bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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 (&lt;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

Abstract
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

Abstract
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

Abstract
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 &lt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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
Abstract 375: Fluorescence-guided surgery leads to improved resection of primary pancreatic cancer and prolonged survival
Authors: Raimo Cristina A. Metildi , Kaushal Sharmeela , Hardamon Chanae R. , Snyder Cynthia S. , Hoffman Robert M. , Bouvet Michael 
Published: August 2012

Abstract
The aim of this study was to determine if fluorescence-guided surgery (FGS) could improve surgical outcomes, reduce recurrence rates and improve overall survival in orthotopic mouse models of human pancreatic cancer. Orthotopic mouse models of human pancreatic cancer were established using the BxPC-3 RFP-expressing pancreatic cancer cell line in nude mice. Two weeks after implantation, the mice were randomized to undergo bright light surgery (BLS) or fluorescence-guided surgery (FGS). Pre- and postoperative images were obtained with the Olympus OV-100 Small Animal Imaging System to assess completeness of surgical resection. Whole body imaging of the mice was performed weekly in the postoperative period to assess for recurrence and follow tumor progression. Additionally, half of the mice were randomly selected to undergo 4 weeks of postoperative gemcitabine treatment. At six weeks postoperatively, or when premorbid, the mice were sacrificed and primary pancreatic tumor burden was measured using ImageJ v1.440. A more complete resection of pancreatic cancer was achieved using FGS compared to BLS: 98.9% vs 77.1%, p=0.005. Sixty-three percent of the mice undergoing BLS had evidence of gross residual disease, whereas 20% of mice undergoing FGS received a complete resection and an additional 75% of the mice were left with minimal residual disease (p=0.0001). At six weeks, the primary pancreatic tumor burden was significantly less with FGS compared to BLS: 19.341 ± 5.26 mm2 vs. 6.194 ± 3.61 mm2, p=0.048. In a pilot survival study, FGS alone was associated with a decreased risk of tumor recurrence (HR=0.093, 95% CI 0.013-0.645), and mean overall survival was lengthened from 18.5 weeks to 28.2 weeks. The addition of adjuvant gemcitabine (GEM) to FGS further lengthened mean overall survival to 42.75 weeks (p=0.019). Three of the four mice in the FGS with adjuvant gemcitabine group were alive at 12 months postoperatively and all of the mice (n=4) were free of tumor at time of sacrifice. In this study, we achieved improved surgical outcomes in primary pancreatic cancer under fluorescence-guidance. FGS afforded a more complete resection of primary tumor and improved disease-free survival and overall survival. The combination of FGS and GEM lengthened disease-free survival and improved overall survival. This novel approach has potential to improve outcomes in the surgical treatment of pancreatic 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 375. doi:1538-7445.AM2012-375