bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3670: Reduced expression of p27 and the occurrence of CpG island methylator phenotype in insulinomas
Authors: Chen Yuan-Jia , Zhou Qiao , Chen Yuan-Fang , Wu Hai-Yan , Xiao Yu
Published: February 2011

Aim Little is known about the molecular pathogenesis of sporadic insulinoma which is a type of rare endocrine tumors, and there is a lack of reliable biomarkers to differentiate benign from malignant tumors. Thus we analysed the CpG island methylator phenotype (CIMP) of multiple genes in sporadic insulinamas, as well as the expression of p27 and the relationship between p27 and CIMP.

Materials and Methods Using methylation specific PCR, we examined the methylation status of p16, MLH1, RAR-β, O6-MGMT, THBS1 in 33 sporadic insulinomas and 20 paired pancreatic tissues. The expression of p27 was detected by immunohistochemistry staining. The experimental data were correlated with clinical-pathological characteristics, and were analysed by t-test, chi-square test or Fisher's exact test.

Results The incidence of CIMP-High was found in 33% of insulinomas, higher than its rate in the paired pancreatic tissues, but the difference was not significant (P=0.209). The methylation status of O6-MGMT and p16 were inversely correlated (P=0.003). Compared with the paired pancreaticl tissues, the expression of p27 was reduced in tumors (85% vs. 39%, P=0.008). Moreover, the reduced expression of p27 was significantly related to the methylation of O6-MGMT (P=0.016). The reduced expression of p27 might be related with higher rate of CIMP, but the difference did not reach significance due to the limited number of tumors. The experimental data were not significantly associated with clinical-pathological characteristics in this study.

Conclusion CIMP-High and reduced expression of p27 were observed in a subtype of insulinomas, and these molecular alterations might play a role in tumorigenesis of insulinoma.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3670.
Abstract 3672: Adrenocortical carcinoma cell lines are sensitive to compounds targeting the G2/M transition
Authors: Datrup Erica , Demeure Michael J. , Bussey Kimberly J.
Published: February 2011

Adrenocortical carcinoma (ACC) is an aggressive tumor of the adrenal cortex. It affects 1-2 per million and has a 5 year survival rate of 25-30% due to late detection and a lack of effective systemic therapy. Mitotane, an isomer of the insecticide DDT, is the only compound approved for the treatment of patients with ACC. It has a poor response rate (22% as a single agent) and a toxicity profile that often results in dose reduction or cessation of therapy altogether. New therapies are desperately needed.

Expression profiling of ACC by ourselves and others highlights the importance of the G2/M transition, the p53 pathway, and signaling of IGF2 through IGF1R. Using this knowledge, we profiled the in vitro chemosensitivity of the two ACC cell lines, H295R and SW-13, to compounds that target aspects of these pathways. Cells were plated, and drug added 24 hours later in a 3-fold serial dilution, with the exception of mitotane which was done as a 1.5-fold serial dilution. Viability was assessed by CellTiter Glo at 3 different time points. The cell lines show sensitivity to compounds that target the G2/M transition (VX-680 and BI-2536) and EGFR (erlotinib). The difference in response between H295R and SW-13 to LY294002 suggests the cell lines harbor a difference in the relative contributions of PI3K signaling versus Ras-Raf-MEK signaling downstream of IGF1R. Additionally, the response of both cell lines to erlotinib suggests that EGFR signaling may play a role in ACC. Neither cell line was particularly sensitive to MDM2 inhibition, indicating that this is not a good target to restore p53 pathway function. Finally, our results suggest that further testing of compounds that target G2/M is warranted, particularly PLK-1 inhibitors.In vitro chemosensitivity profiling in ACC cell linesCompoundMechanism of ActionTime PointAverage IC50 for SW-13 in uMAverage IC50 for H295R in uMMitotaneUnknown, but results in mitochondrial degeneration72 hours12.869.48  96 hours11.039.05  120 hours11.519.99Nutlin-3MDM2 inhibitor72 hours19.2415.81  96 hours16.8614.83  120 hours15.8114.00LY294002PI3K inhibitor72 hours4.3653.86  96 hours4.3122.73  120 hours4.8013.55ErlotinibEGF-R inhibitor72 hours2.73NA  96 hours2.562.29  120 hours2.662.34BI-2536PLK-1 inhibitor72 hours0.00590.35  96 hoursND0.11  120 hoursND0.12VX-680Aurora kinase inhibitor72 hours17.23ND  96 hours6.07ND  120 hours5.21ND

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3672.
Abstract 3674: Inhibition of noncanonical NF-kappa B activation by (−)-DHMEQ in vitro and in adult T-cell leukemia cells
Authors: TAKEIRI Masatoshi , HORIE Ryoichi , UMEZAWA Kazuo
Published: February 2011

[Objective and Rationale]Noncanonical NF-kappa B consisting of RelB and p52 is especially important for the maturation of B-lymphocytes and autoimmune diseases. In one hand, we have designed and synthesized a novel NF-kappa B inhibitor (−)-DHMEQ. It showed potent anti-inflammatory and anti cancer effects in animal models without any toxicity. We have reported (−)-DHMEQ covalently binds to the specific Cys residue of each NF-kappa B component and that it inhibits the DNA binding of canonical NF-kappa B components. However, the effects on noncanonical NF-kappa B has not been studied at the molecular level. In the present research we have studied theinhibitory effect of (−)-DHMEQ on noncanonical NF-kappa B in vitro and in cultured lymphoma cells in which noncanonical NF-kappa B is constitutively activated. [Experimental Design and Results]We prepared recombinant noncanonical NF-kappa B proteins, RelB and p52. (−)-DHMEQ was shown to covalently bind to Cys144 of RelB but not to p52 in MLADI-TOF/MS and mutation analysis. Either RelB or p52 does not form homodimer. Then, we prepared HeLa cells over–expressing full length RelB and p52. (−)-DHMEQ inhibited the NF-kappa B activity in RelB(wild type)/p52 cells but not in RelB(C144S)/p52 expressing cells in EMSA. Thus (−)-DHMEQ was shown to target Cys 144 of RelB in cultured cells to inhibit noncanonical NF-kappa B-DNA binding. It also inhibited RelB/p52 binding to DNA in vitro. Then, we looked for the cell line in which noncanonical NF-kappa B is constitutively activated using anti-RelB in EMSA. MT-1 cells are HTLV-1 transformed T-cells and often used for the adult T-cell leukemia (ATL) model. We found that the highly activated NF-kappa B is mainly consisting with noncanonical one in MT-1 cells. (−)-DHMEQ effectively inhibited the noncanonical NF-kappa B activity in MT-1 cells. [Conclusion] (−)-DHMEQ binds to RelB and effectively inhibited RelB/p52-DNA binding. We have found noncanonical NF-kappa B is highly activated ATL-like MT-1 cells, which was inhibited by (−)-DHMEQ. (−)-DHMEQ may be useful for the treatment of ATL and other diseases induced by noncanonical NF-kappaB activation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3674.
Abstract 3678: Reducing non-specific toxicity of cisplatin in head and neck cancer by targeted therapy using cisplatin-heparin-folic acid nanoparticles
Authors: Peng Xianghong , Wang Yiqing , Huang Donghai , Wang Yuxiang , Chen Zuo Georgia , Nie Shuming , Shin Dong M.
Published: February 2011

Cisplatin(DDP) is a platinum-based chemotherapy drug which was widely used to treat various types of cancer including Head and Neck Squamous Cell Carcinoma (HNSCC). However, very little DDP reaches the tumor tissue due to poor specificity and it induces dose-limiting toxicities. The delivery of DDP selectively into a tumor mass has the potential to minimize toxicity to normal tissues and to improve the antitumor efficiency. We have developed novel nanoparticles by conjugating folic acid to modified heparin, then loaded cisplatin (DDP) into the targeted nanoparticles via the exchange of reaction of Pt from the chloride to the carboxylates on the nanoparticles. Uptake and biodistribution of DDP delivered by the nanoparticles or the free DDP form in vitro and in vivo was quantified by inductively coupled plasma-mass spectrometry (ICP-MS). We showed that DDP-Heparin-Folic Acid (FA) Nanoparticles are specifically internalized by FR-expressing HNSCC KB cells in vitro (17 fold higher than free DDP). Systemic delivery of DDP-Heparin-FA nanoparticles (2.5 mg/kg; 4 times treatment at 3 days intervals) into nude mice bearing KB cell tumors (6 mice/group) lead to selective accumulation of the DDP in subcutaneous tumor lesions (74 ppb/mg tissue for HFDDP, 16.5 ppb/mg tissue for DDP, P<0.05), and have significant antitumor activity. Furthermore, mice receiving DDP-Heparin-FA nanoparticles showed no significant body weight loss or damage to liver or spleen, whereas mice that received free DDP had significant weight loss and massive organ damage. Our results suggest that DDP-Heparin-FA nanoparticles have the potential to be used for delivery of this highly toxic chemotherapeutic agent with reduced side effects in HNSCC. (This research was supported by the National Cancer Institute award 5 P50 CA128613)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3678.
Abstract 3680: The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane
Authors: Berndt Norbert , Yang Hua , Trinczek Bernard , Zhang Ziming , Wu Bainan , Lawrence Nicholas J. , Pellechia Maurizio , Schonbrunn Ernst , Cheng Jin Q. , Sebti Said M.
Published: February 2011

Persistently activated hyper-phosphorylated Akt contributes to human oncogenesis and tumor resistance. TCN-P, the active metabolite of the Akt phosphorylation inhibitor triciribine (TCN), is in clinical trials in patients whose tumors contain hyper-phosphorylated Akt, but the mechanism by which TCN-P, inhibits Akt phosphorylation is not known. In this manuscript, we show that in vitro, TCN-P inhibits neither Akt kinase activity nor the phosphorylation of Akt S473 and T308 by mTOR or PDK1, respectively. However, in intact cells, immunofluorescence and subcellular fractionation experiments demonstrate that TCN inhibits EGF-stimulated Akt recruitment to the plasma membrane and subsequent phosphorylation of Akt on Ser473 and Thr308. Surface plasmon resonance (SPR) demonstrates that TCN-P, but not TCN, binds to full-length, non-phosphorylated (inactive) Akt. However, neither TCN-P nor TCN interacts with full-length, phosphorylated (active) Akt. Furthermore, TCN-P, but not TCN, binds Akt-derived pleckstrin homology (PH) domain with KD values of 690 nM and 1.4 µM as demonstrated by SPR and isothermal calorimetry (ITC), respectively. Consistent with these data, nuclear magnetic resonance (NMR) spectroscopy shows that TCN-P, but not TCN, binds to the PH domain engaging amino acid residues in the vicinity of the PIP3 binding pocket. Thus, SPR, NMR, as well as biochemical studies indicate that the anti-cancer drug TCN-P inhibits Akt function by binding to the PH domain of Akt, blocking its recruitment to the plasma membrane and subsequent phosphorylation, suggesting that this drug may be beneficial to patients whose tumors express persistently activated Akt.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3680.
Abstract 3682: Enhanced anticancer effect of 5-fluorouracil loaded into thermoresponsive conjugated linoleic acid-incorporated poloxamer hydrogel on metastastic colon cancer models
Authors: Bae Woo Kyun , Lee Ji Hee , Park Myong Suk , Hwang Jun Eul , Shim Hyun Jeong , Cho Sang Hee , Guo Ding-Ding , Cho Chong Su , Lee Sang Joon , Park In Kyu , Chung Ik Joo
Published: February 2011

Background: 5-Fluorouracil (5-FU) is a useful chemotherapeutic agent in the treatment of solid tumors. However, it is very short half-life in plasma circulation greatly limited the in vivo antitumor efficacy, and intravenous 5FU injection is unlikely to achieve optimal dose effectiveness within peritoneal cavity. Conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an effective drug delivery system with numerous advantages and has an anticancer activity. It was also shown that paclitaxel loaded in Plu-CLA demonstrated synergistic tumor suppression through robust cell cycle arrest and enhanced apoptosis in tumor compared to paclitaxel in poloxamer hydrogel. The aim of this work is to evaluate the therapeutic efficacy of Plu-CLA as a new intraperitoneal 5FU delivery system.

Methods: Cytotoxicity was evaluated by using CT-26 murine colon carcinoma cell. We established peritoneal metastasis models and hepatic metastasis models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI).

Results: MTT assay indicated that 5-FU loaded in Plu-CLA hydrogel (P-FU) could increase the cytotoxic activity of 5-FU in CT-26. P-FU significantly enhanced apoptosis compared with 5-FU control. It was found that Caspase 3 and p21 were up-regulated, whereas Bcl-2 was down-regulated. Moreover, growth of hepatic metastases in vivo was significantly reduced in mice treated with P-FU. Treatment with P-FU substantially delayed tumor growth of intraperitoneal metastasis greatly and tumor-bearing mice treated with P-FU showed a better survival tendency than the 5-FU alone.

Conclusion: These results were attributed to the synergistic effect of Plu-CLA. 5-FU administered in Plu-CLA hydrogel led to significant enhancement of tumor growth suppression and cellular apoptosis. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophilic 5-FU for the effective treatment of metastatic colon cancer.

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Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3682.
Abstract 3684: Developing STAT3 protein inhibitors as adjuvant therapeutics: Promising synergistic effects in human cancers
Authors: Fletcher Steven , Page Brent D. G. , Yue Piebin , Zhang Xiaolei , Sharmeen Sumaiya , Schimmer Aaron D. , Turkson James , Gunning Patrick T.
Published: February 2011

Signal Transducer and Activator of Transcription 3 (Stat3) protein is a cytosolic transcription factor that relays signals from receptors in the plasma membrane directly to the nucleus, and is routinely hyper-activated in many human cancers and diseases. STAT3 induces anti-apoptotic gene expression programs (e.g. Bcl-xL) and the over-expression of cell cycle regulators (e.g. cyclin D1) that contribute significantly to the resistance of cancer to current chemotherapeutic strategies. Since most cancer drugs aim to initiate apoptosis, tumor cells containing activated STAT3 have an intrinsic resistance to current treatment strategies. It has therefore been postulated that STAT3 inhibitors could play a significant role in the future of adjuvant cancer therapies by sensitizing human tumors to traditional chemotherapy. By examining the protein-protein interaction interface and employing computational modeling, we have thus developed a series of small molecule inhibitors of the transcriptionally active STAT3-STAT3 homo-dimer complex. Lead inhibitors showed potent anti-STAT3 activity in vitro and in tumor cell lines, as well as in malignant cells taken from leukemia patients. More specifically, these compounds displayed single digit micromolar activity against breast, prostate, pancreatic and leukemia cell lines and showed negligible cytotoxic effects on healthy cells treated with high µM concentrations of compounds. Preliminary adjuvant studies with a series of clinically relevant therapeutics have shown impressive synergistic effects in leukemia cell lines, as well as in patient tumor cells.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3684.
Abstract 3685: A strategy to identify therapeutic candidates for chronic lymphocytic leukemia from a library of FDA approved drugs
Authors: Shen Min , Zhang Yaqin , Wiestner Adrian U. , Ashlock Melissa A. , Austin Christopher P. , Auld Douglas S.
Published: February 2011

Chronic lymphocytic leukemia (CLL) is an adult lymphoid malignancy with a variable clinical course. There is considerable interest in the identification of new treatments, as most current approaches are not curative. While most patients respond to initial chemotherapy, relapsed disease is often resistant to the drugs commonly used in CLL and are left without limited therapeutic options. In this study, we used a luminescent cell viability assay based on ATP levels (CellTiter-Glo, Promega) to find compounds that were potent and efficacious in killing CLL cells. We employed an in-house process of quantitative high throughput screening (qHTS) to assess 8-9 concentrations of each member of a 2,816 compound library (including FDA-approved drugs and those known to be bio-active from commercial suppliers). Using qHTS we generated potency values on each compound in lymphocytes donated from each of six individuals with CLL and five unaffected individuals. We found 102 compounds efficacious against cells from all six individuals with CLL (“consensus” drugs) with seven of these showing no efficacy on lymphocytes from a majority of unaffected donors, suggesting some degree of specificity for the leukemic cells. Furthermore, to determine if we could save time and cost we screened the same library using CLL cells pooled from these individuals. We found that over 90% of the 102 drugs identified as efficacious on cells from individuals were also efficacious in the pooled experiment. Importantly, a near perfect correlation was observed in potency values between the single and pooled studies. The results of this “pooling” approach suggests it is rationale to apply pooling and qHTS when screening CLL cells against much larger collections (>300,000 unapproved compounds) where novel compounds could be identified as starting points for drug discovery and development.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3685.
Abstract 3697: Evaluation of monocyte and granulocyte function with and without ex vivo pegylated liposomal doxorubicin (PLD) exposure in blood of healthy volunteers
Authors: Caron Whitney P. , La-Beck Ninh M. , Fong Alan M. , Liu Peng , Hanna Suzan K. , Ngo Tuongvy L. , Zamboni Beth A. , Gehrig Paola A. , Tarrant Teresa , Zamboni William C.
Published: February 2011

Background: PLD is a nanoparticle approved for treatment of refractory ovarian cancer. The reticuloendothelial system (RES), which includes monocytes (MO), may have a key role in clearance (CL) of nanoparticle sized pegylated liposomes such as PLD, though factors affecting the CL of liposomes are unclear. Previously we reported that the CL of liposomes is associated with age and monocyte counts. This study's objective was to characterize the function of MO and granulocytes with and without ex vivo PLD exposure in the blood of healthy volunteers.

Methods: Blood samples were obtained from six (4 males, 2 females) healthy human volunteers, immediately placed on ice and processed. Blood samples were incubated with PLD 10 mcg/mL or 5% dextrose solution (control) for 1 hour (h) at 37°C with 5% CO2. After incubation, PHAGOTEST® and PHAGOBURST® (Orpegen Pharma) tests were performed to evaluate phagocytic activity and respiratory burst activity. PHAGOBURST® tests were performed after fMLP and PMA stimulation. Samples were analyzed using Dako CyAn Flow Cytometer with Summit software. Comparisons were made between samples with and without PLD exposure, gender, and age >60 and <60 years old (yo) based on previously reported trends.

Results: The mean + SD age of healthy volunteers was 45.9 + 14.9 yo. The mean fluorescence per cell, grouped by functional test and age, gender, and with or without PLD exposure are summarized in Table 1.Table 1.Mean Fluorescence Phagocytic ActivityRespiratory Burst Activity with fMLPRespiratory Burst Activity with PMA GranulocytesMonocytesGranulocytesMonocytesGranulocytesMonocytesAge >60 (n=2)447.6323.383.757.7377.789.4Age <60 (n=4)343.3213.5555.538.8663.6163.6p-value0.4590.240.0470.0480.6130.583       Male (n=4)370.2256.860.344.5587.9171.1Female (n=2)393.7236.674.146.4529.174.4p-value0.8940.9080.5290.8790.9320.449       Without PLD (n=6)414.2250.148.839.1542.1114.4With PLD (n=6)378.0250.164.945.1568.3138.9p-value0.6630.9990.2530.6290.9410.761

Conclusions: Differences in phagocytic and respiratory burst activity in granulocytes and MO of healthy volunteers were observed. There is variability in activity based on the type of assay used. There appears to be both age and gender differences in activity. A 1 h ex vivo exposure to PLD does not seem to significantly alter cell function. Future studies will characterize MO and granulocyte function, PLD uptake, and viability with and without PLD exposure in additional healthy subjects and ovarian and breast cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3697.
Abstract 3699: Multi-walled carbon nanotubes induce apoptosis in normal human small airway epithelial cells through proteasome-mediated Mcl-1 protein degradation
Authors: Yuan Bao-Zhu , Chapman Joshua , Rojanasakul Yon , Castranova Vincent , Reynolds Steven H.
Published: February 2011

Engineered carbon nanotubes (CNTs) are emerging as the major building blocks in nanotechnology thanks to their unique physical and chemical properties. However, widespread application of CNTs, including single- and multi-walled (SWCNTs and MWCNT), has resulted in increased public concern regarding potential toxicities from occupational or environmental exposures to CNTs. Recently, both SWCNTs and MWCNTs have been observed to exhibit pulmonary toxicities. To better understand CNT-related pulmonary toxicities, the present in vitro study used normal human small airway epithelial cells (SAEC), which constitute a primary target of respiratory exposure to CNTs, as a model to investigate cell death effects of either SWCNTs or MWCNTs. We observed that, at 24 h after exposure, greater than 5 μg/cm2 MWCNT, but not SWCNT, induced a significant dose-dependent cell death in primary cultured SAEC cells as assayed by WST-1. The cell death was accompanied by DNA damage, as indicated by the appearance of sub G0/G1 cells in a flow cytometry assay, and protein cleavages for PARP, caspases 3, 7 and 9, as revealed by Western blotting. It was further observed that the pro-apotpotic activities of MWCNT were reduced by caspase specific inhibitors, demonstrating that MWCNT, but not SWCNT, can induce a caspase-dependent apoptosis in SAEC cells. To understand regulation of the MWCNT-induced apoptosis, we then examined expression of the anti-apoptotic Bcl-2 family proteins and found that only Mcl-1 was significantly reduced in protein level by MWCNT, but not SWCNT, and such reduction was blocked by proteasome inhibitor MG132. Furthermore, it was found that reduction of Mcl-1 protein expression through Mcl-1 siRNA enhanced sensitivity of SAEC cells to MWCNT-induced apoptosis, suggesting that proteasome-mediated Mcl-1 protein degradation contributes to MWCNT-induced apoptosis. This study reveals a difference in cell death effects on normal human SAEC cells between SWCNT and MWCNT. It also provides new insights into understanding of the MWCNT-induced pulmonary toxicity.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3699.
Abstract 3703: Nanoparticle-induced targeted pro-apoptotic peptide in glioblastoma
Authors: Agemy Lilach , Morvinski Dinorah Friedmann , Kotamraju Venkata Ramana , Sugahara Kazuki N. , Verma Inder M. , Ruoslahti, Erkki
Published: February 2011

Glioblastomas multiforme (GBM) are the most common and lethal form of intracranial tumors. They account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year. Although relatively uncommon, malignant gliomas are associated with disproportionately high morbidity and mortality (median survival is only 12 to 15 months). Malignant gliomas are among the most vascular of human tumors. Tumor vasculature has proven to be particularly well suited as a site for receptor-based targeting. It expresses a multitude of molecules that are not expressed in the vessels of normal tissues. Our laboratory screens phage-displayed peptide libraries in vivo and ex vivo to discover specific targets in tumor vessels. One of the peptides, CGKRK (1) binds to the blood vessels in various kinds of tumors. Initial experiments showed that intravenously injected CGKRK peptide effectively homes to lentiviral (H-RasV12-sip53)-induced glioma in mice. We coupled the CGKRK peptide to the alpha-helical amphipathic peptide D[KLAKLAK]2, which is toxic to eukaryotic cells if it internalized into the cells (2). The chimeric peptide, when added to actively growing HUVEC or U87 glioma cells colocalized with mitochondria, whereas D[KLAKLAK]2 did not. Iron oxide nanoworms (NW) coated with the chimeric D[KLAKLAK]2-CGKRK peptide were 100-200-fold more toxic to the HUVEC and U87 cells than the free peptide in vitro and specifically accumulated in the blood vessels of glioma. Treatment of lentiviral induced glioma in mice with the D[KLAKLAK]2-CGKRK-PEG-NW inhibited tumor growth and showed a significant survival increase compared to control-treated mice.

1. Hoffman, J.A., et al. Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma. Cancer Cell 4, 383-391 (2003).

2. Ellerby, H.M., et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 5, 1032-1038 (1999).

*These authors contributed equally to this work

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3703.
Abstract 3707: Design and characterization of a double packaged system for localized drug delivery for the treatment of cancers
Authors: Williams Eva C. , Toomey Ryan , Gordon Marcia , Williams Donald , Morgan Dave , Alcantar Norma
Published: February 2011

This research aims at developing a drug delivery system that will provide a plethora of benefits such as cost effectiveness, reduction of toxicity and a control over the release of chemotherapeutic drugs in brain and ovarian cancer patients. We have designed a model drug delivery system consisting of non-ionic surfactant vesicles (niosomes) packaged within a biodegradable, temperature and pH sensitive hydrogel (chitosan) network. Optimization of the release rates were accomplished by altering the condition of its two components, chitosan and niosomes. Two main cancer drugs, Paclitaxel and Carboplatin, were used for encapsulation. It was found that medium molecular weight chitosan with a crosslinker: chitosan ratio of 4:1, which corresponded to a pH of 7.4, resulted in the finest controlled release. Surface characteristics, such as the interaction between the niosomes and chitosan were determined using Surface Forces Apparatus. The system was also tested in-vivo in mice models, where the success of the drug delivery has been measured by measuring the drug concentrations of the mice blood with respect to time and by analyzing shrinking effects in induced cancer tumors in mice. Xenogen was used to visualize the release of drugs in-vivo. Release rates of this system have been compared with other delivery methods. Our results will help in the development of low cost and improved methods for drug delivery with applications to brain tumors and intracavitary ovarian cancer treatments.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3707.
Abstract 371: Expression and circulating level of VEGFR-3 in renal cell cancer: Implication for antiangiogenic treatments
Authors: Spano Jean-Philippe , Khaled Wassef , Mouawad Roger , De La Motte Rouge Tibault , Vignot Stephane , Conforti Rosa , Khayat David
Published: February 2011

Background: Regional lymph node metastasis is a common event in solid tumors and is considered a marker for dissemination, increased stage, and worse prognosis. In renal cell cancer (RCC) lymphatic tumor spread exists, but, despite impressive therapeutic advances in metastatic RCC, including targeting of VEGF induced angiogenesis, data on the role of vegfr-3 that's appears to be the signaling pathway for tumor-induced lymphangiogenesis in RCC are rare. In this study, we analyzed the expression and the presence of the soluble VEGFR-3 form in 30 RCC patients and results were correlated with clinicopathological parameters. Patients and Methods: Tumor and sera from 30 RCC patients (20 clear cell (ccRCC) and 10 papillary (pRCC) were included in this study. The expressions of VEGFR-3 on tumor were evaluated by immunohistochemestry. Using ELISA assays, sVEGFR–3 were measured in sera of RCC patients in comparison to 20 healthy controls. Results: A high expression of VEGFR-3 was observed in more than 55% of the patients as compared to the negative control. Regarding circulating VEGF R-3 the level were variable in all samples, but, the median sVEGF- R3 level was significantly higher (p=0.005) in RCC patients as compared to healthy donors. An inverse correlation between VEGFR-3 expression & its soluble form was noted (r=-0.33 p=0.040).. However, when patients were divided into subgroups, the expression as well as the circulating form of VEGFR-3 were significantly higher in pRCC than ccRCC (p= 0.035 and 0.022 respectively). No significant correlation with lymph node status was observed. Furthermore, there was no correlation with any clinicopathological variable in the two subgroups. Conclusions: we showed that in renal cell cancer, VEGFR-3 is expressed and present as soluble form, a different expression pattern in ccRCC and pRCC exist. Therefore, any clinical treatment strategy designed to target lymphangiogenesis in RCC should differentiate between ccRCC and pRCC

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 371.
Abstract 3711: New neocryptolepine derivatives: Mechanism of cytotoxicity and the best substituent
Authors: Masashi Okada , Mei Zhen-Wu , Odawara Tomohito , Tominaga Taihei , Kudoh Takayuki , El-Sayed Ibrahim , Inokuchi Tsutomu , Seno Masaharu
Published: February 2011

Since cancer is one of the major causes of death all over the world, discovery of effective anticancer agents has long been desired. Plant alkaloids are often considered to be potent candidates. Cryptolepsis sanguinolenta is a medicinal plant which habits in West Africa. In a traditional medicine, a decoction of the root of C. sanguinolenta is used to treat fevers. Neocryptolepine, one of the plant alkaloids extracted from the root of C. sanguinolenta, are reported to have several activities such as DNA intercalation, anti-malaria and Topoisomerase inhibition. Topoisomerase (Topo) is double helical DNA relaxation enzyme and responsible for DNA replication, transcription and recombination. Inhibition of Topoisomerase is one of the mechanisms of anti-cancer agent. In this research, we synthesized a number of neocryptolepine derivatives with several substituents added to the backbone and evaluated their inhibitory activities of cell growth and topoisomerase.

The derivatives were synthesized from indole carboxylic acid methyl ester and aniline derivatives through well-known procedure. DNA relaxation activity of the derivatives was assessed on plasmid pBR322 DNA in the presence of TopoI or TopoII. Cell growth inhibition was assessed on six cancer cell lines; K562, LNCaP, MDA-MB-453, SKOv3, A549, and WiDr. Those cell lines were exposed to the derivatives for 72 hours and their 50% survival rate IC50 was estimated by MTT colorimetric assay. Although no derivative inhibited TopoII activity, 12 derivatives inhibited TopoI activity. The inhibition of TopoI by neocryptolepine derivatives appears to be caused by their planar organic constitution, which enable derivatives to intercalate into double helix of DNA. Cell growth inhibitory effect has been improved in some derivatives that received modification at their substituent. Those derivatives also exhibited TopoI inhibition correlating with inhibition of cell growth.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3711.
Abstract 3715: Potent cytotoxins and their prodrugs
Authors: Bajjurri Krishna Mohan , Goswami Rajib K. , Erigala Venkata Reddy , Liu Yuan , Liu Cheng , Sinha Subhash C.
Published: February 2011

Epothilones, dolastatins (auristatins), tubulysins, duocarmycins, and enediynes are among the most potent anticancer agents, which inhibit cell growth of cancer cells with a low or subnanomolar activity. Epothilones inhibit tumor growth by stabilizing the microtubules in a manner similar to Taxol. There are hundreds of natural and synthetic epothilones known, and some of them are undergoing clinical trials. One semisynthetic analog, ixabepilone, has also been approved for the treatment of metastatic breat cancer. Similarly, there are numerous dolastatins, their synthetic analogs - auristatins, and tubulysins known, of which auristatins are currently being developed by Seattle Genetics, Inc. These compounds also inhibit microtubules, however unlike epothilones and Taxol, they function by destabilizing the microtubules. The other compounds, duocarmycins and enediynes, cause toxicity by interacting with DNA; duocarmycins alkylate DNA whereas enediynes cleave. At least one enediyne antibody conjugate, Mylotarg (or Gemtuzumab ozogamycin), prepared from calicheamicin and targeted to CD33, is an approved therapy for the treatment of acute myeloid leukemia.

Not surprisingly, most of these naturally occurring compounds or their synthetic analogs also cause nonselective toxicities to the rapidly dividing normal cells, including those from hair follicles, bone marrow, and gastrointestinal lining. To minimize such indiscriminate toxicity, these compounds can be conjugated to tumor-targeting antibodies, as the case is with auristatins and calicheamicin. While we are developing antibody conjugates, we have also been focusing on a prodrug approach, in that the prodrugs can be activated selectively in tumor and tumor microenvironments by the endogenous tumor-associated proteases. Alternatively, an exogenous enzyme, such as aldolase antibody, 38C2, that are directed using low molecular weight inhibitors of the cell surface receptors overexpressed in tumor cells and tumor microenvironments, can also catalyze the prodrug activation. In this presentation, we will be discussing our studies toward the synthesis and evaluation of many of these cytotoxins and/or their prodrugs, especially those belonging to the auristatins. The prodrugs are targeting to integrins and/or proteases, and activated by the aldolase antibody or the tumor-associated proteases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3715.
Abstract 3716: Targeted therapy of high-grade gliomas using TGF-beta2 inhibitor trabedersen (AP 12009): Results of the Phase IIb study as basis for the Phase III SAPPHIRE Study
Authors: Jachimczak Piotr , Schlingensiepen Karl-Hermann , Heinrichs Hubert , Bogdahn Ulrich ,   AP 12009 study group
Published: February 2011

Background: High-grade gliomas (HGG) strongly overexpress TGF-beta 2. Trabedersen, a phosphorothioate antisense oligonucleotide is a TGF-beta 2 inhibitor administrated intratumorally using convection-enhanced delivery (CED). So far, clinical studies in HGG have included three Phase I/II studies and one randomized, active-controlled, open-label, multinational dose-finding Phase IIb study.

Methods: Main objectives of the Phase IIb study were to compare response rate, survival, and safety of 2 doses of trabedersen (10 µM or 80 µM) vs. standard chemotherapy (TMZ or PCV). 145 patients with recurrent or refractory HGG (AA WHO grade III or GBM WHO grade IV) were randomized. Trabedersen was given intratumorally by convection-enhanced delivery via a single multi-hole catheter with up to 11 treatment cycles (7-d-on, 7-d-off / cycle).

Results: As in the previous Phase I/II studies, treatment with trabedersen led to long-lasting remissions in patients with recurrent or refractory AA or GBM. Trabedersen showed a good tolerability and safety profile. Overall, 10 µM was superior to 80 µM trabedersen in both efficacy and safety.

Overall, the highest efficacy was observed in AA patients treated with the lower dose of trabedersen. The 10 µM trabedersen group showed a consistently higher survival rate compared to 80 µM trabedersen and standard chemotherapy (at 24 months: 83.3%, 53.3% and 41.7%, respectively). Duration of response was about 3 times longer in the 10 µM trabedersen group (29.1 months) compared to the standard chemotherapy group (8.0 months). The median overall survival was higher in both trabedersen groups than in the chemotherapy control group, with a remarkable survival benefit of 10 µM trabedersen over chemotherapy of 17.4 months.

In GBM patients, trabedersen was as efficacious as standard chemotherapy. Furthermore, in a prespecified subgroup (age ≤55 years, KPS >80%), trabedersen patients had a markedly higher 2-year survival rate compared to standard chemotherapy (40.0 vs. 13.3%).

Conclusion and Outlook: Trabedersen treatment is safe and has a clear clinical benefit in HGG. A randomized, multinational and active-controlled Phase III study (SAPPHIRE) with trabedersen as monotherapy in patients with recurrent or refractory AA (WHO grade III) has started and patient enrollment is ongoing. In this pivotal study, patients are randomized either to treatment with 10 µM trabedersen or to standard chemotherapy (TMZ or BCNU).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3716.
Abstract 372: Circulating endothelial progenitor cell levels predict survival benefit in metastatic renal cell cancer patients treated with antiangiogenic agents
Authors: Farace Françoise , Gross - Goupil Marine , Tournay Elodie , Taylor Melissa , Hill Catherine , Escudier Bernard
Published: February 2011

Background: There is no validated biomarker to predict the efficacy of antiangiogenic therapy in patients with metastatic renal cell carcinoma (MRCC). We tested the hypothesis that circulating endothelial cells (CEC) and circulating endothelial progenitor cell (CEP) could predict clinical outcome in MRCC patients undergoing treatment with tyrosine kinase inhibitors (TKI). Methods: Fifty five patients (pts) with MRCC were monitored both at baseline and day 14 after anti-angiogenic treatment (46 pts received sunitinib and 9, sorafenib). CECs were measured in 1ml erythocyte lysed whole blood by four color flow cytometry (FCM) and identified by a CD45−CD31+CD1467-amino-actinomycin (7AAD)− phenotype. CEPs were measured in 10ml blood after progenitor cell enrichment and were identified by FCM as extremely rare events with a CD45dimCD34+VEGFR2+7AAD− phenotype. Relation between CEC and CEP levels and both response to TKI determined by RECIST criteria after 2 cycles with the Wilcoxon-Mann Whitney test, and progression free survival (PFS) and overall survival (OS) with the Cox model (Log-rank test). Results: CEC and CEP levels at both baseline and day 14 were not correlated to response to TKI. No correlation was found between baseline or day 14 CEC values and PFS or OS. However, pre-treatment CEP levels were correlated to PFS (p=0.01) and OS (p=0.01). Patients with elevated pre-treatment levels of CEP (> 2% of circulating CD34+ cells) had an increased risk of tumor progression and poor prognosis. Changes in CEP levels between day 1 and day 14 were also correlated with PFS (p=0.03). Conclusion: Our results indicate that pre-treatment CEP levels could accurately predict survival in MRCC patients treated with TKI. If these data are confirmed, measurement of CEP levels before TKI therapy in MRCC patients will allow to identify patients who will benefit most from treatment and those who will need to be rapidly switched to another treatment.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 372.
Abstract 3726: Sexual function following surgery with or without intracavitary vaginal brachytherapy for early stage endometrial carcinoma
Authors: Quick Allison M. , Seamon Leigh G. , Fernandez Soledad , Salani Ritu , Paskett Electra , Martin Douglas
Published: February 2011

Objective: The purpose of this research study is to describe the effects of intracavitary vaginal brachytherapy (IVB) on sexual function and quality of life of women with early stage endometrial cancer.

Methods: 156 women, ages 20-75, with FIGO stage I to II endometrial cancer from 2002-2007 treated with surgery alone or surgery and IVB were identified and mailed questionnaires. Quality of life and sexual function were measured using the previously validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, the Cervix Cancer module, and the Sexual function-Vaginal changes Questionnaire. Pertinent data from prior surgery and radiation treatments were abstracted. Fisher's exact tests were used to evaluate the association of the variables.

Results: In total, 87 surveys (56%) were returned. 70 patients completed the survey, 17 in the IVB arm and 53 in the surgery alone arm. In general, the overall quality of life was excellent in both treatment arms, with few patients reporting anxiety, depression, pain, or limitations of activities of daily living. However, 12% of patients treated with IVB (2/17) reported difficulty controlling their bowels compared to 8% of surgery alone patients (4/53) (p=0.037) and 30% (5/ 17) vs. 13% (7/ 53) reported edema in one or both legs (p=0.040). 55% of respondents had not been sexually active in the previous month (11/17, 65% IVB and 27/52, 52 % surgery) (p=0.6). Of sexually active patients (45%, N=31), 43% of IVB (3/7) and 42% (11/26) of surgery alone patients complained of vagina dryness during sexual activity (p=0.935) and 29% (2/7) vs. 20 % (5/25) felt their vagina was short (p=0.635). While 29% in both cohorts reported vaginal tightness, 14% of patients in both treatment groups described intercourse as painful. Sexual activity was enjoyable for only 43% (3/7) of the IVB patients and 60% (17/28) of the surgery alone patients (p=0.549).

Conclusions: Overall the quality of life of women with early stage endometrial cancer is excellent following surgery or IVB. Patients treated with IVB report more bowel toxicity and lower extremity edema. Patients in both treatment arms report similar vaginal changes that affect sexual function. It is anticipated that additional data from other institutions participating in the study will allow more definitive exploration of these issues.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3726.