bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2572: Pro-resolving effects of 15-deoxy-α12,14-prostaglandin J2 through activation of Nrf2-mediated CD36 expression in murine macrophages
Authors: Kim Wonki , Lee Ha-Na , Surh Young-Joon
Published: August 2012

The process of resolution of inflammation is actively controlled by a series of endogenous mediators, which activate pro-resovling mechanisms. 15-Deoxy-α12,14-prostaglandin J2 (15d PGJ2), one of the terminal products of cyclooxygenase-2 (COX-2), is an endogenous lipid mediator exerting both anti-inflammatory and pro-resolving effects. Enhanced biosynthesis of 15d-PGJ2 has been suggested to contribute to resolution of inflammation. The phagocytosis of apoptotic neutrophils by macrophages, called effercytosis, is the most important step for complete resolution of inflammation. However, the molecular mechanisms underlying pro-resolving effects of 15d-PGJ2 remain not fully clarified. The phagocytic action of macrophages is known to be mediated by scavenger receptors present on the plasma membrane of these cells. CD36, one of the class B scavenger receptors, is considered to recognize phosphatidylserine on the outer membrane of apoptotic neutrophils, thereby inducing phagocytosis. Recently, NF-E2 related factor 2 (Nrf2) has been reported to be the essential transcription factor involved in the induction of CD36 expression. In the present study, we found that 15d-PGJ2 (1 μM) increased expression and nuclear translocation of Nrf2 in murine macrophage-like RAW264.7 cells. The electrophoretic mobility shift assay revealed that 15d-PGJ2 enhanced the DNA binding of Nrf2. In addition, 15d-PGJ2 upregulated the expression of CD36, thereby stimulating efferocytosis. siRNA knockdown of Nrf2 abolished 15d-PGJ2-induced CD36 expression, resulting in reduced efferocytosis. embryonic fibroblasts from Nrf2-null mice failed to up-regulate CD36 expression upon 15d-PGJ2 treatment. Moreover, unlike 15d-PGJ2, its non-electrophilic analog 9,10-ihidro-15d-PGJ2 could not induce expression of Nrf2 and CD36, suggesting that the α,β-unsaturated carbonyl group located in the cyclopenenone ring of 15d-PGJ2 is essential for Nrf2-induced CD36 expression. Taken together, these results suggest that 15d-PGJ2 might expedite resolution of inflammation by activating efferocytosis which appears to be mediated through Nrf2-induced CD36 expression in macrophages.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2572. doi:1538-7445.AM2012-2572
Abstract 2581: Curcubitacin B exhibits cytotoxic effects by inhibiting ILK-Paxillin signaling in breast cancer cells
Authors: Gupta Parul , Srivastava Sanjay K.
Published: August 2012

Integrins are known to play an important role in promotion of cell motility and survival though activation of Integrin-Linked Kinase (ILK) signaling. Therefore ILK has been an attractive target to inhibit metastasis and tumor growth. Curcubitacin B (CuB) is a steroidal class of chemical present in the plants belonging to cucurbitaceae family. CuB has shown cytotoxic potential in several cancers by causing G2/M cell cycle arrest and inhibition of JAK/STAT3 pathway. However, the exact mechanism of CuB and its role in metastasis is not known. Integrins transmit cell survival signals through ILK-Paxillin complex and further play role in activating AKT signaling. This cascade ultimately works through the activation of Rho kinases like ROCK1 and RhoA. Our results show that CuB significantly suppressed the growth of MDA-MB-231 and MCF-7 breast cancer cells in a concentration and time-dependent manner. CuB also induced apoptosis and down-regulated ILK1 expression. In addition, CuB suppressed the phosphorylation of AKT at Ser473, paxillin at Tyr118 and down-regulated ROCK1 protein expression. Previous studies have shown that heregulin, a ligand of HER2 induces paxillin expression, indicating a correlation between HER2 and paxillin. Interestingly we observed significant downregulation of paxillin in HER2 overexpressing breast cancer cells, suggesting that CuB is equally effective in HER2 overexpressing tumor cells. Taken together our results indicate the anti-cancer effects of CuB in breast cancer cells by targeting paxillin, ILK and ROCK. Further detailed mechanistic work is in progress. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute].

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2581. doi:1538-7445.AM2012-2581
Abstract 2583: Green tea polyphenols cause stabilization and increased transcriptional activity of p53 by increasing its acetylation through inhibition of class I histone deacetylases
Authors: Thakur Vijay S. , Gupta Karishma , Gupta Sanjay
Published: August 2012

p53, a major tumor suppressor and transcription factor protects the cells from both internal and external stress by modulating cell cycle and apoptotic pathways. p53 is mutated in more than 50% of human cancer and in most others, its pathway is defective. p53 undergoes a number of posttranslational modifications including acetylation of lysine (Lys) residues on its C-terminal. Acetylation of p53 at Lys373 and Lys382 has been reported to decrease its degradation and increased binding to DNA, leading to increased transcription of its downstream targets such as p21/waf1 and Bax. The process of acetylation is regulated by a group of opposing enzymes histone acetyltransferase (HATs) and histone deacetylases (HDACs). Class I HDACs (HDAC 1, 2, 3 and 8) are shown to be upregulated in a variety of human cancers including prostate cancer and their inhibition by HDAC inhibitors leads to cell cycle arrest and apoptosis in cancer cells. In pursuit of safe and effective HDAC inhibitors, we earlier demonstrated that green tea polyphenols (GTP) and its major constituent, (-) epigallocatechin-3-gallate (EGCG) has ability to inhibit class I HDACs in human prostate cancer cells. Here we demonstrate that GTP and EGCG activates p53 through acetylation at the Lys373 and Lys382 residues by inhibiting class I HDACs in human prostate cancer LNCaP cells. Treatment of cells with GTP (2.5-10μg/ml) and EGCG (5-20μM) resulted in dose and time dependent inhibition of class I HDACs, albeit at varying levels. Discontinuation of treatment with GTP/EGCG resulted in the loss of p53 acetylation at both the sites in these cells. GTP/EGCG treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels. The increased GTP/EGCG-mediated p53 acetylation enhanced its binding on the promoters of p21/waf1 and Bax, which was associated with the increase accumulation of cells in the G0/G1 phase of the cell cycle and induction of apoptosis. Taken together, our findings indicate that GTP/EGCG causes acetylation of p53 by inhibiting class I HDACs which is likely to be part of the mechanism that control the physiological activity of p53.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2583. doi:1538-7445.AM2012-2583
Abstract 2589: Novel chemopreventive combinatorial regimen significantly suppresses NF-kB and PI3-kinase/Akt pathways in the Syrian golden hamster pancreatic cancer model
Authors: Thakkar Arvind , Grandhi B. Karthik , Wang Jeffrey , Prabhu Sunil
Published: August 2012

Pancreatic cancer caused 40,000 deaths in 2010 and is currently ranked as the fourth leading cause of deaths in the United States. Due to poor prognosis of this disease, it is imperative that chemopreventive strategies be developed to control the formation of the initial neoplastic lesions. We have previously reported the effectiveness of a low dose combination regimen of aspirin, curcumin and sulforaphane (ACS) on MIA-PaCa-2 and Panc-1 pancreatic cancer cell lines. The objective of the current study was to use the ACS combination regimens in vivo to demonstrate the molecular targets responsible for prevention of pancreatic cancer in N-nitrosobis(2-oxopropyl) amine (BOP) carcinogen treated Syrian golden hamsters. BOP treated Syrian golden hamsters (n=6/group) were sacrificed after 24 weeks of treatment with a low (20+45+1.6), medium (67+150+5) and high (200+450+16) doses (in mg/kg) of ACS, respectively. Saline and BOP controls were included in the study. The pancreatic tissues were processed for isolation of nuclear and cytoplasmic proteins, and 20 mg of tissue was used for isolation of total RNA. Results from the Western blot show that low dose of ACS combined regimen down-regulated active NF-κB by inhibiting phosphorylation of IαBβ and p65. Low dose ACS also inhibited phosphorylation of Akt, needed for IKK activation. Consequently at the transcription level, low dose ACS significant down-regulated NF-κB regulated gene products TNFα, IL1α and IL6 compared to BOP controls (p<0.05). Thus, low dose ACS inhibited the translocation of NF-κB into the nucleus by inhibiting the phosphorylation of IαBβ and p65. In addition, RT qPCR analysis of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cyclin D1 show >2 fold down-regulation in low dose regimen compared to BOP controls. With the high and medium doses, a trend similar to the low dose ACS was evident, whereby the effects were more significant at higher doses (p<0.001), thus demonstrating a dose-dependent response. The significance of this work is in the demonstration of the effectiveness in gene regulation of ACS even at the low-dose level which shows its potential as a powerful combinatorial regimen for pancreatic cancer prevention.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2589. doi:1538-7445.AM2012-2589
Abstract 2660: Prevalence of obesity among subjects with a personal history of cancer: A call for action among cancer survivors and care providers
Authors: Moten Ambria , Jeffers Kayin , Larbi Daniel , Smith-White Roxanne , Taylor Teletia , Wilson Lori L. , Frederick Wayne , Laiyemo Adeyinka O.
Published: August 2012

Background: Studies have suggested that obesity is a risk factor for many common cancers and has a negative impact on the prognosis of those with cancer. Aim: To determine the prevalence of overweight and obesity among cancer survivors. Methods: We used the 2007 Health Information National Trends Survey (HINTS) data and identified those with (n = 966) and without (n = 6,093) a personal history of cancer. We calculated responders’ body mass index (BMI) using self-reported height and weight data and formed 3 categories: BMI < 25 kg/m*2 (normal); BMI 25 - 29 kg/m*2 (overweight); and BMI ≤ 30 kg/m*2 (obese). We used multinomial regression models to evaluate the association of personal history of cancer with BMI categories and calculated risk ratios (RR) and 95% confidence interval (CI). Results: The mean age of responders was 54.2 years and 60.5% were females. Cancer survivors were older (65.4 versus 52.4 years; P value <0.001), but there were no differences by sex or education level. After adjusting for age, sex, education, smoking, race, income, marital status and health insurance status, cancer survivors were as likely to be obese as responders without a history of cancer (Table). Conclusion: In this nationally representative sample of US adults, there is a high prevalence of obesity among cancer survivors. Maintenance of healthy weight should be an integral part of routine care of cancer survivors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2660. doi:1538-7445.AM2012-2660
Abstract 2661: Healthcare utilization by race and sex among a nationally representative sample of adults with and without a personal history of cancer
Authors: Burnside Clinton D. , Williams Mark D. , Hudson Tamaro , Caldera Ricardo , Freeman Clyde , Ricks-Santi Luisel , O'Neal Patricia , Laiyemo Adeyinka 0.
Published: August 2012

Background: Men and minorities suffer higher burdens from cancer. Healthcare utilization differences may contribute to this major public health problem. Aim: To compare utilization of healthcare services by race and sex among adults with and without a history of cancer as measured by having at least one doctor's visit within the last 12 months. Methods: We analyzed data from 7,229 responders to the 2007 Health Information and National Trends Survey (HINTS). We identified participants with and without a personal history of cancer and compared them by race and sex with having a doctor's visit within the previous 12 months. We used logistic regression models to calculate Odd Ratios (OR) and 95% confidence intervals (CI). Results: The mean age of respondents was 54.1 years, 38.8% males, 76.1% whites, 9.4% blacks, and 8.6% Hispanics. Of the respondents, 88.8% had health insurance (92.5% whites, 78.9% blacks, and 69.1% Hispanics; P value <0.001). Although there was no difference in health insurance coverage by sex (P value = 0.506), men were less likely to have seen a doctor within the previous 12 months (OR=0.40; 95% CI: 0.31-0.51). Cancer survivors were more likely to have seen a doctor (OR=2.70; 95% CI: 1.68-4.36), but there was no difference by race. After adjusting for age, education, race, income and insurance status, men were less likely to have seen a doctor if they did not have a personal history of cancer (Table). Conclusion: Our study suggests that men improve in their compliance to doctors’ visits only after cancer diagnosis. Targeted interventions to promote use of preventive care services by men are needed. Table: Comparison of doctors’ visit within the previous 12 months by personal history of cancer

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2661. doi:1538-7445.AM2012-2661
Abstract 2670: Genetic variants in human epidermal growth factor receptor (HER) family gene predict tumor recurrence in breast cancer
Authors: Zhang Henry(Xiong Jia) , Paez David , Giamas Georgios , Filipovic Aleksandra , Yang Dongyun , Bohanes Pierre , Ning Yan , Gerger Armin , LaBonte Melissa J. , Stebbing Justin , Lenz Heinz-Josef
Published: August 2012

Background: Epidermal growth factor receptor (EGFR or HER) family is composed of 4 members: HER1 (EGFR), HER2 (neu), HER3 and HER4. In breast cancer, besides HER2, other HER family members may also overexpressed and their dimerization may contribute to chemo-resistance. Single nucleotide polymorphisms (SNPs) in HER family genes have been associated with breast cancer risk and outcome. We tested 7 functional SNPs in HER family genes (HER1-4) (HER1 rs2227983, HER2 rs1136201, HER3 rs2271189 and HER4 rs4673628, rs839523, rs707284, rs6735267) in a cohort of Estrogen receptor (ER) positive breast cancer patients to determine their association with clinical outcome. Method: Tissue samples of 221 patients with ER positive primary invasive breast cancer (median age=56 years; range=28-90 years), who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. The median follow-up was 6.5 years and 96 of 221 patients (43%) had tumor recurrence with a 5-year probability of recurrence of 40%. Genomic DNA was extracted from formalin fixed paraffin embedded (FFPE) tissue samples and SNPs were analyzed using direct DNA-sequencing or PCR-RFLP. Results: In univariable analysis, EGFR R497K (rs2227983), and HER2 I655V (rs1136201) were associated with time to tumor recurrence (TTR)(log-rank P=0.007 and 0.041, respectively). In multivariable analysis, EGFR R(G)497K(A) remained significantly associated with TTR. Patients with EGFR 497 AA genotype (n=15) had a shorter median TTR 4.8 years (95%C.I 0.9-6.3 years) compared to those harboring AG or GG genotype (n=201), had median TTR=6.9 years (95%C.I 5.3-8.4 years). (Wald test p value = 0.041 in the Cox model adjusting for lymph node status, tumor size and HER2 staining). Conclusion: Genetic variants in the HER family gene may be potential molecular markers to predict tumor recurrence in advanced ER positive breast cancer. Further large, prospective trials are needed to confirm our preliminary findings.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2670. doi:1538-7445.AM2012-2670
Abstract 2680: Characterization of cultured circulating melanoma cells for individualized therapy
Authors: Kolostova Katarina , Hroncova E. , Liberko M. , Hoffman Robert M. , Arenbergerova M. , Rossmeislová L. , Romzova M. , Bobek Vladimir
Published: August 2012

In the presented study circulating melanoma cells (CMSs) have been isolated from a B16 mouse melanoma model and from melanoma patients. Culture of CMCs has enabled us to perform drug sensitivity testing on them. The main hypothesis was to compare drug sensitivity of primary tumor cells grown in culture with the sensitivity of CMCs grown in vitro after capture. B16 murine melanoma was implanted i.p. in mice. Fourteen days after peritoneal injection, mice were sacrificed and blood obtained by cardiac puncture for CMCs-capture. The CMCs were captured either by immunomagnetic separation (Adnagen, AdnaTest Melanoma Select™, Germany) and/or blood added to culture flask containing growing medium. Sensitivity to cisplatin (CDDP) was tested with the MTT-assay at different concentrations. Primary melanoma and disseminated tumor cells (DTCs) were also cultured and tested. The DTCs were isolated from peritoneal washing (ascites like cells), lymph nodes and peritoneal fat tissue. CMCs and DTCs were found less sensitive to CDDP than primary melanoma cells. The ability to capture and culture CTCs enabled these studies which can be used for individualized therapy design.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2680. doi:1538-7445.AM2012-2680
Abstract 2688: Color-coded imaging of the pre-metastatic niche in the lung and liver indicates the involvement of cancer-associated fibroblasts
Authors: Suetsugu Atsushi , Momiyama Masashi , Osawa Yosuke , Moriwaki Hisataka , Bouvet Michael , Saji Shigetoyo , Hoffman Robert M.
Published: August 2012

We report here a color-coded imaging model in which the development of pre-metastatic niches in the lung and liver can be identified. The transgenic green fluorescent protein (GFP)-expressing mouse was used as the host which expresses GFP in all organs but dimly in the parenchymal cells of the liver. Mouse breast cancer cells (MMT), expressing red fluorescent protein (RFP), were injected in the tail vein of GFP nude mice to establish a lung metastasis model and in the spleen of GFP nude mice to establish a liver metastasis model. Niche formation in the lung and liver metastasis was observed using the Olympus OV100, IV100, and FV1000 imaging systems. In the lung, GFP host- mouse cells accumulated around a single RFP cancer cell. In addition, GFP host cells were observed to form circle-shaped niches in the lung even without RFP cancer cells, which was possibly a niche in which future metastasis could be formed. In the liver, as with the lung, GFP host cells could form circle-shaped niches without RFP cancer cells. The accumulation of host GFP cells before metastasis formation was observed in the live mouse, enabling cancer-cell niche-interaction to be observed as well as the premetastatic niche in real time. The liver and lung metastases were removed surgically and cultured in vitro. MMT-RFP cells and GFP cancer-associated fibroblasts (CAFs) were observed in the dish, suggesting that CAFs initiated the premetastatic niche. This is in contrast with previous studies which suggested that bone marrow cells initiated the premetastatic mice (Nature 438, 820-827, 2005).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2688. doi:1538-7445.AM2012-2688
Abstract 2694: The impact of curcumin plus docetaxel on neuroendocrine features, or not, in castration-resistant prostate cancer: A prospective study
Authors: Planchat Eloïse , Eymard Jean-Christophe , Curé Hervé , Durando Xavier , Barthomeuf Chantal , Gadéa Emilie , Abrial Catherine , Thivat Emilie , Chollet Philippe , Mahammedi Hakim
Published: August 2012

Background &Aims: Curcumin, a polyphenol derived from Curcuma Longa is known for his anti-cancer activity and may exert synergic effects with cytotoxic agents. In parallel, neuroendocrine differentiation in castration-resistant prostate cancer provides an aggressive phenotype to disease. In this prospective phase II study, we assessed the impact of a new combination, docetaxel plus curcumin, in patients with or without neuroendocrine features. Methods: In this phase II study, thirty patients received docetaxel 75 mg/m*2 (perfusion given every 3 weeks) in combination with curcumin orally at 6 g/day (day-4 to day+2 of docetaxel). Neuroendocrine features were determined by serum chromogranin A and neuron-specific enolase, before each cycle. Variations were divided in 3 groups: an increase > 25%, a decrease of 50% or greater and stability. Treatment response were measured by PSA >50% decrease (PSA response) and objective response rate on evaluable metastatic lesions. Results: Initially, 53% of patients had an elevated chromogranin A and 33% an elevated neuron-specific enolase. During treatment, 7% performed a > 50% chromogranin A decrease and 30% a neuron-specific enolase decrease. PSA response was observed in 59% of patients and 40% out of patients with evaluable targets had a partial response. PSA and objective response rate were identical whatever neuroendocrine feature. A positive correlation was found between chromogranin A and PSA, age, weight and palliative radiotherapy. Conversely, neuron-specific enolase was negatively correlated with PSA and patients'age. Conclusions: Curcumin and docetaxel had a global action on tumors with or without neuroendocrine features. Chromogranin A was the best neuroendocrine marker in correlation with clinical parameters. This association delivered then remarkable results on neuroendocrine differentiation of castration-resistant prostate cancer, in comparison with pivotal study data with docetaxel alone (TAX 327).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2694. doi:1538-7445.AM2012-2694
Abstract 2730: Anti-Her2/neu immunotoxins: Impact of monovalent and bivalent designs on in vitro and in vivo antitumor efficacy
Authors: Cao Yu , Marks John W. , Liu Zhigang , Chueng Lawrence H. , Hittelman Walter N. , Rosenblum Michael G.
Published: August 2012

Immunotoxins and designed fusion constructs have significant potential for improved cancer therapy and reduced toxic side effects. We compared the efficacy of anti-Her2/neu immunotoxins containing recombinant gelonin (rGel) in either monovalent or bivalent formats. The bivalent conjugate was Herceptin/rGel chemical conjugate and the monovalent constructs were Herceptin-derived scFv (4D5) fused to rGel in two orientations: 4D5/rGel and rGel/4D5. All three immunotoxins retained the affinity and specificity of the original antibody as well as the biological activity of rGel toxin. Cytotoxicity studies against a panel of Her2/neu expressing tumor cell lines revealed significant differences among these constructs. Both Herceptin/rGel conjugate and rGel/4D5 displayed the best cytotoxicity and specificity whereas 4D5/rGel was the least potent. IC50 values ranged from 0.1-1nM for Herceptin/rGel conjugate and rGel/4D5, but were 10-1000 fold higher for 4D5/rGel. BT474 M1 HR cells with acquired resistance to Herceptin, either by constitutive Akt activation or external factor stimulation, remained sensitive to these constructs compared to the parental cells. The cytotoxicity of all constructs was generally restricted to cells expressing high levels of Her2/neu indicating that Herceptin-based immunotoxins may not be toxic to normal tissues with endogenous (low or medium) levels of Her2/neu. Treatment of nude mice bearing well-developed SKOV3 tumor xenografts with either Herceptin/rGel or rGel/4D5 resulted in impressive tumor inhibition compared to either Herceptin or 4D5/rGel. These studies demonstrate that engineered fusion constructs are competitively effective compared with chemically-generated immunotoxins with longer plasma circulation times. Further characterization of the constructs on Her2/neu overexpressing tumor cells with MDR/MRP resistance is currently ongoing. In conclusion, our studies suggested that smaller, engineered monovalent fusion constructs have excellent, comparable activity compared to intact bivalent antibody conjugates. In addition, the orientation of rGel/scFv vs scFv/rGel can significantly impact the in vitro and in vivo therapeutic activity and should be a consideration in design optimization. Research conducted, in part, by the Clayton Foundation for Research.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2730. doi:1538-7445.AM2012-2730
Abstract 2733: LJM716: an anti-HER3 antibody that inhibits both HER2 and NRG driven tumor growth by trapping HER3 in the inactive conformation.
Authors: Garner Andrew , Sheng Qing , Bialucha Uli , Chen Dongshu , Chen Yan , Das Rita , Elis Winfried , Heidt Analeah , Kunz Christian , Li Sharon , Liang Jinsheng , Murtie Joshua , Saxena Parmita , Schuller Alwin , Sineshchekova Olga , Sprague Elizabeth , Wang Hui Qin , Huang Alan , Ettenberg Seth
Published: August 2012

HER3 (ErbB3) is a member of the ErbB family of receptor tyrosine kinases (RTK). Inappropriate HER2/ HER3 dimerization as a result of HER2 or neuregulin (NRG) over-expression in cancer results in HER3 mediated activation of PI3K signaling. Consequently, HER3 is a mediator of oncogenic transformation. Although, ligand blocking HER3 antibodies inhibit growth of neuregulin driven xenograft models they are ineffective in models of HER2 amplified cancer as HER2 mediated activation of HER3 occurs in a ligand- independent manner. LJM716 is a high affinity HER3- targeted antibody selected from a Human Combinatorial Antibody Library (HuCAL) specifically for its ability to neutralize multiple modes of HER3 activation. LJM716 is a potent inhibitor of HER3/ AKT phosphorylation and proliferation in a range of HER2 amplified and NRG expressing cell lines in vitro. LJM716 induced tumor regression in Fadu (NRG expressing, HNSCC) tumor xenografts and significant tumor growth inhibition (>80%) in a variety of xenograft models including BT474 (HER2 amplified breast). Furthermore, the combination of LJM716 with trastuzumab, cetuximab or PI3K- targeted agents was synergistic in a panel of in vitro cell lines while the in vivo combination of LJM716 with trastuzumab or erlotinib was efficacious in BT474 and L3.3 (pancreatic) tumor xenografts respectively. To further understand the mechanism by which LJM716 inhibits multiple modes of HER3 activation we solved the crystal structure of LJM716 bound to the HER3 extra-cellular domain. This data revealed that LJM716 binds to a novel conformational epitope contained within domains 2 and 4 and appears to trap HER3 in the inactive conformation. Interestingly, LJM716 does not block NRG binding to HER3 nor does it affect the binding affinity of the HER3/ NRG interaction. LJM716 therefore possesses a novel mechanism of action; it prevents the structural rearrangements required for HER3 activation induced by either HER2 or NRG. Thus LJM716 is the first HER3 antibody to display efficacy in both HER2 and ligand driven xenograft models. Based on preclinical data, combining LJM716 with either trastuzumab, cetuximab or PI3K- targeted agents may lead to greater and more sustained clinical efficacy in ErbB driven cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2733. doi:1538-7445.AM2012-2733
Abstract 2738: c-Met antibody LY2875358 (LA480) has pre-clinical enhanced efficacy with gastric cancer standard-of-care in vitro and in vivo
Authors: Wortinger Mark A. , Peek Victoria , Zeng Wei , Yan Lei , Tetreault Jonathan , Xia Jinqi , Jirong Lu , Chow Chi-Kin , Manro Jason R. , Stephens Jennifer R. , Merzoug Farhana , Vaillancourt Peter , Yan S. Betty , Liu Ling
Published: August 2012

cMet is a member of the receptor tyrosine kinase family and is the receptor for hepatocyte growth factor (HGF). cMet has been implicated in the initiation and progression of cancer due to the range of activities that cMet stimulates including proliferation, migration, morphogenesis, and survival. Inappropriate activation of c-Met can be induced by ligand-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation, or by ligand-dependent autocrine or paracrine mechanisms. Indeed, amplification of the c-Met gene, with consequent protein overexpression and constitutive kinase activation, has been reported in a number of human cancers, including gastric, esophageal and non-small-cell lung carcinomas. It has been reported that ∼10-20% of gastric tumors have increased copy numbers of the MET gene and overexpression of c-Met significantly correlates with poor prognosis in gastric cancer. c-Met antibody LY2875358 treatment reduces proliferation of gastric cancer cell lines with ligand-independent activation of c-Met resulting from gene amplification. The ability of LY2875358 to internalize and deplete cell surface c-Met is implicated in its activity against ligand-independent driven gastric cell lines. Here, we demonstrate that the pre-clinical combination of c-Met antibody LY2875358 with gastric cancer standard-of-care treatment has better efficacy than either treatment alone, both in vitro and in vivo. These data suggest that LY2875358 in combination with standard-of-care may be a promising treatment for gastric cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2738. doi:1538-7445.AM2012-2738
Abstract 2745: INK128, a TORC1/2 kinase inhibitor, enhances the efficacy of cytotoxic therapies in endometrial tumor models
Authors: Kessler Linda , Jessen Katti , Janes Matthew , Staunton Jocelyn , Kucharski Jeff , Guo Xin , Elia Marikka , Banerjee Urmi , Lan Lucy , Wang Shunyou , Stewart Josh , Luzader Angelina , Darjania Levan , Li Liansheng , Chan Katrina , Martin Michael , Ren Pingda , Rommel Christian , Liu Yi
Published: August 2012

Background: The mammalian target of rapamycin (mTOR), which comprises two protein complexes, TORC1 and TORC2, regulates tumor cell growth, metabolism and motility. In endometrial cancer, the mTOR pathway is aberrantly activated by constitutive mitogen stimuli, such as FGFR2 and multiple genetic mutations such as PIK3CA, PIK3R1/2, PTEN and LKB1. The activation of multiple signaling pathways, cross-feedback and redundancy of these pathways led us to explore the combination of mTOR kinase inhibitor with chemotherapeutic agents for achieving maximal efficacy in preclinical mouse models of endometrial cancer. Results: INK128 is a potent and selective TORC1/2 inhibitor with excellent drug-like properties currently advancing in clinical development. INK128 inhibits endometrial tumor cell proliferation in vitro and displays tumor growth inhibition in endometrial tumor models. In most instances, the anti-tumor activity of INK128 is cytostatic compared to the cytotoxic effect of taxol and carboplatin. In endometrial tumor cells of diverse genetic backgrounds, combining INK128 with taxol resulted in a synergistic inhibition of tumor cell proliferation, sustained suppression of PI3K/AKT/mTOR pathway activity, skewed cell cycle and an increase in apoptosis. INK128 decreased the expression of anti-apoptotic protein MCL-1 and therefore mechanistically enhanced taxol-triggered apoptosis. In endometrial mouse tumor models with PTEN and FGFR2 mutations, the combination induced marked tumor regression and significantly delayed tumor re-growth upon discontinuation of the treatment compared to taxol treatment alone. The combination therapy was well-tolerated and the enhanced anti-tumor efficacy correlated with mechanism-based inhibition of several TORC1 and TORC2 pharmacodynamic markers and induction of apoptosis in vivo. Additionally, combining INK128 with taxol or carbotaxol resulted in tumor regression in taxol-resistant endometrial tumor models. The opportunity of optimizing dose and schedule combination regimens as well as biomarkers predicting sensitivity/resistance to INK128/taxol combination will be discussed. Conclusion: The combination of mTOR kinase inhibitors with chemotherapeutic agents is a compelling strategy to improve therapeutic outcome and to overcome chemo-resistance for tumor types with aberrant activation of the PI3K/mTOR pathway such as endometrial cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2745. doi:1538-7445.AM2012-2745
Abstract 2746: Thiazolidinediones augment anticancer effects of gemcitabine on human pancreatic cancer cells through PPARδ activation
Authors: Koga Hironori , Selvendiran Karuppaiyah , Sivakumar Ramadoss , Yoshida Takafumi , Torimura Takuji , Ueno Takato , Sata Michio
Published: August 2012

In order to improve the prognosis of patients with unresectable pancreatic cancer, there is an urgent need for enhancement of the anticancer effect of gemcitabine (Gem), a first-line drug for the disease. Here, we demonstrated that ligands for peroxisome proliferator-activated receptor ≤ (PPARδ) such as pioglitazone (Pio) and rosiglitazone potentiated the cytotoxic action of Gem on human pancreatic cancer cells in a dosage-dependent manner. Notably, the synergistic effect was PPARδ-dependent, since the effect was augmented by PPARδ overexpression and was attenuated by both a PPARδ inhibitor (GW9662) and PPARδ-specific siRNA. To further increase the collaborative effect, the histone deacetylase (HDAC) inhibitor valproic acid (VPA), a known potentiator for PPARδ function, was added to the combinatorial treatment, robustly inducing apoptosis mediated by highly expressed death receptors, including Fas/CD95 and DR5. In xenograft tumor experiments in nude mice, Gem plus Pio significantly suppressed tumor growth as compared with the control treatment, while Gem-only treatment did not. Triple treatment with Gem, Pio, and VPA failed to demonstrate a significant antitumor effect when compared with Gem plus Pio in the current setting. Considered together, Gem plus PPARδ ligands, including Pio, may have therapeutic advantage in the treatment of advanced pancreatic cancer. Since Pio is widely used in the treatment of diabetes mellitus, it may become a feasible partner of Gem-based chemotherapy, fine-tuning the strength of the therapy in a dosage-dependent fashion.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2746. doi:1538-7445.AM2012-2746
Abstract 2755: Enhanced anti-tumor effects using a combinatorial targeted treatment strategy in a preclinical model of prostate cancer
Authors: Yamamoto Yutaka , De Velasco Marco A. , Hatanaka Yuji , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Kodama Mitsumasa , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu
Published: August 2012

Recently developed strategies use molecular targeting agents specifically designed to target core regulatory signaling pathways of prostate cancers. Growth factors mediate such signaling pathways that include the PI3K/Akt/PTEN/mTOR and Ras/Raf/MEK/MAPK as well as other essential pathways. However various mitigating factors such a genetic variation, molecular diversity, diverging and converging of signaling pathways make it improbable that treatment with any single agent will result in any long-term enhanced tumor. To overcome such problems we investigated the toxicity and antitumor effects of combined targeted therapy with the mTOR inhibitor everolimus and the mulitkinase inhibitor sorafenib in a prostate-specific PTEN conditional knockout mouse model of human prostate cancer. Non-castrated and castrated (castrate-resistant prostate cancer model, CRPC) PSACre;PTENloxP/loxP mutant mice, harboring prostate tumors, were treated with everolimus and sorafenib alone or in combination for 4 weeks beginning at 16 weeks of age. All mice appeared healthy and there were no significant differences in body weights, appearance or histological findings between treatment and control groups at the end of the experiment. Our analysis shows that combination therapy has a significant additive inhibitory effect on tumor growth in non-castrate prostate cancer model (8.8 mm2, 7.7 mm2, 7.1 mm2 and 5.2 mm2 in control, everolimus, sorafenib and combination treatment groups, respectively, p=0.005). Ki67 expression was decreased and positive TUNEL apoptotic bodies was increased in combination treatment groups compared to everolimus and sorafenib monotherapy in both non-castrated and CRPC treatment groups. We also show that combination therapy, but not monotherapy, cooperated to inhibit phosphorylation of the eukaryotic translation initiation factor 4B (eIF4B). Our study provides preclinical evidence that a targeted combination treatment strategy with everolimus and sorafenib is tolerable and leads to improved treatment efficacy over single agent therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2755. doi:1538-7445.AM2012-2755
Abstract 2758: Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors: Evidence for the role of C-Jun N-terminal kinase activation
Authors: Cheng Hairong , Hong Bo , Zhou Lanlan , Allen Joshua , Dicker David , El-Deiry Wafik
Published: August 2012

Discovery of the molecular targets of chemotherapeutic medicines and their chemical footprints can validate and improve the use of such medicines. In the present study, we investigated the effect of mitomycin C (MMC), a well-known chemotherapeutic agent on cancer cell apoptosis induced by TRAIL. We found that MMC not only potentiated TRAIL-induced apoptosis in HCT116 (p53-/-) colon cancer cells but also sensitized TRAIL-resistant colon cancer cells HT-29 to the pro-apoptotic cytokine. MMC also improved the pro-apoptotic effects of two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab. At a mechanistic level, MMC downregulated cell survival proteins including Bcl2, Mcl-1 and Bcl-XL, upregulated cell pro-apoptotic proteins including Bax and Bim, and induced the cell surface expression of TRAIL death receptors DR4 and DR5. Gene silencing of DR5 by short hairpin RNA reduced the apoptosis induced by combination treatment of MMC and TRAIL. Induction of DR4 and DR5 was independent of p53, Bax and Bim, but was dependent on c-Jun N-terminal kinase (JNK) as JNK pharmacologic inhibition and the JNK siRNA abolished the induction of the TRAIL receptors by MMC. The results provide insights into strategies for the development of novel combinatorial cancer therapy combinations that may be further tested in the clinic.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2758. doi:1538-7445.AM2012-2758
Abstract 276: Targeting signaling networks via RNAi to improve therapy for ovarian cancer
Authors: Liu Hanqing , Serebriiskii Ilya , Einarson Margret B. , Pecherskaya Anna , Zhou Yan , Pathak Harsh , Godwin Andrew K. , Golemis Erica A.
Published: August 2012

Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy, and the leading cause of death from gynecological cancers. At the time of presentation, most ovarian cancers are no longer dependent on single genetic determinants for growth and/or survival, and targeted therapies used as single agents typically do not work in this disease. We hypothesized that network-based synthetic lethality screens would help identify critical pathways to target in combination therapy. We have used RNAi screening with a targeted library to identify a set of gene candidates that influence the response of EOC cells to the Src-targeting agent dasatinib, a promising agent for treatment of EOC. We identified sets of siRNAs that specifically modulated cell resistance to dasatinib, or directly affected EOC cell survival. We then compared this set of siRNAs with previously identified modulators of response to EGFR-targeting agents and cytotoxic drugs, contrasting action in EOC cell lines versus other types of cancer cell lines. From a set of 60 siRNAs intrinsically reducing cell growth and survival, some (16 siRNAs) were specific for EOC cells. In contrast, 38 siRNAs antagonized the response of EOC cells to dasatinib, and are promising drug treatment-resistance biomarkers. We concluded validation of EOC-specific hits. Mapping the pattern of drug treatment-resistance hits together with drug treatment-sensitive hits revealed suggestive clusters of very closely interacting proteins clustering with well validated modulators of cancer cell survival, implying we have identified key cancer signaling nodes. Screening candidates, e.g., PTPN12, Spry4, and HSPA8, which cluster with well-validated cancer-related signaling hubs, are being examined. These studies offer an opportunity to employ a functional approach to identify critical drug response-modifying genes that can be therapeutically targeted as biomarkers and drug targets to improve EOC treatment outcomes with emerging targeted agents. (This work was supported by the fellowship grant from Sass Foundation for Medical Research, Inc, Roslyn, New York to H. Liu, NIH FCCC-UPenn ovarian cancer SPORE (P50 CA083638), and NIH (R01 CA140323).)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 276. doi:1538-7445.AM2012-276
Abstract 2760: Gemcitabine induced lytic EBV replication and confers ganciclovir susceptibility to EBV-positive gastric cancer
Authors: Kim Hyemi , Lee Hyun Gyu , Park Jeon Han , Lee Jae Myun ,   Brain Korea 21 Project for Medical Sciences
Published: August 2012

Epstein-Barr virus (EBV) is a dsDNA human gamma herpes virus which infects more than 90% of human populations. It is associated with the development of malignancies such as Burkitt's lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Gastric cancer is the second most common cancer in the world and the highest incidence is in Korea. The constant presence of the viral genome in EBV associated gastric cancer tissue offers the potential for novel EBV targeted therapies using antiviral nucleoside drug. Ganciclovir (GCV) is the drug of choice in herpes virus infection, however, GCV alone have been unsuccessful in the treatment of EBV associated malignancies because the virus maintains a latent state of replication in tumor, and thymidine kinase (BXLF1) and protein transferase (BGLF4), express only during lytic state of replication. In recent years, novel treatment strategies are being investigated where in lytic replication of the virus in EBV associated cancer is induced prior to the use of GCV. We investigate Gemcitabine (Gem), which is one of newly discovered potential lytic inducers found from FDA approved drug library screen using BZLF1 promoter reporter system. We examined whether the combination of GCV and Gem is more effective than Gem alone for killing EBV-positive gastric cancer cells. We found GCV significantly enhanced the ability of Gem to kill EBV-positive, but not EBV negative, gastric carcinoma cells in vitro. Also we found that low dose (2.5ng/ml) and short term exposures (24hr) of the EBV positive gastric cancer cell line SNU719 to Gem induced expression of the EBV lytic phase proteins. Viral kinases were also induced by short term and low dose exposure. Short term and low dose exposure to Gem in combination with GCV induced tumor cell death and cell proliferation inhibition. In conclusion, pharmacologic induction of the lytic viral kinases in tumor cells using Gem, followed by treatment with GCV is useful in EBV associated gastric cancer in vitro. And this virus-targeted antitumor strategy may provide a new therapeutic approach to EBV-associated gastric cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2760. doi:1538-7445.AM2012-2760