorne Carol , Chen Chang-Rung , France Dennis S. , Clark Edwin , Chan Thomas C.K. 
Published: June 2012

Abstract
Fibroblast growth factor receptor (FGFR) tyrosine kinase family members have gained increasing attention as potential therapeutic targets. Gene amplification, or gain-of-function translocations and mutations of these receptors, have been implicated in a variety of cancers including breast, gastric, bladder, ovarian, endometrial, lymphoma and myeloma. We have previously described the biological profiling of ARQ 087, a potent small-molecule pan-FGFR kinase inhibitor that shows anti-tumor activity in FGFR dysregulated tumor cells in vitro and in vivo. A number of cell lines with genetically-altered FGF receptors were identified that were sensitive in anti-proliferative assays to ARQ 087, including FGFR2 amplified gastric carcinoma lines KATO III and SNU-16, and endometrial lines AN3CA, MFE-296 and MFE-280 harboring FGFR2 mutants, as well as a breast cancer cell line with increased FGFR1 gene copy (MDA MB-157). Western blot pharmacodynamic analysis demonstrates that ARQ 087 inhibits FGFR phosphorylation and downstream pathway markers in these cell lines in a concentration-dependent manner. Using antibody arrays specific for known cytokines as well as regulatory proteins involved in angiogenesis and apoptosis, we have identified a number of protein biomarkers in cell lysates and in conditioned media of sensitive cell lines that changed in response to ARQ 087 exposure. Three proteins (cytochrome c, clusterin, and HTRA2) decreased in SNU-16 (ARQ 087-sensitive, FGFR amplified) but not DLD1 (ARQ 087-resistant, non FGFR expressing) cells. VEGF decreased and IL-1rα increased in SNU-16 but not in DLD1 conditioned media in response to ARQ 087. Furthermore, analysis of mouse plasma from animals bearing AN3CA tumors treated with ARQ 087 revealed a decrease in human VEGF, CXCL16, MMP-9, Serpin E1 and MIF and an increase in RANTES, IL-1β, IP-10, SDF-1, IL-1rα. TNFα, GM-CSF, IL-2, sTREM-1, sICAM-1, MIP-1β, IL-8. In summary, we have identified a number of cell lines from a broad cell line screening campaign that exhibited dysregulated FGFR pathway function and are sensitive to the anti-proliferative effects of ARQ 087. These cell lines, in turn, have been used as models in which to identify candidate biomarkers that may greatly facilitate subsequent clinical evaluation of this molecularly targeted anti-tumor agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3571. doi:10.1158/1538-7445.AM2011-3571
Abstract 3573: A small molecule PLK1 inhibitor, MLN0905, yields broad anti-tumor activity in human xenograft tumor models, and synergizes with taxane therapy
Authors: Lasky Kerri , Shi Judy , Shinde Vaishali , Stringer Bradley , Qian Mark G. , Liao Debra , Liu Ray , Duffey Matthew O. , Vos Tricia J. , D'Amore Natalie , Hyer Marc , Rao Youlan 
Published: June 2012

Abstract
PLK1 is a serine/threonine mitotic kinase that plays a key role in mitotic cell cycle progression, and its over-expression has been linked to poor patient prognosis. We have discovered a potent and selective small molecule inhibitor of PLK1, MLN0905, which reduces cell viability and inhibits cell proliferation in a broad range of human tumor cells. We explored the pharmacokinetic, pharmacodynamic, and anti-tumor properties on MLN0905 in human xenograft models grown in rodents. MLN0905 rapidly and extensively distributed to xenograft tumor with a high tumor-to-plasma exposure ratio. In human xenograft tumor tissue, MLN0905 modulates the pharmacodynamic biomarker phospho-Histone H3 (in a dose dependent fashion), enabling us to track pathway modulation in vivo. MLN0905 demonstrated robust anti-tumor activity (partial and complete responses) in a variety of solid and hematological human xenograft models, including cancers derived from colon (HCT-116, HT29), NSCLC (Calu-6), Ovarian (SKOV3), and Lymphoma (OCI-LY19, OCI-LY10, and the primary lymphoma PHTX-22L). Significant anti-tumor activity was observed when dosing on either a continuous (daily) or intermittent schedule, underscoring the dosing flexibility with this compound. In the SKOV3 and Calu-6 xenograft models, MLN0905 yielded a synergistic anti-tumor response when combined with the standard of care therapy Taxane. This is the first report of a PLK1 inhibitor synergizing with taxane therapy in vivo. In summary, our findings indicate MLN0905 has good drug-like pharmacokinetic properties, modulates the biomarker phospho-Histone H3, and yields significant anti-tumor activity in multiple xenograft models. These preclinical data support further evaluating MLN0905 as a novel anti-cancer agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3573. doi:10.1158/1538-7445.AM2011-3573
Abstract 3580: Discovery and SAR study of a novel and potent Itk inhibitor as a targeted therapeutic agent for T-cell lymphoma and leukemia
Authors: Liu Ruiwu , Guo Wenchang , Ma Aihong , Sanchez Eduardo , Wang Yan , Li Jixian , Xu Chunping , Ning Jinying , Huang Wenzhe , Mazloom Anisha , Song Aimin , Lam Kit S. , Xia Michelle , Chen Yiyou , Kung Hsing-Jien 
Published: June 2012

Abstract
Itk (IL2-inducible T-cell kinase) is a non-receptor protein tyrosine kinase. It is selectively expressed in T cells, Mast cells, and NK cells. It plays an important role in T-cell maturation, proliferation, and malignancies. Using Western blotting, Itk was only detected in three T-cell lymphoma and leukemia cell lines (Jurkat, Molt-4, and Hut78) out of 41 different cancer cell lines. A small molecule named CTA056 showed potent and selective inhibition of Itk kinase activity and growth in each of the three T-cell cancer cell lines. After treatment of Jurkat cells with CTA056, Itk phosphorylation was inhibited in a dose-dependent manner. In addition, apoptosis was induced in Jurkat cells following treatment with CTA056. In order to better understand structure-activity relationship (SAR) on CTA056, a series of analogs of CTA056 were designed, synthesized, and tested for their inhibition of both Itk phosphorylation and cancer cell growth. Several analogs showed better activity and selectivity. The results will be presented. Success in this endeavor could lead to the development of novel targeted therapy, rather than traditional chemotherapy, for T-cell lymphomas and leukemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3580. doi:10.1158/1538-7445.AM2011-3580
Abstract 359: Neuropeptides promote castration-resistant prostate cancer through intracrine androgen biosynthesis
Authors: Yang Joy C. , Kung Hsing-Jien , Gao Allen C. , Evans Christopher P. 
Published: June 2012

Abstract
Introduction and Objectives: Neuroendocrine differentiation is associated with castration resistant prostate cancer (CRPC) with detectable increased serum levels of chromogranin A in patients. Neuropeptides secreted from the neuroendocrine cells are believed to activate androgen receptor (AR) in low or no androgen environments. We hypothesize that neuropeptides sustain CRPC by promoting intracrine androgen synthesis.
Methods: We engineered LNCaP cells overexpressing gastrin-releasing peptide (GRP) and examined the level of androgen biosynthetic enzymes by RT-PCR and Western blots. Inhibition of androgen-free growth of LNCaP-GRP cells was performed with siRNA to AKR1C3 or CYP17A1 with or without Src inhibitor saracatinib. PSA and total testosterone levels were assessed in LNCaP-GRP cells, serum from tumor-bearing animals and xenografts.
Results: The androgen biosynthetic enzymes were up-regulated in LNCaP-GRP cells, with AKR1C3, CYP17A1 and HSD17B2 displaying over 40 fold increase compared to the control line by real-time RT-PCR analysis. Transfection of siRNA against AKR1C3 and CYP17A1 inhibited LNCaP-GRP cell growth in androgen-free medium. Specific Src family kinase inhibitor saracatinib inhibits androgen-independent LNCaP-GRP cell growth in vitro and tumor metastasis in vivo. Saracatinib also reduced the expression of AKR1C3, AKR1C1/2 and HSD3B1/2 in GRP cells at both RNA and protein levels. When combined with siRNA for AKR1C3 and CYP17A1, saracatinib further inhibited androgen-independent LNCaP-GRP cell growth. Testosterone was detectable by EIA assay in LNCaP-GRP cell lysates (109.1 and 44.5 pg/mg protein vs. 18.3 in control), serum from castrated mice bearing GRP tumors (2235.5 pg/ml serum) and xenograft tissue (59.2 pg/mg tumor). These enhanced T levels were greatly reduced when treated with saracatinib, to 594 pg/ml serum and 12 pg/mg tumor, respectively.
Conclusions: Secretion of neuropeptides promotes CRPC through up-regulation of intracrine androgen biosynthesis. Saracatinib not only targets neuropeptide-mediated AR activation but also blocks steroidogenesis in CRPC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 359. doi:10.1158/1538-7445.AM2011-359
Abstract 3590: The Bruton tyrosine kinase inhibitor PCI-32765 prevents activation of pro-survival NF-kB pathways in OCI-Ly10 ABC DLBCL cells
Authors: Balasubramanian Sriram , Crowley Richard , Sirisawad Mint , Buggy Joseph J. 
Published: June 2012

Abstract
PCI-32765 is a potent and selective small molecule inhibitor of Bruton tyrosine kinase (BTK), a Tec family kinase that is essential to signaling via the B-cell Receptor (BCR) (Honigberg, Proc. Natl Acad. Sci. USA 107:13075, 2010). PCI-32765 is showing encouraging clinical activity in an ongoing Phase I trial (Advani et al., ASCO 2010 meeting, JCO 28: 8012, 2010) in patients with chronic lymphocytic leukemias (CLL), as well as in B-cell Non-Hodgkin's Lymphoma (NHL), including mantle cell, follicular, and diffuse large B-cell lymphomas. Nevertheless, in tissue culture, even at concentrations of PCI-32765 that lead to full occupancy of the active site of Btk, many of the cell lines derived from B cell malignancies do not undergo apoptosis or have significantly reduced growth. This is likely because most established B-cell lines no longer depend on antigen stimulation of the BCR for survival. Recently, Davis et al identified DLBCL cells of the ABC subtype such as OCI-Ly10 that have chronic active BCR signaling and are very sensitive to Btk inhibition by PCI-32765 (Davis et al, Nature 463: 88, 2010). Here we show that PCI-32765 potently and irreversibly inhibits the growth of OCI-Ly10 (EC50 continuous exposure = 10 nM, EC50 1 hour pulse = 50 nM) but not OCI-Ly3 cells, another ABC-DLBCL line in which NF-kB pathway is activated by a mutation in CARD11, which is downstream of BTK. In addition, induction of apoptosis, as shown by caspase activation, Annexin-V flow cytometry and increase in sub-G0 fraction is observed in OCI-Ly10 but not in OCI-Ly3 cells. Both sensitive and resistant cells express Btk at similar levels, and the active site of BTK is fully occupied by the inhibitor in both as shown using a fluorescently-labeled affinity probe. OCI-Ly10 cells are shown to have chronically active BCR signaling to NF-kB which is dose-dependently inhibited by PCI-32765. The activity of PCI-32765 in these lines are further characterized by comparing signal transduction profiles (Lyn, Syk, Btk, PLCγ, ERK, NF-kB), cytokine secretion profiles and mRNA expression profiles, both with and without BCR stimulation, and observed significant differences in these profiles that could lead to clinical biomarkers that identify the most sensitive patient populations to PCI-32765 treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3590. doi:10.1158/1538-7445.AM2011-3590
Abstract 3594: Conformational control of FMS kinase for treatment of human malignancies
Authors: Wise Scott C. , Hood Molly M. , Smith Bryan D. , Lister Deanne , Lu Wei-Ping , Kaufman Michael D. , McConville Patrick , Flynn Daniel L. 
Published: June 2012

Abstract
FMS kinase is involved in the process of osteoclast maturation. Osteoclasts have been shown to play a role not only in arthritic diseases but also in a cancers ability to metastasize to the bone. This is especially true for breast, lung and prostate cancer. Taken together the ability to prevent osteoclast maturation and accumulation through FMS inhibition should be a good target for small molecule therapy of bone metastasis. Using Deciphera Pharmaceutical's approach to kinase inhibition, compounds have been designed that potently inhibit FMS kinase. These inhibitors can be highly selective with lead compounds inhibiting only a single kinase within 20 fold of FMS activity in a 300 kinase profile. A second class broadens the profile to include anti-angiogenic kinase targets in addition to potent FMS inhibition. This presentation will highlight the attributes and development status of these compounds for treatment of human malignancies.
Deciphera's FMS program has afforded potent inhibitors that achieve single digit nanomolar inhibition in biochemical assays of FMS activity. The inhibitors retain this same level of potency in the presence of high (5mM) ATP concentrations. These same compounds are also selective with some inhibiting as few as three kinases within 50 fold of FMS potency. In addition, proliferation and FMS phosphoprotein assays performed with M-NFS-60 and THP-1 cells have demonstrated excellent inhibitory profiles with achieved potencies in the low nanomolar range. In functional osteoclast differentiation models, key compounds have demonstrated single digit nanomolar inhibition as assessed by TRAP assays. In vivo evaluation of the inhibitors produced excellent tolerance in two week MTD studies. Potent and durable efficacy in pharmacokinetic/pharmacodynamic xenograft models was also observed demonstrating on target effects. In vivo models of bone invasion coupled with non-invasive translational image-based biomarkers potentially provide a powerful method for visualization and quantification of osteoclast activity and FMS inhibition. Early results in imaging of bone invasion will be presented using micro CT and fluorescent activateable probes.
Deciphera's FMS inhibitors show acceptable ADME properties in cell permeability, cytochrome p450 inhibition, microsomal clearance and are orally bioavailable in rat and dog. Key prototype compounds have been evaluated in a two week rat tolerability study. These data demonstrate that Deciphera's technology has been used to identify potent and selective FMS inhibitors to be developed for treatment of cancers where metastasis to bone is an issue.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3594. doi:10.1158/1538-7445.AM2011-3594
Abstract 3602: Antitumor effects of epidermal growth factor (EGF) and insulin-like growth factor (IGF) inhibitors in the treatment of metastatic renal cell carcinoma
Authors: Elkahwaji Johny E. , Hauke Ralph J. 
Published: June 2012

Abstract
Background: Renal cell carcinoma (RCC) is associated with mutation or loss of function of the von Hippel-Lindau gene resulting in hypoxia-inducible factor 1-alpha accumulation and production of growth factors involved in proliferation and angiogenesis. Radical nephrectomy remains the primary treatment option for two thirds of RCC patients who present with tumors confined to the kidney. However, approximately one half of patients will develop metastatic RCC. Treatment of RCC has been hampered by its resistance to most chemotherapy and hormonal therapy, although selected patients have long term remission from high dose of interleukin-2. Despite the recent availability of several active targeted agents in this disease, therapy is not curative. As a result, there is continued demand for improving therapy for metastatic disease to enhance both clinical benefits and patients overall survival. The EGF and IGF-1 pathways have been implicated as potential therapeutic targets in RCC. The objective of this study was to investigate the antitumor response to EGF and IGF inhibitors as a novel combination therapy in metastatic RCC.
Methods: RCC cells lines (Caki-1 and Caki-2) were cultured in appropriate media supplemented with 10% FBS in a 5% CO2 incubator. Cells were treated for 24, 48, 72h, and 96h with different doses of EGFR (AG1478) and/or IGF-1R (AG1024) inhibitors (0-100 µM) given as single agent or in combination therapy. The epithelial cell proliferation was determined by AlamarBlue proliferation assay.
Results: Both AG1478 and AG1024, given as single agent, decreased the epithelial cell proliferation of RCC human malignant cell lines (Caki-1 and Caki-2) (p&lt;0.05). The inhibition occurred in a dose-dependent manner and was more pronounced at higher doses of AG1478 or AG1024 (100 µM), and when both agents were given as combination therapy.
Conclusions: These data suggest that both inhibitors exhibit a synergistic antitumor effect when given as combination therapy. This synergistic benefit exhibits an anti-proliferative and pro-apoptotic effects on RCC cell lines in vitro and warrants further investigation as a potential therapeutic approach for metastatic RCC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3602. doi:10.1158/1538-7445.AM2011-3602