bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3678: Combination analysis of oncogenic mutations and signaling pathway proteins identifies effective therapeutic targets in colorectal cancers
Authors: Lee Jeeyun , Kim Phillip S. , Lee Tani , Kuller Anne , Princen Fred , Singh Sharat , Kim Hee C.
Published: August 2012

Despite overall improvements in colorectal cancer (CRC) therapies, an understanding of reasons for therapeutic response/non-response as well as disease recurrence remains poor. Currently, the gold standard for CRC prognosis remains the clinicopathological staging of tumors. Addition of molecular markers for predicting prognosis and therapeutic outcomes can significantly enhance the clinical managements of CRCs. A comprehensive molecular characterization of 116 stages I to IV Asian CRC patients that also included 2 paired normal samples and 19 hepatic metastases of which 10 were from paired primary tumor samples (total 136 specimens) was performed. Somatic mutational analysis scored for 12 different mutations resident within the KRAS, BRAF and PIK3CA oncogenes alongside a parallel determination of kinase activation profiles for HER1, HER2, HER3, c-MET, IGF1R, PI3K, Shc, AKT and ERK using the multiplexed Collaborative Enzyme Enhanced Reactive (CEER™) immunoassay. CEER is a highly sensitive and specific proximity assay that relies on the formation of a triple antibody complex surrounding the target protein. Various mutations of KRAS and BRAF were found in 41% (48/116) and 4% (5/116) of patients, respectively. Incidence of PIK3CA mutations were 11% (13/116) in this cohort. Overall, KRAS G12D and G13D mutations were the most frequent in this cohort. Several primary as well metastatic CRCs with KRAS mutations demonstrated a second mutation in the PIK3CA gene. While both ErbB-driven and non-ErbB-driven pathway signatures were observed in this cohort, there was no apparent correlation found between the KRAS mutational status of the tumors and the activation status of the downstream/upstream pathway signals. Molecular characterization of CRC samples for oncogenic mutations should be complemented with functional pathway profiling to pinpoint potential therapeutic target(s). The tumor's dependence on specific pathway cannot be predicted based on mutations alone hence it is critical to also evaluate pathway activation for selecting more effective clinical strategy. Our study also demonstrated modulation in signaling pathways concomitant with disease recurrence. Such clinical validations and comprehensive molecular profiles of CRC tumors can allow for the implementation of these companion biomarkers in CRC therapeutic clinical trials.

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 3678. doi:1538-7445.AM2012-3678
Abstract 3683: Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases
Authors: Muralidhara Chaitanya , Ramachandran Abhijit , Jain Vinay K.
Published: August 2012

Introduction: Crenolanib (CP-868,596) is a benzimidazole tyrosine kinase inhibitor (TKI), known to potently inhibit the platelet derived growth factor receptors (PDGFR) alpha and beta, and the Fms-like tyrosine kinase 3 (FLT3). Crenolanib has been evaluated as a single agent (Lewis N, et al, J Clin Oncol 2009), and in combination with docetaxel ± axitinib (Michael M, et al, Br J Cancer 2010), and was found to be well tolerated, with transient elevation of liver enzymes at higher doses. We describe here the characterization of crenolanib as a unique chemotype, mutant-specific Type I TKI. Methods: The relative affinities of tyrosine kinase inhibitors for phosphorylated and non-phosphorylated ABL1 have been previously used to accurately distinguish type I from type II inhibitors (Wodicka LM, et al, Chem Biol 2010). The effect of ABL1 A-loop phosphorylation on crenolanib affinity was investigated in a competition binding assay (Karaman MW, et al, Nat Biotech 2008). The binding constants (Kds) of crenolanib for FLT3 (wild-type and five mutant isoforms) were also determined using the KINOMEscan KdELECT Assay (DiscoveRx, San Diego, CA), and compared with the Kds of 442 TKIs reported (Davis MI, et al, Nat Biotech 2011). The Kds of crenolanib for PDGFRα, PDGFRα, and c-KIT (wild-type and two mutant isoforms) are being determined. Results: The Kd of crenolanib for phosphorylated ABL1 and ABL(T315I) were 7- and 15-fold lower than the Kds for non-phosphorylated ABL1 and ABL(T315I) respectively. Based on this higher affinity for p-ABL1 relative to np-ABL1, crenolanib appears to be a Type I inhibitor. Furthermore, crenolanib has a 10-fold affinity shift between the non-autoinhibited and autoinhibited states of FLT3, which is in the range of affinity shifts reported for other Type I TKIs, in contrast to the 100- to 1000-fold affinity shift reported for Type II TKIs. Crenolanib also has the highest affinity for three constitutively activate isoforms of FLT3 (FLT3-ITD, FLT3-D835Y, FLT3-D835V) compared to 442 kinases reported (Davis MI, et al, Nat Biotech 2011). Crenolanib is a next-generation, mutant-specific TKI, currently in Phase II development in adult and pediatric gliomas, and in PDGFRAD842V-mutant GIST. The unique and specific kinase inhibition profile is hypothesized to translate to greater therapeutic effect, accompanied by fewer adverse events 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 3683. doi:1538-7445.AM2012-3683
Abstract 3689: Association of thymidylate synthase gene polymorphisms with efficacy and toxicity of oral fluoropyrimidine based chemotherapy in advanced gastric cancer
Authors: Kim Gun Min , Jeung Hei-Cheul , Kwon Woo Sun , Rha Sun Young , Kim Hyo Song , Jung Inkyung , Nam Byung-Ho , Lee Kyung Hee , Chung Hyun Cheol
Published: August 2012

Purpose: Oral fluoropyrimidines (S-1 or capecitabine) are metabolized by different enzymes. We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6), carboxylesterase 2(CES 2), thymidylate synthase (TS), and excision repair cross complementation group 1 (ERCC1) and toxicity of advanced gastric cancer patients treated with oral fluoropyrimidine based chemotherapy. Methods: A total of 123 patients received S-1 80mg/m2 or capecitabine 2000 mg/m2 plus oxaliplatin 130 mg/m2 for advanced gastric cancer. We analyzed polymorphisms of CYP2A6, CES 2, TS and ERCC1 by using genomic DNA extracted from prospectively collected peripheral blood sample. Associations between polymorphisms and toxicity of these patients treated with oral fluoropyrimidines based chemotherapy were evaluated individually. Results: Patients who were 2R/3R for the double repeat in the TS promoter region had more toxicity of oral fluoropyrimidines. Patients with a 2R/3R and 2R/2R or 3R/3R genotype had a grade 2 or more gastrointestinal toxicity rate of 50 and 22%, respectively (P = .049). Response rate was higher in patients with a 2R/3R than those with a 2R/2R or 3R/3R (50% vs. 32%, P = .082). Polymorphisms of CYP2A6, CES 2, and ERCC1 were not associated with efficacy and toxicity of oral fluoropyrimidine based chemotherapy for advanced gastric cancer. Conclusion. This study demonstrated that TS genotyping could be of help in predicting toxicity to oral fluoropyrimidine based chemotherapy in advanced gastric cancer patients.

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 3689. doi:1538-7445.AM2012-3689
Abstract 3691: The correlation analysis of postoperative anxiety scale of colorectal cancer patient and the postoperative complication
Authors: Wang Xiaodong , Fang Chao , Hu Zongli , Yang Jiqiao , Shu Bingyan , Li Li
Published: August 2012

Objectives Aim at evaluating the influence of postoperative anxiety scales on postoperative complications of colorectal cancer by clinically using the Hamilton anxiety. Methods Prospectively enrolling 126 patients definitely diagnosed with colorectal cancer from February to May in 2010at the Center of Gastrointestinal Surgery, West China Hospital, Sichuan University. By dividing them into three groups according to the anxiety scales, postoperative complication rates were compared between groups, relating postoperative anxiety factors were evaluated and clinical rating value between postoperative anxiety scale and postoperative complication incidence rate of patients was explored. Results There was a significant different of post complication rates among the three groups(x2=17.904, P<0.001), and the potential anxiety group(anxiety score=7-13)'s postoperative complication rate is lower than non-anxiety group(anxiety score<7) (x2=11.027, p=0.002)and anxiety group(anxiety score>14)(x2=20.677, P<0.001).The difference between the anxiety group and the non-anxiety group had no statistical significance(x2=1.636, p=0.274). The risk factors for postoperative anxiety were type of expense(p=0.053), resides(p=0.018), medical complication(p=0.014), neoadjuvant chemotherapy(p=0.053), the DUKE'S stage(p=0.009), the ordinary diet day after operation(p=0.001).After analyzing, the critical value was 17 point for anxiety score and the postoperative complication morbidity of patients was higher when the post anxiety scale was over 17(X2=12.538, P=0.004). Conclusions the postoperative anxiety scale of the colorectal patients has some corelations with the postoperative complication morbidity, and the ones whose score are high in anxiety scale are more likely to suffer from postoperative complications. However, the postoperative complication morbidity is relatively low in moderate anxiety patients.

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 3691. doi:1538-7445.AM2012-3691
Abstract 3692: Single center phase II study of yttrium-90 radioactive resin microspheres in the treatment of liver predominant metastatic colorectal adenocarcinoma after failure of 1st-line combination chemotherapy
Authors: Roeland Eric J. , Dad Shakeela , Shimabukuro Kelly , Fanta Paul , Rose Steven , Reid Tony
Published: August 2012

Background: Colorectal cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer death. Liver metastases develop in half of all the colorectal cancer (CRC) cases and cause death in ∼90% of patients. We are evaluating the treatment of liver metastases through the incorporation of selective internal radiation therapy (SIRT) using Yttrium-90 radioactive microspheres for subjects with liver progressive disease following failure of first-line FOLFOX (± bevacizumab). We are presenting our preliminary data for the phase II study evaluating the tumor response rates, PFS, and long-term safety and toxicity to SIRT following FOLFOX (± bevacizumab) prior to FOLFIRI. Methods: Subjects with predominantly hepatic metastatic CRC whose disease progressed on first-line FOLFOX (± bevacizumab) based therapy are eligible. Interventional radiology and nuclear medicine assess the liver lesions and the subject receives their SIRT treatment(s) followed by second-line FOLFIRI based therapy 4-6 weeks after the final SIRT treatment. Optimal timing for microsphere treatment relative to chemotherapy is not clearly established. Results: To date, 9 metastatic CRC subjects have been treated and 11 subjects enrolled (goal 30 subjects). One subject was withdrawn due to progressive lung metastases. Four of 8 subjects (50%) achieved PFS at 6 months and average TTP is 6.7 months (0.7-17.3 months). Overall treatment has been well tolerated, but one possible study related SAE of liver failure occurred (Subject 8). The OS endpoint has not been achieved. Conclusions: Historically, second-line FOLFIRI has achieved a 2.5 months median PFS. In 8 subjects with predominant liver metastatic CRC, we have observed 50% PFS at 6 months. These encouraging results demonstrate the utility of an innovative direct approach to metastatic CRC after failure of first-line combination chemotherapy.

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 3692. doi:1538-7445.AM2012-3692
Abstract 3695: Efficacy of gemcitabine combined with hyperthermia therapy in the treatment of unresectable pancreatic cancer: Phase II study
Authors: Tsuchiya Reiko , Ishikawa Takeshi , Okajima Manabu , Matsuyama Tatsuzo , Yoshida Naohisa , Katada Kazuhiro , Kamada Kazuhiro , Sakamoto Naoyuki , Uchiyama Kazuhiko , Handa Osamu , Takagi Tomohisa , Ysuda Hiroaki , Sakagami Jyunichi , Konishi Hideyuki , Yagi Nobuaki , Kokura Satoshi , Naito Yuji
Published: August 2012

[Background] Pancreatic cancer is an aggressive malignant tumor. Gemcitabine is the standard first line therapy for pancreatic cancer. Several gemcitabine based chemotherapy combinations were studied for the treatment of pancreatic cancer, but these combination therapies showed no major success over single agent gemcitabine in the treatment of pancreatic cancer. Hyperthermia has been shown to increase the cytotoxic effects of some anticancer agents by facilitating drug penetration into tissue, and Gemcitabine has recently been shown to be a potent hyperthermic sensitizer in preclinical studies. We conducted a phase II study to determine the availability of combination therapy with gemcitabine and hyperthermia in the treatment of unresectable pancreatic cancer. [Methods] Patients who participated in the study had advanced pancreatic cancer and their performance status score ware 0-2. The primary end point was one-year survival rate. And the secondary end points were safety and response rate. We set the expectation one-year survival rate to 30% Gemcitabine (1000mg/m2) was given weekly for 3 weeks (day 1,8,15) in four-week cycles, and hyperthermia (40min/once) weekly. This schedule was repeated until disease progression. [Result] From November 2008 to November 2009,18 patients were enrolled in this study. Median patient age was 64 years old(range 47-78), male/female:10/8 All patient died until September 2011, and the one year survival rate is 33.3%, exceeded the expected rate. Disease control rates (CR+PR+SD) were 61.1% (PR/SD/PD=2/9/7) Median survival times were 6 months. Adverse events (Grade3/4) were neutropenia (16.7%), anemia (16.7%), anorexia (5.6%), gastrointestinal bleeding (5.6%). [Conclusion] Combination therapy with gemcitabine and hyperthermia is both a safe and effective treatment in patients with advanced unresectable pancreatic cancer. To clarify the effects of sequential combination of hyperthermia and Gemcitabine as compared with Gemcitabine monotherapy, further studies should be performed, particularly prospective randomized trials.

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 3695. doi:1538-7445.AM2012-3695
Abstract 3700: Anticancer effects and mechanisms of action of novel flavonoid didymin in neuroblastomas
Authors: Nagaprashantha Lokesh , Singhal Jyotsana , Awasthi Sanjay , Singhal Sharad S.
Published: August 2012

Neuroblastomas arise from the neural crest cells and represent the most common solid tumors outside the nervous system in children. The amplification of N-Myc plays a primary role in the pathogenesis of neuroblastomas whereas acquired mutations of p53 lead to refractory and relapsed cases of neuroblastomas. In this regard, dietary compounds which can target N-Myc and exert anti-cancer effects independent of p53 status acquire significance in the management of neuroblastomas. Hence, we investigated the anti-cancer properties of the flavonoid didymin in neuroblastomas. Didymin effectively inhibited proliferation and induced apoptosis irrespective of p53 status in neuroblastomas. Didymin down regulated PI3K, pAkt, Akt, vimentin and up regulated RKIP levels. Didymin induced G2/M arrest along with decreasing the levels of cyclin D1, CDK4 and cyclin B1. Importantly, didymin inhibited N-Myc as confirmed at protein, mRNA and transcriptional level by promoter-reporter assays. HPLC analysis of didymin (2 mg/kg b.w.) treated mice serum revealed effective oral absorption with free didymin concentration of 2.1 µM. Further in vivo mice xenografts studies revealed that didymin (2 mg/kg b.w.) treated animals had significant reductions in tumors size compared to controls. Didymin strongly inhibited the proliferation (Ki67) and angiogenesis (CD31) markers as well as N-Myc expression as revealed by the histopathological examination of paraffin embedded section of resected tumors. Collectively, our in vitro and in vivo studies elucidated the anti-cancer properties and mechanisms of action of a novel, orally active and palatable flavonoid didymin which makes it a potential new approach for neuroblastoma therapy (NANT) to target pediatric neuroblastomas. (Supported in part by NIH grant CA 77495)

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 3700. doi:1538-7445.AM2012-3700
Abstract 3712: Gap junction enhancer potentiates cytotoxic effect of cisplatin
Authors: Ding Ying , Nguyen Thu A.
Published: August 2012

Cisplatin is one of the most widely used anti-cancer drugs due to its highly effective apoptosis induction and DNA damage function. However, increasing reports of side effects and drug resistances indicate the limitation of cisplatin in cancer therapeutics. Recent studies showed that inhibition of gap junctions is one of the reasons that diminishes the cytotoxic efficiency and contributes to drug resistance. Therefore, identification of molecules that counteracts gap junctional inhibition without decreasing the anticancer effect of cisplatin in combinational treatment is essential to reverse resistance and potentiate drug efficacy. This study investigates the effects of combinational treatment of cisplatin and substituted quinoline PQ1, a gap junction enhancer, in T47D breast cancer cells. Cell viability was studied by both trypan blue method and morphology change. Ki67 was used as a marker to examine cell proliferation. Gap junction activity was examined by scrap load/dye transfer (SL/DT) and the expressions of connexins, the components of gap junction. Expressions of apoptotic factors, caspase-8, caspase-9, caspase-3, Bax, and Bcl-2, were measured by western blot analysis. Our results showed that compared with single cisplatin treatment, combinational treatment of PQ1 and cisplatin increased gap junctional intercellular communication (GJIC) as well as expressions of connexins (Cx26, Cx32 and Cx43), and subsequently decreased cell viability. Ki67 was greatly decreased by combinational treatment indicating the inhibition of proliferation. Expressions of pro-apoptotic factors, caspase-3, caspases-8, caspase-9, and bax, were activated or increased by pretreating T47D cells with PQ1; whereas, the pro-survival factor, bcl-2, was decreased by the pretreatment. Our studies imply that PQ1 has the potential to be used in the combinational treatment to counteract the drug resistance and potentiate the efficacy of cisplatin in breast cancer treatment.

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 3712. doi:1538-7445.AM2012-3712
Abstract 3714: Characterization of a selective focal adhesion kinase (FAK) inhibitor in a panel of glioblastoma cell lines identify rational drug-drug combination strategies
Authors: Chen Shujuan , Johnson Natalie , Auger Kurt R. , Xiao Yonghong , Ying Haoqiang , Marszalek Joseph , Middleton Richard , Andersen Jannik N. , McGrath John P. , Chin Lynda
Published: August 2012

Focal Adhesion Kinase (FAK) is a key regulator of cancer cell migration and invasion and overexpression of FAK and Src has been associated with resistance to current anticancer therapies. Thus, inhibition of FAK may represent a promising therapeutic approach to anti-cancer treatment. We investigated the anti-cancer activity of the FAK inhibitor (GSK2256098) in a panel of 26 human glioblastoma (GBM) cell lines. GBM is one of the most aggressive and lethal forms of cancer, characterized by exponential growth and diffuse invasiveness. Herein, we report that 8/26 GBM cell lines displayed sensitivity to FAK inhibition in both migration and Matrigel invasion assays. GSK2256098 had minimal effect on 2D cell proliferation. Integrated genomic and proteomic analyses revealed up-regulation of the PI3K and MAPK pathways in the FAK inhibitor-resistant GBM cell lines, suggesting possible drug combination strategies. To test this hypothesis, we assessed the effects of combining GSK2256098 with a PI3K inhibitor and a MEK inhibitor in the FAK inhibitor-resistant GBM cell lines. Our results suggest that multi-agent inhibition of FAK and MEK or PI3K may provide an attractive therapeutic strategy for GBM.

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 3714. doi:1538-7445.AM2012-3714
Abstract 3717: Pigment epithelium-derived factor prolongs survival and enhances the in vivo antitumor activities of low-dose chemotherapy in castration-refractory prostate cancer
Authors: Filleur Stephanie , Pardue Natalie , Rinard Katherine , Gillen Jessica , Nelius Thomas
Published: August 2012

Background: The development of metronomic/low-dose administration of conventional chemotherapeutic drugs has recently shown great promise in the treatment of castration-refractory prostate cancer (CRPC). Pigment Epithelium-Derived Factor (PEDF) is a natural angio-inhibitor which has been shown to be down-regulated in prostate cancer. We have previously demonstrated that the over-expression of PEDF in human CRPC PC3 cells decreased tumor growth in vivo. In the present study, we further validated PEDF anti-tumor properties in the highly metastatic CRPC LNCaP-derivative CL1 cells. We also hypothesized that PEDF could enhance the cytotoxic effects of low-dose docetaxel (Doc) and cyclophosphamide (CTX) chemotherapies in vivo. Methods: Human CRPC PC3 and CL1 cell lines were genetically modified to stably co-express the fluorescent DsRed Express protein with PEDF. Resulting cell lines were characterized in vitro for PEDF expression by Western blot and for proliferation by growth curves and clone formation in Matrigel. PEDF anti-tumor effects were assessed on established subcutaneous xenografts in mice treated with Doc (5mg/kg ip every 4 days, 1mg/kg ip daily for 10 days, 0.5mg/kg ip every other day), CTX (10-20mg/kg in the drinking water) or placebo. Survival studies were performed by injecting CL1 cells, pre-mixed with 50nM hr-PEDF or carrier control, into the left lobe of the dorsal prostate of anesthetized mice. Results: We showed that PEDF inhibits the proliferation and induces the differentiation of all CRPC cells tested in vitro. Similarly, PEDF expression decreases the development of subcutaneous PC3 and CL1 tumors in immune-compromised mice by 85% and 70%, respectively. In the survival study, we found that all control animals die within 61 days after surgery while 50% of PEDF-pretreated animals were still alive. Most importantly, we demonstrated that PEDF enhances the cytotoxic effects of low-dose chemotherapy on established tumors (best Doc dose: 1mg/kg for PC3 and 5mg/kg for CL1; best CTX dose: 10mg/kg for both PC3 and CL1). Conclusions: This data reinforces the significance of PEDF as a potential new target for the treatment of advanced prostate cancer. It also emphasizes PEDF as a promising new agent to enhance the anti-tumor efficacy of low-dose Doc and CTX chemotherapies.

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 3717. doi:1538-7445.AM2012-3717
Abstract 3718: Oncolytic reovirus synergizes with bortezomib and dexamethasone in overcoming therapy resistance of multiple myeloma
Authors: Thirukkumaran Chandini M. , Shi Zhong-Qiao , Luider Joanne , Bahlis Nizar , Neri Paola , Morris Don
Published: August 2012

Introduction: Multiple myeloma (MM) is an incurable hematologic malignancy that accounts for 10% of hematopoietic neoplasms. Recently we have demonstrated the potential of reovirus as novel therapeutic agent for a majority of MM cell lines and ex vivo patient tumor. However, therapy resistant disease still remains a problem. In the present study we demonstrate that reovirus acts synergistically with bortezomib and/or dexamethasone in oncolysis of therapy resistant MM cell lines. Methods: The MM cell lines RPMI 8226, U266, NCIH929, U266, INA-6, KMS11 and OPM2 were incubated with live (LV) or UV-inactivated (DV) reovirus at a multiplicity of infection (MOI) of 40 for 24, 48, and 72 hours respectively and cell death was assessed via the WST assay. Reovirus resistant OPM2 and moderately sensitive KMS-11 that are also resistant to bortezomib and dexamethasone were selected for combination therapy and treated with reovirus and drugs at various concentrations to evaluate Effective Dose 50% (ED50) values. ED50 values for each drug and reovirus was combined in various concentrations but with consistent ratios and percent toxicity was determined. Using Calcusyn software, combination index (CI) values were generated and synergism determined as per Chou-Talalay method. Results: Highly synergistic cytotoxicity was observed with reovirus and bortezomib in both reovirus and drug resistant cell lines OPM2 and KMS-11 at all drug combination ratios. Dexamethasone and reovirus treatment induced synergy in OPM2 cells. Conclusion: Not all MM cell lines are amenable to reovirus mediated cell death. This has important implications for the future use of reovirus as a therapeutic agent for cancer as phase II clinical trials for MM are underway. This study highlights the importance of preclinical studies in evaluating effective reovirus drug combinations for future use that could be extrapolated to a clinical setting. Currently we are evaluating the effects of these drug combinations under in vivo conditions in a mouse model that represents the clinical course of MM. The underlying mechanism of reovirus and drug induced cytotoxicity is also being investigated at present. Understanding the signalling pathways of resistant tumor will help develop a more personalized approach of reovirus therapy for cancer patients in the future.

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 3718. doi:1538-7445.AM2012-3718
Abstract 3720: Combination treatment with hypoxia-activated prodrug TH-302 and the mTOR inhibitor everolimus results in enhanced antitumor efficacy in preclinical models
Authors: Sun Jessica D. , Ahluwalia Dharmendra , Liu Qian , Wang Yan , Matteucci Mark D. , Hart Charles P.
Published: August 2012

TH-302, a 2-nitroimidazole triggered hypoxia-activated prodrug, releases bromo-isophosphoramide mustard (Br-IPM), which induces DNA crosslinking in hypoxic cells. It shows broad antitumor activity in a number of preclinical models, both as a single agent and in combination with conventional chemotherapeutics. The intracellular kinase mTOR plays a key role in multiple pathways which are important in cancer progression. Everolimus directly targets mTOR and results in reduced tumor cell proliferation, decreased tumor angiogenesis, and an inhibiton of tumor cell metabolism. Here we investigated whether TH-302 in combination with everolimus could improve the efficacy profile versus the agents as monotherapies. Two renal cell carcinoma (RCC) ectopic xenograft models and a neuroblastoma ectopic xenograft model were established by subcutaneous implantation of Caki-1, 786-O, or SK-N-BE(2) cells into the flanks of nude mice. When tumor size was approximately 150mm3, animals were treated with everolimus (5mg/kg, QDx19, oral), TH-302 (50mg/kg, QDx5/wk x 3wks, ip), or both everolimus and TH-302. In the Caki-1 model, 87% Tumor Growth Inhibition (TGI) was observed in the combination group versus 52% TGI from everolimus monotherapy or 16% TGI from TH-302 monotherapy. A pharmacodynamic immunohistochemistry study showed that after 7 days of treatment with everolimus, cell proliferation (by Ki67), microvessel density (by CD31) and phosphorylation of the S6 ribosomal protein (by p-S6) was significantly decreased. In the 786-O model, everolimus alone showed 49% TGI, while TH-302 alone did not demonstrate statistically significant efficacy. However, when TH-302 was combined with everolimus, a TGI of 85% was reached. In the ectopic SK-N-BE(2) neuroblastoma model, TH-302 or everolimus alone demonstrated 45% and 40% TGI, respectively, while the combination therapy yielded 65% TGI. Importantly, body weight loss was very minor (<5%) in all groups tested, indicating no significant added toxicity in the combination groups. In summary, there is additive antitumor activity when TH-302 is combined with everolimus. The efficacy profile of TH-302 in combination with the mTOR inhibitor temsirolimus also shows an additive effect in the combination therapy setting. These studies provide a translational rationale for combining TH-302 with mTOR inhibitors to increase the treatment benefit.

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 3720. doi:1538-7445.AM2012-3720
Abstract 3722: Quinacrine and sorafenib combination as potential therapy for anaplastic thyroid cancer
Authors: Abdulghani Junaid , Gallant Jean-Nicolas , Whitcomb Tiffany , Dicker David , Smith Charles D. , Goldenberg David , El-Deiry Wafik S.
Published: August 2012

Anaplastic thyroid cancer (ATC) is uncommon and represents 2-5% of all thyroid cancers. It remains amongst the most lethal human cancers with a reported median survival of 6 months despite therapy. ATC represents over 50% of all thyroid cancer fatalities annually. We have previously shown the effectiveness of quinacrine in combination with standard therapies in hepatocellular and colon carcinoma. Quinacrine has been used in the past to treat lupus and malaria and in addition to being available and affordable (∼30 USD/month of therapy) it has a well-known and acceptable toxicity profile. Here, we evaluate the efficacy of quinacrine in combination with sorafenib on a panel of human anaplastic thyroid cancer tumor cells. We observed that quinacrine as a single agent effectively kills anaplastic thyroid cancer cells in vitro in a concentration-dependent manner as assessed by CellTiter-Glo and sub-G1 analysis. Quinacrine in combination with sorafenib provides an additive effect in vitro. On analyzing, we observe that the anti-apoptotic Bcl-2 family member Mcl-1, which is over-expressed in a number of solid tumors is down-regulated with this combination treatment. Unlike chloroquine that inhibits autophagy, our previous results have not shown that quinacrine's anti-tumor efficacy involves alterations in autophagy. We are testing the quinacrine plus sorafenib combination in vivo by sub-cutaneous or orthotopic injection in immune-deficient mice of established cell lines as well as freshly isolated cells from patients with anaplastic thyroid cancer. Our findings suggest that quinacrine in combination with sorafenib may be an effective therapeutic strategy for anaplastic thyroid 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 3722. doi:1538-7445.AM2012-3722
Abstract 3726: Allyl isothiocyanate (AITC), a naturally occurring compound, combined with platinum-based therapies enhances apoptosis in vitro, and inhibits lung tumor growth in vivo
Authors: Ling Xiang , Westover David , Cao Felicia , Cao Shousong , Li Fengzhi
Published: August 2012

Lung cancer is the leading cause of cancer-related death in the United States, and it is estimated more than 220,000 new cases will be diagnosed in 2011. The first-line therapy for advanced lung cancer almost always contains a platinum-based chemotherapeutic agent, regardless of the disease's histological profile. In vitro studies have shown that isothiocyanate compounds can sensitize lung cancer cells to cisplatin treatment, however the underlying mechanisms have not been well defined and until now, there have been no in vivo demonstrations to support the in vitro results. Our lab recently discovered that allyl isothiocyanate (AITC), a naturally occurring isothiocyanate molecule found in cruciferous vegetables such as horseradish and mustard seeds, can sensitize lung cancer cells to cisplatin treatment. Our data demonstrate that the combination of cisplatin and AITC can induce apoptosis more effectively than cisplatin alone. Furthermore, drug combination index (CI) analysis from cancer cell-based ex vivo studies showed synergistic effects between AITC and cisplatin in defined dose ranges. Mechanistic studies revealed that combination treatment of cisplatin and AITC decreases the expression of survivin and Bcl-2 and concomitantly increases caspase-3 activation, PARP cleavage and DNA fragmentation, hallmarks of apoptosis. Most importantly, our data demonstrate that cisplatin, in combination with orally administered AITC, shows significantly improved suppression of lung tumor growth in human lung tumor xenograft mouse models compared to cisplatin or AITC alone. Given its oral bioavailability and potential to overcome cisplatin resistance, AITC shows promise as a chemotherapeutic-sensitizer for the treatment of advanced lung 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 3726. doi:1538-7445.AM2012-3726
Abstract 3730: Cisplatin treatment enhancement with acetaminophen in a model of human medulloblastoma in nude rats
Authors: Lewin Seth , Muldoon Leslie , Wu Jeffrey , Guillaume Daniel , Neuwelt Edward
Published: August 2012

Purpose: To determine the efficacy of cisplatin treatment when enhanced by high dose acetaminophen (APAP) and followed by N-acetylcysteine (NAC) rescue in a nude rat model of medulloblastoma. Methods: Human medulloblastoma (DAOY) cells were inoculated into the cerebellum of female athymic nude rats (rnu/rnu). On day 10, rats were randomized to treatment groups (n = 6 per group): (1) saline controls; (2) IP cisplatin 2 mg/kg; (3) PO APAP 600 mg/kg + IP cisplatin; and (4) APAP + cisplatin + NAC 1 g/kg. All treatments were given twice a week for two weeks. Cisplatin treatment was given one hour after APAP, and NAC was given 4 hours following cisplatin. T2 and contrast-enhanced T1 magnetic resonance (MR) imaging sequences were performed prior to treatment and just prior to sacrifice at 14 days following initial treatment. Cerebrospinal fluid (CSF) was collected for polymerase chain reaction (PCR) assay of human DNA. In vitro cell sensitivity to a dose escalation of APAP and cisplatin was assessed in medulloblastoma cell lines DAOY and D238-MED. Results: In vitro viability assays showed that combination APAP plus cisplatin induced synergistic toxicity in human medulloblastoma cells. In saline control rats, the tumor xenograft localized within the cerebellum with spread to the meningeal surfaces and brainstem, and had a volume of 27.1 ±6.7mm3 (mean±SEM). All cisplatin therapy treatment groups showed a significant reduction in final tumor volume when compared to the control group (P < 0.0004). A trend for the cisplatin single therapy group to be less efficacious when compared to the combined cisplatin treatment groups was observed however, the difference was not significant. No reduction in efficacy was seen in the NAC rescue group, with a tumor volume of 4.42±1.36 mm3, compared to 3.30±0.99 mm3 in the APAP plus cisplatin group. Tumor response was not measurable by MR, however the presence of human DNA in the CSF, was correlated with tumor size. Conclusions: This treatment model for medulloblastoma may provide a mechanism to improve chemotherapy efficacy without increasing chemotherapy dose. In vivo and in vitro data correlate to show that the pretreatment with APAP sensitizes cells to cisplatin allowing efficacy at a lower doses, meanwhile delayed treatment with NAC staves off the systemic toxicity normally associated with cisplatin treatments. APAP enhancement with NAC rescue may provide a less toxic option to patients who might otherwise experience systemic toxicity from high doses of cisplatin.

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 3730. doi:1538-7445.AM2012-3730
Abstract 3731: Directing combinatorial therapy of breast cancer using signaling pathway predictors
Authors: Jhan Jing-Ru , Andrechek Eran
Published: August 2012

Heterogeneity in human breast cancers reflects the complexity of cancer, and has been characterized in both histology and gene expression patterns. In addition, heterogeneity is observed in the differential response to therapy. Indeed, the response of molecular-based target therapies, such as Herceptin, in specific populations of patients points out the importance of characterizing heterogeneity prior to therapy. However, only 35-50% of HER2+ patients are responsive to Herceptin and among those, some also developed drug resistance. Taken together, this indicates that combination targeted therapy in conjunction with an accurate diagnosis of they type of breast cancer is critical for development of effective breast cancer treatment. Here we develop a new strategy to develop combination therapies for subtypes of breast cancer. Using bioinformatic methods to analyze gene expression profiles of heterogeneous mammary tumors in MMTV-myc mice, we have developed combinatorial therapeutic treatment plans specific to the cell signaling pathways that have been activated. The activity of the cell signaling pathways was determined through a gene expression analysis coupled with training data for key signaling pathways. Our initial data shows that the individualized therapeutic combinations for certain histological subtypes of Myc tumors are safe for mice. The therapeutic efficacy will be evaluated first in immune-competent wild-type mice bearing with tumors from the heterogeneous MMTV-myc mice. The results will demonstrate a proof of principle in an effective, approach to rationalize breast cancer therapy using a limited number of available drugs after predicting the response to therapy. These results will also be expected to facilitate our understanding in roles of heterogeneity in breast cancer in response to 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 3731. doi:1538-7445.AM2012-3731
Abstract 3732: New aspirin analogs for targeted therapy of ER+ breast cancers with activated NFkB inflammatory pathway
Authors: Kastrati Irida , Litosh Vladislav A. , Thatcher Gregory R.J. , Frasor Jonna
Published: August 2012

Approximately 75% of breast cancers express estrogen receptor (ER), classified as either ER+ luminal A or luminal B. Five year survival rate of luminal B breast cancers is ∼50% compared to ∼95% for luminal A, making luminal B subtype a target for better understanding the mechanisms of carcinogenicity and improved therapy. Inflammation and activation of its nuclear factor NFkB, is linked clinically and epidemiologically to cancer. Activation of NFkB in a subset of ER+ cancers is associated with poor prognosis and resistance to therapy. We were the first to show synergy between ER and NFkB in a specific gene signature that highly correlates with luminal B ER+ breast cancers, suggesting a potential functional role for NFkB inhibition in this subset. Based on these findings, we hypothesized that co-targeting ER and NFkB may achieve clinical efficacy in luminal B breast cancer. To target the ER, a selective estrogen receptor modulator (SERM) was employed. To target NFkB pathway, an NSAID-based therapy would be safe and, based on epidemiological data, is suggested to be chemopreventive in breast cancer. For NFkB targeting, we characterized a family of aspirin (ASA)-based analogs (x-ASA) that also serve as pro-drugs for quinone methide formation. We found that x-ASA analogs inhibited TNFa induction of NFkB via a reporter assay in a dose-dependent fashion in MCF-7 cells, and also shut down several genes typically up-regulated by the ER-NFkB crosstalk. Next we tested the co-targeting approach in mammosphere formation assays: the combination significantly reduced overall mammosphere number and size. While the mechanisms of action remains to be elucidated, the aspirin analogs in combination with a SERM show promise in treating ER+ breast cancers with activated NFkB where standard endocrine therapy alone fails.

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 3732. doi:1538-7445.AM2012-3732
Abstract 3743: NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform alpha impairs angiogenesis and microvascular permeability.
Authors: Schnell Christian R. , Barbe Stephanie , Caravatti Giorgio , Brachmann Saskia , Guthy Daniel , Maira Sauveur Michel , Cozens Robert , Hofmann Francesco , Fritsch Christine
Published: August 2012

Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged, tortuous, leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF. In the present study, we investigated the effect of NVP-BYL719, a novel, synthetic low molecular mass compound, which potently and selectively inhibits class I PI3K isoform alpha activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues via tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay. The antiangiogenic effect of NVP-BYL719 and its impact on tumor progression was also assessed in an U87MG glioblastoma subcutaneous xenograft tumor model. Pathway inhibition was confirmed using tumor histology and Reverse Phase Protein Array (RPPA) approaches. NVP-BYL719 inhibits VEGF driven tissue formation as well as neo-vascularization of the newly formed tissue. Moreover, the compound strongly inhibited microvessel permeability in normal tissue as determined in the modified miles assay. Similarly, tumor interstitial fluid pressure (IFP), a phenomenon that is directly dependent on tumor vessel permeability, was significantly reduced (up to 43%) by NVP-BYL719 in a dose-dependent manner, upon oral administration in BN472 mammary carcinoma grown orthotopically in syngeneic rats. Concomitantly, tumor growth was significantly inhibited in BN472 mammary carcinoma and U87MG xenografts. The compound was well tolerated with no significant body weight loss at any tested dose. In conclusion, our data suggest that NVP-BYL719, a Class I PI3K selective inhibitor of p110 alpha, interferes with the tumor vasculature system. Thus, the anti-angiogenic proprieties of NVP-BYL719 might participate to the antitumor activity (or efficacy) of the compound.

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 3743. doi:1538-7445.AM2012-3743
Abstract 3747: Pulsatilla saponin D suppresses angiogenesis and induces apoptosis via inhibition of PI3K/Akt/mTOR signaling pathway in hepatocellular carcinoma
Authors: Hong Sang-Won , Jung Kyung Hee , Lee Hee-Seung , Zheng Hong-Mei , Choi Myung-Joo , Son Mi Kwon , Park Byung Hee , Hong Soon-Sun
Published: August 2012

Constitutive activation of PI3K/Akt/mTOR signaling pathway has been shown in hepatocellular carcinoma, which plays a central role in promoting survival, proliferation, and angiogenesis. Here, we assessed efficacy of Pulsatilla saponin D (designated SB365) on the progression of HCC and regulation of PI3K/Akt/mTOR signaling. SB365 strongly suppressed the growth of HCC cells in a dose-dependent manner. Also, SB365 induced apoptosis by increasing the proportion of sub-G1 apoptotic cells from 8% to 21% through induction of expression of Bax and cleaved-caspase-3. In vivo study showed that SB365 significantly inhibited tumor growth in HCC xenograft model, inducing apoptosis by increasing the expression of the cleaved caspase-3 and DNA fragmentation. In addition, SB365 showed a potent anti-angiogenic activity to decrease the expression of hypoxia-inducible factor-1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF) known as a key molecule for tumoric angiogenesis. Furthermore, SB365 suppressed tube formation and migration of HUVECs, and in vivo neovascularization in a mouse Matrigel plug assay as well. The expressions of VEGF and CD34 in the tumor tissue were decreased by SB365 treatment. In a mechanism study, we also found that SB365 effectively suppressed the phosphorylation of PI3K downstream factors such as Akt, mTOR, and p70S6K both in vitro and in vivo. Taken together, our study demonstrates that SB365 not only induces apoptosis but also inhibits cell growth/proliferation and angiogenesis through modulation of PI3K/Akt/mTOR pathway in human HCC. We suggest that SB365 may be a new chemotherapeutic candidate against HCC. Keywords: SB365; HCC; Apoptosis; Angiogenesis; PI3K

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 3747. doi:1538-7445.AM2012-3747