bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5348: In vivo and in vitro alveolar rhabdomyosarcoma cell growth is affected by TNK2 expression
Authors: Arnaldez Fernanda I. , Yeung Choh L. , Helman Lee J. 
Published: June 2012

Abstract
Rhabdomyosarcoma is the most common pediatric soft tissue tumor. The two major histologic subtypes are embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS); which have different genetic alterations: 11p15 LOH in ERMS and PAX3 (or PAX7)-FOXO1 translocation in ARMS. Despite utilization of aggressive multimodal therapy, patients with recurrent or metastatic disease remain essentially incurable. This is particularly true in patients with alveolar rhabdomyosarcoma. New therapies are needed to improve outcomes in this disease.
To detect genes that are critical for rhabdomyosarcoma cell growth and survival, we performed a loss-of-function shRNA screen in ARMS and ERMS cell lines using a regulated shRNA library that was delivered to RMS cells using retrovirus. We hypothesized that genes whose loss of function significantly influence the growth and survival of ARMS cells with relatively no impact on ERMS cells represent a critical vulnerability or “Achilles’ heel” for ARMS. We sorted our gene list using this approach. In this study, we identified TNK2 (tyrosine kinase, non-receptor 2; also known as ACK1) as a critical gene is ARMS cell survival and as a potential therapeutic target.
TNK2 is a non-receptor tyrosine kinase that integrates signals from different membrane receptors, including integrins, EGFR and IGFR. Reported downstream targets include CDC42 and AKT. The TNK2 gene is located at 3q29. TNK2 amplification has been described in prostate, lung and breast cancer and its role in invasion and metastasis has recently been suggested. However, its role in rhabdomyosarcoma has not been previously explored. We initially confirmed that TNK2 is uniformly expressed RMS. In addition, analysis of TNK2 expression in primary tumor samples of RMS using a publicly available database indicated that rhabdomyosarcomas with higher TNK2 expression show lower overall survival.
We used a tetracycline-inducible shRNA construct to knock down TNK2 expression in rhabdomyosarcoma cells. TNK2 knock down resulted in significant decrease in cell growth in ARMS. We characterized the specificity of our findings using 5 different shRNA sequences targeting this gene delivered via lentivirus. In addition, we have been able to rescue the effect of an shRNA targeting the 3’UTR of this gene using TNK2 cDNA. We validated our in vitro data in an in vivo model using tumor xenografts. Downstream pathways under investigation include but are not limited to AKT, MAPK and CDC42.
These data suggest that TNK2 could represent a therapeutic target in ARMS and highlight the role of loss of function shRNA screens to improve the understanding of tumor biology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5348. doi:10.1158/1538-7445.AM2011-5348
Abstract 5352: Novel treatment approaches in retinoblastoma: Impact of combination therapy on tumor burden
Authors: Houston Samuel K. , Decatur Christina , Murray Timothy G. , Shah Nikesh , Cavalcante Ludimila , Pina Yolanda 
Published: June 2012

Abstract
Purpose: The purpose of the current study is to examine vessel targeting, chemotherapy, and mammalian target of rapamycin (mTOR) inhibitor agents in LHBETATAG retinal tumors and their impact on tumor burden.
Methods: Group A: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of anecortave acetate (AA; 1200, 600, 300, and 150 µg) delivered to right eyes only. Group B: Ten-week-old, LHBETATAG mice (n=30) received a single subconjunctival injection of AA (600, 300, and 150 µg) delivered to right eyes only, either during a cycle of carboplatin (six subconjunctival deliveries) or after the completed cycle. Carboplatin was delivered at the subtherapeutic concentration of 62.5 µg. All animals were euthanatized at 16 weeks of age, and the eyes were examined histopathologically. Group C: Eighteen-week-old, LHBETATAG mice received (n=30) subconjunctival injections of rapamycin once weekly for two consecutive weeks (0.00333, 0.167, 3.33, and 6.67 mg/kg). Tumor sections were analyzed for tumor burden with immunohistochemistry techniques.
Results: A statistically significant reduction in tumor burden was detected after a single periocular injection of AA. The reduction of tumor burden followed a U-shaped dose-response curve. Tumor burden was significantly decreased when AA and carboplatin were combined. However, varying doses and delivery schedule of these agents had significant impact on the effectiveness of the combined treatment. The most effective scheme was delivering a low dose (150-300 µg) of AA after a complete cycle of carboplatin. Reduction in tumor burden were significantly different between rapamycin doses and control (p&lt;0.002). Eyes treated with rapamycin at 0.167, 3.33 and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (p=0.019, p=0.001, p=0.009, respectively) and the 0.00333 mg/kg dose response (p=0.023, p=0.001, p=0.010, respectively). Histopathological evaluation showed no signs of retinal toxicity to either treatment used.
Conclusions: AA, as monotherapy or as adjuvant therapy, significantly controlled tumor burden in a murine model of retinoblastoma. Moreover, adjuvant therapy enabled the use of typically subtherapeutic carboplatin doses without decreasing efficacy of the therapy. Inhibition of mTOR reduced tumor burden during late disease in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5352. doi:10.1158/1538-7445.AM2011-5352
Abstract 5357: Pediatric preclinical evaluation of the PARP inhibitor olaparib
Authors: Norris Robin E. , Adamson Peter C. , Fox Elizabeth 
Published: June 2012

Abstract
Purpose: Olaparib (AZD2281) is an oral poly(ADP)-ribose polymerase (PARP) inhibitor in clinical development as a single agent and in combination with cytotoxic therapy in adults with solid malignancies. In BRCA-1 deficient tumors, olaparib concentrations of 30 nM result in significant PARP inhibition (Rottenberg, PNAS, 2008). Adult patients appear to tolerate olaparib doses associated with a Cmax of 10 µM (Fong, NEJM, 2009). We evaluated the interaction of olaparib with commonly used cytotoxic drugs in a panel of pediatric solid tumor cell lines.
Methods: In vitro growth inhibition was assessed using the sulforhodamine B assay in pediatric solid tumor cell lines including: osteosarcoma (MG-63), neuroblastoma (NGP), Ewings sarcoma (RD-ES), medulloblastoma (Daoy), and rhabdomyosarcoma (RD). IC50's were determined following a 120 h exposure to vehicle, olaparib, cytotoxic agent (carboplatin, melphalan, irinotecan, doxorubicin, vincristine) or olaparib in combination with each cytotoxic agent. The combination index (CI) of Chou-Talalay was used to test for synergy of combinations.
Results: As a single agent, olaparib was cytotoxic in all cell lines studied, with a median (range) IC50 of 1.7 (0.3-5.3) μM. The Ewings sarcoma cell line was the most sensitive line with a mean (SD) IC50 of 0.7 (0.3) μM. The combination of olaparib with melphalan or irinotecan was synergistic (CI &lt; 1), while the addition of olaparib to doxorubicin or carboplatin appeared additive to synergistic (CI &lt; 1). The combination of olaparib and vincristine trended toward antagonism (CI &gt; 1).
Conclusions: The addition of olaparib to DNA damaging agents resulted in additive or synergistic growth inhibition in a panel of pediatric solid tumor cell lines. Further preclinical and clinical evaluation to determine if olaparib can enhance the efficacy of current pediatric chemotherapy regimens is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5357. doi:10.1158/1538-7445.AM2011-5357
Abstract 5363: Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated antitumor efficacy in primary HCC cancer in vitro and in vivo
Authors: Shao Huanjie , Tang Haikuo , Gao Chun , Zhang Hao , Dy Grace , Yu Chunrong , Adjei Alex , Roberts Lewis 
Published: June 2012

Abstract
The mammalian target of rapamycin (mTOR) consists of two distinct complexes, mTORC1 and mTORC2. mTOR plays a pivotal role in Hepatocellular Carcinoma (HCC). Previous studies indicated that inhibition of mTORC1 only moderately enhanced histone deacetylase inhibitors (HDACis)-mediated anti-tumor activity. This limited effect may be attributable to the increase of AKT activation through S6K1-IRS1-PI3K negative feedback loop triggered by selective mTORC1 inhibition. While as AKT is the downstream effector of mTORC2, we hypothesize that dual targeting of mTORC1/C2 would be more efficient in suppressing AKT and in enhancing anti-tumor activity of HDACi. In this study, the interactions between mTOR kinase inhibitors (mTORKis) and HDACis were examined in vitro using established HCC cell lines and in vivo using patient-derived HCC tumor xenografts on SCID mice. Our results demonstrate that inhibition of both mTORC1/2 not only effectively blocked mTORC1 signaling, but also abrogated negative-feedback activation of AKT caused by mTORC1 inhibition. Furthermore, inactivation of mTORC1/C2 by mTORKis substantially enhanced HDACi-induced anti-tumor activity. Either dysfunction of mTORC2 by knockdown of Rictor (a component of mTORC2), or diminution of AKT1 significantly lowered the threshold of HDACi-induced apoptosis. Lastly, in vivo study indicated that the combination of AZD8055 and Vorinostat yielded much greater tumor-growth inhibition compared to either agent alone in primary HCC xenografts without obvious adverse effects. Conclusion: Dual mTORC1/2 inhibition is more efficient than selective mTORC1 inhibition in enhancing anti-tumor activity of HDACi due to abrogation of negative-feedback activation of AKT induced by selective mTORC1 inhibition. Our findings suggest that combining regimen of mTORKi and HDACi may be an effective therapeutic strategy for HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5363. doi:10.1158/1538-7445.AM2011-5363
Abstract 5369: Prostate cancer radiosensitization through PARP-1 hyperactivation
Authors: Dong Ying , Bey Erik A. , Li Longshan , Boothman David A. 
Published: June 2012

Abstract
The clinical experimental agent, beta-lapachone (Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether beta-lapachone may warrant clinical evaluation as a radiosensitizer. Beta-lapachone killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species (ROS), irreversible DNA single strand breaks (SSBs), PARP-1 hyperactivation, NAD+/ATP depletion, and µ-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), beta-lapachone radiosensitized NQO1+ prostate cancer cells, under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSBs, gamma-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of µ-calpain-induced programmed cell death. Radiosensitization by beta-lapachone was blocked by the NQO1 inhibitor, dicoumarol, or the PARP-1 inhibitor, DPQ. In a mouse xenograft model of prostate cancer, beta-lapachone synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ∼60% of human prostate tumors evaluated relative to adjacent normal tissue, where beta-lapachone might be efficacious alone or in combination with radiation. Our findings offer a rationale for clinical assessment of beta-lapachone (Arq501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation. Since similar data have been found for all NQO1 endogenously over-expressing cancers, including nonsmall cell lung, pancreatic and breast cancer, this strategy should have a broad use for many cancers and in combination with many DNA damaging agents used for cancer therapy. This work was supported by NIH grant 2 R01 CA102792 to DAB
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5369. doi:10.1158/1538-7445.AM2011-5369
Abstract 5376: Potentiation of the anti-proliferative and cytotoxic activity of ARQ 197 & gemcitabine with a pulsatile exposure regimen
Authors: Chen Chang-Rung , Abbadessa Giovanni , McSweeney Denise , Szwaya Jeffrey , Chan Thomas CK , France Dennis S. 
Published: June 2012

Abstract
ARQ 197 is a small molecule that inhibits c-MET kinase and is being evaluated clinically both as a monotherapy and in combination with other anti-cancer agents, including gemcitabine. Prompted by clinical observations, in vitro studies were conducted to explore the combination of ARQ 197 and gemcitabine with the goal of determining the most effective exposure regimen and to further refine the strategy of an ongoing phase 1b combination clinical trial. Gemcitabine and ARQ 197 both induce cell cycle arrest in cancer cells, but in different phases. Gemcitabine induces a G1/S-phase arrest, while ARQ 197 arrests cells in the G2/M phase. We hypothesized that the efficacy of combining these two agents might be enhanced by deliberate pulsatile treatment with ample time allowed for gemcitabine-treated cells to re-enter the cell cycle and to therefore potentially increase their vulnerability to ARQ 197-induced cell cycle arrest and apoptosis. A 7-day MTS cytotoxicity assay was employed in which the cells were seeded on Day 0, treated with gemcitabine for 24 h on Day 2, drug free medium added on Day 3, and ARQ 197 added on Day 5 for 24 h and then replaced with drug free medium. Cell viability was assayed with MTS reagent at the end of Day 7. To determine whether this pulsatile schedule was more advantageous then a regimen with no intervening “drug holiday”, control cultures were not replenished with drug free medium on Day 3 and ARQ 197 was added on Day 5. When the pulsatile schedule was employed, the combinatorial cytotoxicity of these two agents was significantly enhanced in several cancer cell lines (including NSCLC, bladder, pancreatic, breast, ovarian and uterine carcinomas). Mechanistic studies confirmed the G1/S-phase arrest of gemcitabine-treated cells, and G2/M arrest was observed following exposure to ARQ 197 in this regimen. Furthermore, this potentiation was also observed if ARQ 197 was exposed to the cancer cells as the first agent on Day 2 and gemcitabine added as the second agent on Day 5, as long as the pulsatile regimen was employed. These data suggest that modifications to dosing schedules of ARQ 197 and gemcitabine may improve the potential for synergistic anti-tumor activity in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5376. doi:10.1158/1538-7445.AM2011-5376
Abstract 5378: SB225002 induces apoptosis in acute lymphoid leukemia cells
Authors: Vasconcellos Jaira F. , Laranjeira Angelo B. A. , Leal Paulo C. , Nunes Ricardo J. , Yunes Rosendo A. , Brandalise Silvia R. , Libermann Towia A. , Zerbini Luiz F. , Yunes José A. 
Published: June 2012

Abstract
Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. We have recently shown that the leukemic bone marrow (BM) contains high levels of interleukin-8 (IL-8), whose cognate receptor CXCR2 is expressed by most primary ALL cells. ALL cell lines are sensitive to SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea), a CXCR2 antagonist. Surprisingly, the inhibitory effect of this drug was found to be independent of CXCR2 expression by leukemic cells. The current study was conducted to determine the mechanism of action of SB225002 against ALL cells, using as prototype the T-ALL cell line Jurkat. Cell cycle analysis showed that SB225002 induces G2-M cell cycle arrest. Transcriptional profiling by microarray analysis revealed that SB225002 induces 174 genes and represses 41 genes. SB225002 induced-apoptosis triggered a transcriptional program of genes involved in activation of the JUN and p53 pathways and inhibition of the TNFα pathway. Results were further confirmed by Q-PCR and/or Western blot analysis. Treatment of Jurkat cells with SB225002 also induced the activation of phospho-p44/42 MAPK (ERK1/2), which was suspected to be an anti-apoptotic pathway triggered by injured cells. In fact, the inhibition of ERK1/2 with pharmacologic inhibitors, in combination with SB225002, resulted in the enhancement of apoptosis, suggesting the blockage of ERK1/2 pathway as a strategy to increase the sensitivity of ALL cells toward SB225002. Connectivity Map analysis of the SB225002 gene signature demonstrates a positive correlation with the signatures for PI3K and HSP90 inhibitors (connectivity score 1 and 0.944, respectively), which mediate apoptosis through effects on AKT, TNFα and NF-κB, while SB225002's mediated-apoptosis demonstrated only to inhibit TNFα pathway. Furthermore, SB225002 gene signature demonstrates a positive correlation with Nocodazole and Podophyllotoxin (connectivity score 0.895 and 0.859, respectively), which are inducers of cancer cell apoptosis by interfering with microtubule polymerization and inhibiting topoisomerase II, respectively. Our data demonstrate for the first time that JUN, p53, and TNFα pathways are modulated by SB225002, and that ALL cells are sensitized to SB225002-induced apoptosis after phospho-p44/42 MAPK inhibition. Overall these data support SB225002's therapeutic potential in ALL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5378. doi:10.1158/1538-7445.AM2011-5378
Abstract 5390: A serotype 5/3 adenovirus expressing MDA-7/IL-24 infects renal carcinoma cells and promotes toxicity of agents that increase ROS and ceramide levels
Authors: Bareford Mary Danielle , Hamed Hossein A. , Park Margaret , Grant Steven , Fisher Paul , Dent Paul 
Published: June 2012

Abstract
It recognized that agents that generate reactive oxygen species (ROS) enhance MDA-7/IL-24 lethality. The present studies focused on clarifying how such agents enhanced MDA-7/IL-24 toxicity in renal cell carcinoma cells (RCCs). Infection of RCCs with a tropism-modified serotype 5/3 adenovirus expressing MDA-7/IL-24, Ad.5/3-mda-7, caused plasma membrane clustering of CD95 and CD95 association with pro-caspase 8, effects that were enhanced by combined exposure to 17AAG, As2O3 or 4HPR, and which correlated with enhanced cell killing. Knock down of CD95 or expression of c-FLIP-s blocked enhanced killing. Inhibition of ROS generation, elevated cytosolic Ca2+, or de novo ceramide synthesis blocked Ad.5/3-mda-7 +/- agent-induced CD95 activation and the enhancement of apoptosis.Ad.5/3-mda-7-increased ceramide levels in a PERK-dependent fashion that were responsible for elevated cytosolic Ca2+ levels that promoted ROS generation; 17AAG did not further enhance cytokine-induced ceramide generation. In vivo, infection of RCC tumors with Ad.5/3-mda-7 suppressed the growth of infected tumors that was enhanced by exposure to 17AAG. Our data indicates that in RCCs Ad.5/3-mda-7-induced ceramide generation plays a central role in tumor cell killing and inhibition of multiple signaling pathways may have utility in promoting MDA-7/IL-24 lethality in renal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2011-5390
Abstract 5394: Dual inhibition of the androgen receptor by ligand blockade and antisense-mediated downregulation is associated with synergistic antitumor activity model of prostate cancer
Authors: Zhang Yixian , Dumble Melissa , Castaneda Stephen , Milesky Mary , Kim Steven , Qu Zhengxing , Greenberger Lee M. , Horak Ivan D. 
Published: June 2012

Abstract
Background: Although new agents to treat prostate cancer have recently been approved, and new investigational drugs (Abiraterone and MDV3100) that mediate hormone deprivation show promising data from late-stage clinical trials, these therapies typically extend overall survival up to 4 months in patients with advanced disease who have failed conventional androgen deprivation therapy. Hence, there continues to be great medical need. EZN-4176 is a novel LNA-based antisense oligonucleotide (EZN-4176) that down regulates androgen receptor (AR) expression. Previously, antitumor activity of EZN-4176 in multiple xenograft models including both androgen-sensitive and castrate-resistant tumors was shown. More importantly, a synergistic effect was also found when EZN-4176 was combined with MDV3100. Further exploration of the mechanistic underpinning of the effect was explored here. Methods: The mRNA, growth, luciferase activity, protein, and prostate specific antigen (PSA) were evaluated by qRT-PCR, MTT, SteadyGlo, western blot analysis, and ELISA assay, respectively. The effect of EZN-4176 on AR transcriptional activity was evaluated in cells stably express luciferase gene regulated by AR. In vivo, the effect of EZN-4176 on AR transcriptional activity was evaluated in a bone tumor model developed by intratibia injection of C4-2b-AR-luc cells. Results: Combination of EZN-4176 with MDV3100 resulted in a much improved inhibitory effect in colony formation assay in vitro. This effect was not associated with enhanced efficiency of AR mRNA down-modulation as treatment with EZN-4176 with or without MDV3100 showed similar effects on the level of AR mRNA. However, when AR transcriptional activity was examined, we found that the combined effect was greater than each agent alone. In C4-2b-AR-luc bone tumor model, EZN-4176 potently and specifically down-modulated AR-luciferase reporter activity. Further examinations of the anti-tumor effect in this model will help understand the potential of the combinatorial effect in a highly relevant disease model. Conclusions: Our preliminary data suggest that the synergistic anti-tumor effect of EZN-4176 in combination with MDV3100 is in part associated with much reduced transcriptional activity of AR. EZN-4176 alone or in combination with anti-androgens offers great potential in treating patients with advanced prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5394. doi:10.1158/1538-7445.AM2011-5394