bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2698: Improved therapeutic activity of Isoflavone-G2535 and Docetaxel combination in hormone refractory prostate cancer
Authors: Banerjee Sanjeev , Ali Shadan , Azmi Asfar , Kong Dejuan , Ahmad Aamir , Bao Bin , Sarkar Fazlul H. 
Published: August 2012

Abstract
The emergence of Castrate Resistant Prostate Cancer (CRPC) and its subsequent metastasis to the bone is in part driven by Androgen Receptor (AR) signaling, and contributes to overall poor survival of prostate cancer patients. Here, we present in vitro and in vivo preclinical evidence of chemo-sensitization of CRPC cells to the most clinically useful therapeutic agent, Docetaxel (Taxotere) by G2535, an isoflavone that attenuates AR signaling. In vitro studies were done using AR+ prostate cancer (PCa) cell lines (LNCaP and C4-2B) to understand the molecular basis of combination therapy. We found that the combination was significantly more effective in inhibiting cell growth and induction of apoptosis (p&lt;0.01), down-regulation of AR and its target, prostate specific antigen (PSA) (p&lt;0.01) with suboptimal concentrations of Docetaxel (1nmole/L) compared to monotherapy. It is known that resistance to chemotherapy in CRPC is partly associated with constitutively activated NF-κB/Akt signaling pathways, which becomes further activated by chemotherapeutic drugs, and these molecular targets were found to be down-regulated by G2535 treatment. Of greater significance were the results from in vivo tumor growth inhibition studies conducted in a SCID-hu model of experimental bone metastasis induced by C4-2B cells. Tumor volume, AR and serum PSA was used as response markers to evaluate therapeutic activity of the combination therapy relative to a single regimen and untreated control. At termination, we found 75% reduction in tumor volume elicited by the combination treatment relative to the untreated control group. Most importantly, the anti-tumor activity was associated with the down-regulation of molecular markers in tumor tissue remnants that were similar to those observed in vitro (down regulation of NF-κB, Bcl-2 and survivin) accompanied by a significant reduction in serum PSA. Using qPCR, we found that the level of miR-34a, which target AR, was increased by 1.5 fold after G2535 treatment alone whereas this increase was found to be 3-fold in the combination group. Increased expression of miR-34a resulted in the down regulation of AR and PSA in this in vivo model. Based on our findings, we conclude that the combination of G2535 and Taxotere could be an alternative promising regimen for the treatment of CRPC and its metastases for which curative treatment is urgently needed.
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 2698. doi:1538-7445.AM2012-2698
Abstract 2700: The use of a novel receptor targeted (CD206) Tc99m-labeled intraoperative node mapping agent for preoperative SPECT/CT in imaging head/neck cancer, breast cancer and melanoma Phase 3 trials: Localization and concordance in lymph nodes
Authors: Metz Wendy Rich , Hall Nathan , Povoski Stephen , Agrawal Amit , Shuping Jo , Abbruzzese Bonnie , Blackburn Simon , Potter Beth , Cope Frederick O. 
Published: August 2012

Abstract
The intraoperative lymphaticmapping (ILM) concept, based on evidence that colored agents injected into tissues leads to tracing of the agents into lymphatic structures, has carried over from observations dating back to the 1920s. The modern concept of using the pathological status of the lymph nodes to decide whether regional lymphatic clearance should be done was clearly articulated by Cabanas in 1977. Refinement of the concept as it would be reduced to a practical methodology of lymph node identification both in Europe and the United States began in earnest in the 1990s. Development of the application of sentinel node mapping has been built upon the concept of an anatomic/biologic nexus between the solid tumor bed and the immediate versus the distal lymphatic structures. It is the “biological proximity” that defines the probability of found disease in the adnexa, between the tumor bed and the lymphatic structures. It is inferred that the probability of disseminated disease in any lymphatic anatomy is highest when anatomic or biologic nexuses actually exist, as opposed to the lack of any anatomic nexuses where disease dissemination probabilities in lymphatic structures are lowest. To date, agents that have been employed in this procedure bear only simple designs that utilize simple physiologic pulse/draining of the lymphatics and provide no specificity for targeting the lymphatic tissue of interest. We present here patient results of three Phase III studies in head/neck squamous cell carcinoma, breast cancer, and melanoma where a novel 99mTc-labeled receptor targeted agent (99mTc-tilmanocept) not only out performed standard of care agents, but lent itself to remarkable concordance of intraoperative nodal localization with preoperative SPECT/CT imaging. The conclusion of these studies is that 99mTc-tilmanocept provides higher localization rates, degree of localization, lower failed detection rates, and reliable concordance between imaging and intraoperative findings. This work was supported by Neoprobe Corporation, Dublin, OH 43017
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 2700. doi:1538-7445.AM2012-2700
Abstract 2707: Long-term significance (15 years) of pathological complete response after dose-dense neo-adjuvant chemotherapy in breast cancer
Authors: Wang-Lopez Qian , Abrial Catherine , Planchat Eloise , Mouret-Reynier Marie-Ange , Cure Hervé , Gimbergues Pierre , Dubray-Longeras Pascale , Gallon-Bernard Dominique J. , Kwiatkowski Fabrice , Chollet Philippe J. , Durando Xavier 
Published: August 2012

Abstract
Purpose: As a contribution to the discussion of pathological complete response (pCR) as surrogate end-point, after neo-adjuvant chemotherapy (NACT), we studied disease-free survival (DFS) and overall survival (OS) at 15 years with THP-doxorubicin, vinorelbine, 5-Fluorouracil and cyclophosphamide (TNCF regimen). Patients and methods: This retrospective cohort study has been done in 61 patients treated with neo-adjuvant semi-intensive chemotherapy. PCR rate was analysed separately in breast (no histological evidence of invasive tumor cells and / or presence of in situ carcinoma tumor cells) and in nodes (no metastasis). Univariate and multivariate analysis (COX regression) have been used to assess the potential prognostic factors with a median follow up of 13.8 years. Results: Thirty two patients relapsed and 21 died. At 15 years, DFS and OS were 53% and 88% respectively for the patients who achieved pCR compared to 33% and 53% respectively for those who did not achieve pCR. Multivariate analysis with COX model showed that pCR in breast and the number of involved nodes at surgery were 2 factors who can significant predict patients’ DFS and these two factors were significantly related. Conclusion: In this current study, pCR in breast can be used as surrogate marker to predict survival outcome, even with a long-term follow-up of 15 years. When pathological response was incomplete in primary tumor, the number of involved nodes (n &gt; 4 vs n &lt;/= 4) significantly predicted survival.
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 2707. doi:1538-7445.AM2012-2707
Abstract 271: Validation of Polo-like Kinase 1 as a novel therapeutic target in alveolar rhabdomyosarcoma
Authors: Thalhammer Verena , Herrero-Martin David , Hecker Regina , Niggli Felix K. , Schäfer Beat W. 
Published: August 2012

Abstract
Oncogenic transcription factors are the second most frequently mutated class of proteins. They represent ideal therapeutic targets because oncogene addiction is common to a broad spectrum of tumors and their inhibition may help to develop further alternative treatment strategies to improve therapy and to minimize treatment related side effects. However, thus far it has not been possible to target these oncogenic transcription factors as they usually do not respond to small-molecule inhibition. As a model system we use alveolar rhabdomyosarcoma (aRMS), an aggressive childhood tumor, which often displays resistance to conventional chemo-and radiotherapy. aRMS is characterized by the expression of the tumor-specific chimeric transcription factor PAX3/FKHR that is essential for survival of tumor cells. This transcription factor is post-translationally modified by phosphorylation which is required for efficient transcriptional activity. We believe that identification of upstream protein kinases mediating PAX3/FKHR phosphorylation will be an efficient strategy to impair the activity of the oncogenic fusion protein and subsequently induce tumor cell specific apoptosis. Having performed both siRNA and kinase-inhibitor library screens against the human kinome, we claim that Polo-like Kinase 1 (PLK1) might represent a very attractive and specific potential therapeutic target in aRMS. Its inhibition by RNAi and the small-molecule inhibitor BI 2536 reduces PAX3/FKHR activity and consequently aRMS cell viability. Moreover drug treatment causes tumor regression in xenograft mouse models. Therefore we are elucidating mechanisms causing these antitumorigenic effects and especially focus on the interaction of PLK1 and PAX3/FKHR. Our data suggest that PLK1 warrants further investigations as a novel drug target for the treatment of aRMS and may lead to a general strategy for treatment of tumors addicted to post-translationally modified oncogenic transcription factors.
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 271. doi:1538-7445.AM2012-271
Abstract 2786: Potent inhibition of human liposarcoma cell growth and survival by novel modulators of the MDM2-p53 interaction
Authors: Zhang Yixiang , Remillard Stephen P. , Demetri George D. , Wang Shaomeng , Debussche Laurent , Wagner Andrew J. 
Published: August 2012

Abstract
The tumor suppressor p53 is commonly inactivated in human malignancies. One mechanism is by genomic amplification and consequent overexpression of the ubiquitin E3 ligase MDM2, which targets p53 for proteosome-mediated degradation. The MDM2 gene is amplified in &gt;95% of human liposarcomas, a disease for which the efficacy of systemic therapies is limited. Here, we compared the effects of two novel highly potent and selective inhibitors of the MDM2-p53 interaction, with the classic MDM2 inhibitor Nutlin-3 on the expression and activity of p53 and the resulting changes in human liposarcoma cell proliferation and survival. We determined MDM2 copy number, p53 mutational status, and relative expression levels of MDM2 and p53 proteins in 8 human liposarcoma cell lines and normal human preadipocytes/adipocytes. TP53 status was wild type in 7 of 8 liposarcoma cell lines, which also had genomic amplification of MDM2. MDM2 protein expression correlated with the degree of amplification and was highly expressed in comparison to normal preadipocytes/adipocytes. The two spiro-oxindole derivatives - Compounds A and B- (1) and Nutlin-3 were applied to liposarcoma cell lines with or without p53 siRNA and the biological consequences were determined by immunoblot, cell viability, cell cycle and apoptosis assays. Treatment with MDM2 inhibitors led to increased p53 protein levels and induction of its transcriptional targets MDM2 and p21. Cell viability was markedly decreased in a dose-dependent manner in liposarcoma cells with wild-type p53, with IC50 values of 0.40-4.23 μM, 0.37-1.88 μM and 2.72-9.83 μM for Compound A, Compound B, and Nutlin-3, respectively. These effects were markedly abrogated by siRNA-mediated p53 knockdown and in a cell line harboring a de novo p53 mutation. Compound A and Compound B also induced cell cycle arrest and apoptosis at approximately 5 fold lower concentrations than Nutlin-3. At low concentrations, G0/G1 cell arrest occurred, whereas higher concentrations resulted in G2/M arrest and induction of apoptosis. Cell line and tumor xenograft experiments are ongoing. These data demonstrate that Compounds A and B are highly potent and specific inhibitors of MDM2 with activity in genetically characterized liposarcoma cells. Further study and clinical development in this disease is warranted. 1. Wang S. et al., AACR, Orlando FL, 2011, Abstract LB-204
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 2786. doi:1538-7445.AM2012-2786
Abstract 2795: Safety profile and therapeutic potential in breast cancer of STX140, an original tubulin binding agent
Authors: Meyer-Losic Florence , Fiore Ann , Carlson Mark , Lauer Jeffrey , Roubert Pierre , Bernetière Sonia , Oligo Charleen , Vignaux Laurent , Gaudry Hervé , Foster Paul A. , Newman Simon P. , Purohit Atul , Leese Matthew P. , Kasprzyk Philip G. 
Published: August 2012

Abstract
STX-140 is an anti-tubulin binding agent which has demonstrated a good anti-tumor efficacy profile. Although the binding site on tubulin differs from other classical tubulin binders, one could anticipate the same type of safety issues with such an agent, namely neurotoxicity. In order to differentiate this compound, we evaluated its efficacy in a transgenic model of mammary cancer, its neurotoxicity potential, and its therapeutic index in a breast cancer model. STX140 efficacy was evaluated in C3(1) Tag transgenic mice which develop mammary carcinomas. In those transgenic animals, the disease progresses in a similar fashion to human breast cancer, with the development of tumors which show the same histological characteristics as the human pathology. In these mice, STX140 was able to significantly increase the survival of the animals and to suppress the emergence of metastases, whereas paclitaxel was completely inactive on both parameters. Neurotoxicity potential was assessed in a thermal hyperalgesia model in comparison with paclitaxel. Continuous oral treatment of mice with STX-140 did not induce an increase sensibility to heat as measured by the latency of paw withdrawal after a heat stimulus. However, paclitaxel increased this heat sensitivity starting after the second i.v. administration, underlying the neurotoxicity of this compound, which is observed in the clinic. Finally, in MDA-MB-231 breast cancer xenografts, two different schedules of oral administration were evaluated in order to determine the therapeutic index and PK parameters were measured in parallel to the anti-tumor efficacy. Continuous (QD) and intermittent (Monday, Wednesday, Friday; MWF) treatments were evaluated and a large panel of doses were tested. The therapeutic index was determined as the ratio of the exposure observed between the first toxic dose and first active dose. The TI for the QD schedule was 2.1 and was 1.7 for the MWF schedule, showing the potential good safety index of this compound. Taking into account the previous data reported elsewhere and new data presented here, which underline the great efficacy and safety profile of STX140, this compound is considered for further preclinical and clinical development.
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 2795. doi:1538-7445.AM2012-2795
Abstract 2796: Efficacy and biomarker modulation by AZD1208, a novel, potent and selective pan-Pim kinase inhibitor, in models of acute myeloid leukemia
Authors: Keeton Erika , McEachern Kristen , Alimzhanov Marat , Wang Suping , Cao Yichen , Bao Larry , Palakurthi Sangeetha , Grondine Michael , Chen Yuching , Dillman Keith , Chinnappan Dharmaraj , Shen Minhui , Dakin Les , Zheng Xiaolan , Lamb Michelle , Wu Allan , Chen Huawei , Lyne Paul , Huszar Dennis 
Published: August 2012

Abstract
The Pim serine/threonine kinase family is composed of three highly homologous members; Pim-1, Pim-2 and Pim-3, identified by the ability of the prototype member Pim-1 to drive lymphomagenesis in mice. Upregulation of Pim-1 and Pim-2 is observed in leukemias and lymphomas, including AML, NHL and CLL, highlighting the potential of these kinases as therapeutic targets in these indications. Overexpression of Pim-1 or Pim-3 has also been observed in prostate, pancreatic, gastric, bladder and hepatocellular cancers. Pim kinases are downstream effectors of many cytokine and growth factor signaling pathways and are direct transcriptional targets of STAT transcription factors activated by these pathways. Pims can phosphorylate multiple substrates to mediate cell proliferation and survival. Here we describe the activity of AZD1208, an orally available, potent and highly selective Pim inhibitor that effectively inhibits all three isoforms. AZD1208 inhibits the growth of several AML cell lines and sensitivity correlates with the level of Pim-1 expression, STAT5 activation and presence of protein tyrosine kinase mutation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells in culture. This is accompanied by a dose-dependent reduction in phosphorylation of BAD, 4EBP1 and p70S6K. AZD1208 suppresses the growth of MOLM-16 and KG-1a xenograft tumors in vivo in a dose proportional manner. In addition, AZD1208 leads to potent inhibition of colony growth of primary AML cells from bone marrow aspirates and downregulates phosphorylation of Pim targets. These results underscore the therapeutic potential of Pim kinase inhibition by AZD1208 for the treatment of AML. They also further support investigation of this inhibitor in other hematological and solid tumor malignancies where PIM signaling may play a role in tumorigenesis and survival.
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 2796. doi:1538-7445.AM2012-2796
Abstract 28: The Netrin-1 receptor UNC5C is a tumor suppressor in colorectal malignancies
Authors: Coissieux Marie-May , Tomsic Jerneja , Lasset Christine , Hampel Heather , Scoazec Jean-Yves , Wang Qing , Tanner Stephan M. , Bernet Agnès , de la Chapelle Albert , Mehlen Patrick 
Published: August 2012

Abstract
The Netrin-1 receptors UNC5A, B and C belong to the functional family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer a tumor suppressor activity to these receptors. Expression of one of these dependence receptors at the surface of a tumor cell is thus speculated to render this cell dependent on ligand for its survival, hence inhibiting cell proliferation or migration outside the ligand availability zone. Here we show that the expression of the UNC5C gene is down-regulated in colorectal cancers, mainly because of tumor-associated specific promoter methylation. In addition, inactivation of UNC5C in mice is associated with increased intestinal tumor progression, demonstrating its tumor suppressor role. Moreover, mutations in UNC5C that turn down the pro-apoptotic activity of the receptor are found in patients with familial form of colorectal cancer. This germline coding mutation in UNC5C has been detected in five different families from France and USA and co-segregates with the disease. We further, determine that this anti-apoptotic mutation arose from a common founder. In summary, our study strongly indicates that the genetic inactivation of the tumor suppressor UNC5C may be a major promoter of familial predisposition to colorectal tumorigenesis.
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 28. doi:1538-7445.AM2012-28
Abstract 280: Genetics and functions of Kaposi's sarcoma-associated herpesvirus (KSHV) glycoproteins in virion egress, infectivity and tumorigenesis
Authors: D'Auvergne Oswald , Subramanian Ramesh 
Published: August 2012

Abstract
Kaposi's sarcoma-associated herpes virus (KSHV), or human herpes virus 8, is a lymphotropic oncogenic virus that has been implicated in the pathogenesis of Kaposi's sarcoma; body cavity-based B-cell lymphoma (BCBL), or primary lymphoma; and some forms of Multicentric Castleman's disease. We have developed a conditional silencing system for partial inhibition of KSHV viral glycoprotein synthesized genes that are not susceptible to siRNA inhibition. We have successfully used this system to demonstrate that KHSV glycoprotein B (gB) is necessary for virion egress from BCBL-1 cells and virus infectivity (Subramanian, D'Auvergne, et al. J. Virol. 2008, 82:7144-54). To investigate the potential role of gB in tumorigenesis, BCBL-1 cells were transiently transfected with anti-gB siRNAs and codon optimized gB were mixed with matrigel and injected subcutaneously in nude mice. Direct measurement of tumors revealed that BCBL-1 cells transfected with anti-gB siRNAs produced tumors significantly smaller than mock-transfected BCBL-1 cells. Co-transfection of codon optimized gB appeared to abrogate the inhibition of tumor formation by siRNAs. These results show that gB is important for infectivity, virion egress and pleural effusion lymphoma (PEL) formation in mice.
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 280. doi:1538-7445.AM2012-280