bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2662: Radiosensitizing potential of the PI3K inhibitor, BKM-120 and the HSP 90 inhibitor, HSP990, is dependent on PTEN status of glioblastoma cells
Authors: Wachsberger Phyllis Rachelle , Lawrence Richard Y. , Feo Nick , Liu Yi , Andersen Barbara , Dicker Adam P. 
Published: June 2012

Abstract
Introduction: Radiation therapy plays an essential role in the treatment of Glioblastoma Multiforme (GBM), the most common primary adult brain tumor. GBMs frequently contain mutations in the tumor suppressor gene, PTEN, a down regulator of the pro-survival phosphatidylinositide-3-kinase (PI3K) pathway. PTEN loss causes overactivation of the pathway inducing radioresistance. Heat-shock protein (HSP) 90 is overexpressed in GBM; it is a chaperone for many oncogenic proteins and plays a key role in assisting tumor cell survival, proliferation, invasion, metastasis and tumor angiogenesis. The purpose of this study was to investigate the radiosensitizing potential of an HSP 90 inhibitor, (HSP990) and a PI3K inhibitor, (BKM-120) in U87 GBM cells expressing PTEN or null for PTEN.
Methods: Two isogenic U87 cell lines, stably transfected with wildtype PTEN (U87 wtPTEN) or lacking PTEN (U87PTEN null) were used. Radiosensitivity was determined by clonogenic and apoptotic assays (Annexin V kit). DNA damage and repair was assessed by quantifying gamma Histone 2AX (γH2AX) foci. Immunoblots were performed to assess pAkt levels. HSP990 and BKM -120 were provided by Novartis Pharmaceuticals.
Results: Neither HSP990 or BKM -120, alone or in combination, potentiated radiation-induced DNA damage in either cell line, as assessed by γH2AX foci. Radiation alone (6 Gy) activated AKT phosphorylation, with maximum activity occurring one hour post-radiation in both cell lines. Radiation-induced Akt phosphorylation was strongly inhibited by BKM -120 alone or in combination with HSP990 but not by HSP990 alone in both cell lines. In clonogenic assays, both drugs (alone or in combination), sensitized PTEN positive and PTEN null cells to radiation. Whereas the two drugs had similar efficacy in PTEN null cells, HSP990 was a better radiosensitizer than BKM -120 in U87 wtPTEN cells. Apoptosis assays revealed very little cell death 1 hr or 24 hr following drug and RT treatments. After 5 days, the percentage of apoptotic/necrotic cells increased &gt;30% over control following treatment with BKM -120 alone or in combination with HSP 990 in PTEN null cells. In contrast, PTEN positive cells were more resistant to cell death following BKM -120.
Conclusions: The results suggest that PI3K inhibition with BKM -120 will enhance radiotherapy for GBM lacking PTEN activity. HSP 90 inhibition by HSP990 may be of benefit in enhancing radiotherapy for GBM expressing functional PTEN. Thus, it appears that the optimal choice of radiosensitizer depends upon PTEN status.
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 2662. doi:10.1158/1538-7445.AM2011-2662
Abstract 2714: High HIV-1 DNA copy number defines a unique subset of AIDS-related lymphoma
Authors: Huysentruyt Leanne C. , Bracci Paige M. , McGrath Michael S. 
Published: June 2012

Abstract
Despite highly active antiretroviral therapy (HAART), the risk of developing non-Hodgkin lymphoma is ∼100X greater in the HIV-infected population compared to non-infected individuals and AIDS-related lymphoma (ARL) prevalence is expected to rise in the future. Preliminary reports have suggested that some ARLs contain HIV-infected macrophages that may contribute to ARL pathogenesis. A recent study evaluating HIV sequence evolution in the contest of metastatic ARL found lymphoma specific HIV compartmentalized within sites of lymphoma that was distinct from HIV present in non-lymphoma sites (Salemi et al, PLOSone Dec 3, 2009). These data suggested the existence of a lymphoma specific form of HIV evolving within individuals who develop ARL. The goal of this research was to determine the prevalence and quantity of HIV-1 DNA in 119 ARL biopsies from the entire span of the HIV epidemic (1982-2007) by utilizing whole genomic amplified (WGA) ARL DNA, provided by the AIDS and Cancer Specimen Resource (ACSR). The presence of HIV-1 DNA was determined by quantitative amplification of the HIV gag gene using single copy genes to define HIV copy numbers per genomic equivalent. Of the 119 ARL cases, 45% contained detectable levels of HIV-1 DNA (&gt; 1 copy per 30,000 cells). The relationship between HIV DNA presence and tumor immunophenotype was determined using ARL data from the ACSR on the cases studied. The level of HIV per genomic equivalent in the 45% HIV DNA positive cases was as high as one/cell equivalent. There was a significant (p&lt;0.01) decrease in the prevalence of HIV-1 DNA-positive ARL cases post-HAART (after 1996; 39%) as compared to pre-HAART (before 1996; 54%). Additionally, our data suggest that the overall amount of HIV-1 DNA present in ARLs was less in the post-HAART era when compared to the pre-HAART era. The HIV DNA positive cases fell into a positive outcome category (MUM1 negative and CD10 positive) based on lymphoma immunophenotype literature (p&lt; 0.02). Thus, a subset of ARLs containing high levels of HIV DNA, falls into a better outcome category based on immunophenotype data and may represent a different lymphoma pathogenic process. The existence of lymphoma specific variants of HIV is currently under investigation.
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 2714. doi:10.1158/1538-7445.AM2011-2714
Abstract 2722: Transcription factor NF-kB in esophageal squamous cell carcinoma: Alterations in activity and expression during Human Papillomavirus infection
Authors: Hussain Showket , Singh Neha , Salam Irfana , Bhat Mohammad A. , Kakkar Nandita , Mir Mohammad M. , Siddiqi Mushtaq A. , Basir Seemi F. , Bharti Alok C. , Bharadwaj Mausumi , Das Bhudev C. 
Published: June 2012

Abstract
Background: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir (J&K) region of India. A substantial proportion of esophageal carcinoma is associated with infection of high risk HPV type 16 and HPV18, the oncogenic expression of which is controlled by host cell transcription factor Nuclear factor kappa B (NF-kB). We therefore have investigated the role of DNA binding and expression pattern of NF-kB in esophageal cancer with or without HPV infection.
Methods: Seventy five histopathologically-confirmed esophageal cancer and an equal number of corresponding adjacent normal tissue biopsies from Kashmir were analyzed for HPV infection, DNA binding activity and expression of NF-kB family of proteins by PCR, gel shift assay and immunoblotting respectively.
Results: A high DNA binding activity and elevated expression of NF-kB proteins was observed in esophageal cancer tissue biopsies whereas, it was undetectable or reduced in all corresponding normal adjacent tissues but did not differ with respect to different grades of ESCC. In order to examine the composition of functional NF-kB complex both in HPV positive and negative esophageal tumors gel supershift assays were performed by adding specific antibodies to all 5 members of NF-kB family proteins (p50, p52, p65, RelB, and cRel). Supershift analysis revealed that p50 was a major binding partner and showed a preferential homodimerization in HPV negative esophageal tumors (61/75) and this participation was more evident in advanced grade of the disease (MDSCC+PDSCC; 46/61). On the other hand, HPV16 infected tumor tissues (n=14) showed hetrodimerization between p50 and cRel in more than 85% (12/14) of esophageal tumors. Interestingly, 2 cases with HPV infection p65 was also found to participate along with p50 and cRel in well-differentiated state of esophageal cancer. It is quite likely that the functional NF-kB complex formation in advanced grade of esophageal cancer comprises of p50/p50 homodimerization whereas in HPV infected esophageal tumors p50/cRel hetrodimerization occurs along with p65 in well differentiated state of the disease.
Conclusion: Differential NF-kB dimerization and expression of its specific proteins between HPV – positive and HPV – negative cases indicate that NF-kB may play an important role during HPV induced esophageal carcinogenesis.
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 2722. doi:10.1158/1538-7445.AM2011-2722
Abstract 2768: Single molecule approach detects significant mutation heterogeneity at the androgen receptor locus in prostate tumors
Authors: Makridakis Nick , Mukhopadhyay Sudurika , Chen Desheng 
Published: June 2012

Abstract
Studying the impact of genomic instability in cancer has been traditionally performed with PCR-based techniques. PCR-based methods may underestimate the total number of somatic mutations present in heterogeneous tumor genomes. Using standard PCR based methods we identified many missense somatic mutations of the DNA repair polymerase genes pol beta, pol eta and pol kappa in 30 prostate tumors. However, using a single molecule random cloning/sequencing method we uncovered a very high frequency of somatic alterations in prostate tumors: 0.52 somatic alterations per Kb of genomic DNA sequence (which corresponds to 1.8 million alterations per tumor cell genome). We then examined the somatic alteration frequency present in exon 2 of the androgen receptor (AR) gene, an established “driver” gene in prostate tumor progression. Exon 2 of the AR gene includes part of the DNA binding domain of this trancription factor. We report a similarly high somatic alteration frequency (including 50 missense AR mutations) and extreme AR mutation heterogeneity in prostate cancer patients with Gleason scores 5-9. Each somatic mutation was present in 1-5% of the tumor clones. Thus most of these “driver” mutations are not detectable by direct sequencing of a PCR product. All four cysteine residues that comprise the first Zinc-finger (Zf1) of the AR DNA-binding domain (the only zinc finger present in exon 2) had missense mutations in these patients (including recurrent mutations). In fact, we found missense or stop codon mutations of almost all Zf1 residues in these tumors. Some of these mutations have been shown to confer higher oncogenic transformation potential and hormone promiscuity to the androgen receptor. These data provide a molecular basis for the understanding of both a) the impact of genomic instability and b) anti-androgen drug resistance during prostate cancer progression.
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 2768. doi:10.1158/1538-7445.AM2011-2768
Abstract 2797: Breast cancer methylomes establish an epigenomic foundation for metastasis
Authors: Chan Timothy A. , Fang Fang , Turcan Sevin , Rimner Andreas 
Published: June 2012

Abstract
Cancer-specific alterations in DNA methylation are hallmarks of human malignancies. The nature of the breast cancer epigenome and its effects on metastatic behavior remain obscure. To address this issue, we used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Here, we describe the identification of novel groups of breast tumors characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating the existence of a breast-CpG island methylator phenotype (B-CIMP). B-CIMP imparts a distinct epigenomic profile and is a strong determinant of metastatic potential. Specifically, the presence of B-CIMP in tumors is associated with low metastatic risk and survival, and the absence of B-CIMP is associated with high metastatic risk and death. B-CIMP loci are highly enriched for genes comprising the metastasis transcriptome. Importantly, methylation at B-CIMP genes accounts for much of the transcriptomal diversity between breast cancers of varying prognosis, indicating a fundamental epigenomic contribution to metastasis. Comparison of the loci affected by B-CIMP with those affected by the hypermethylator phenotype in glioma and colon cancer reveals the presence of a CIMP signature shared by multiple human malignancies. These data provide a unifying epigenomic framework linking breast cancers with varying outcome and transcriptomic changes underlying metastasis. Our findings have significant implications for the understanding of breast cancer oncogenesis and for the development of new diagnostic and therapeutic modalities for this common malignancy.
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 2797. doi:10.1158/1538-7445.AM2011-2797
Abstract 2825: Characterization of a novel small molecule antagonist of 6-phosphofructo-2-kinase that suppresses glucose metabolism and tumor growth
Authors: Clem Brian , Tapolsky Gilles H. , O'Neal Julie , Chand Pooran , Clem Amy , Trent John , Telang Sucheta , Chesney Jason 
Published: June 2012

Abstract
Over-expression of HIF-1α, activation of Ras and loss of p53 tumor suppressor function are associated with the development of human cancers and each of these genetic alterations converge on glycolysis by activating the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB). The PFKFB enzymes interconvert fructose-6-phosphate (F6P) and fructose-2,6-bisphosphate (F2,6BP) and F2,6BP is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and control point in the glycolytic pathway. There are four PFKFB family members which are encoded by separate genes (PFKFB1-4) and characterized by distinct kinase:bisphosphatase ratios. The PFKFB3 family member is of particular interest since it has been found to be activated in human cancer cell lines and tumors, to be increased by hypoxic exposure via HIF-1α and by oncogenic Ras, and to be required for tumorigenic growth.
We recently discovered a competitive antagonist of PFKFB3 (3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one [3PO]) that reduces the glucose uptake, F2,6BP, lactate secretion, steady-state concentration of ATP, and growth of multiple transformed cell lines. Using a rationale design based approach, we have synthesized derivatives of 3PO and identified a compound (PFK-015) that: (i) more potently inhibits recombinant PFKFB3 (IC50:110 nM); (ii) inhibits PFKFB3 activity in cancer cells (IC50: 20 nM); (iii) is not a Pgp substrate as determined by transport and cell permeability assays in Caco-2 and MDCK-MDR1 (Papp A-B / B-A results 1.8 / 4 and 5 / 5 10−6 cm/s); (iv) inhibits cancer cell proliferation in a panel of 17 cancer cell lines; and (v) suppresses glucose uptake in cancer cells. Rodent PK studies following IV dosing at 5 mg/kg resulted in a profile with a satisfactory half-life (5.1 hours), exposure (AUCinf 1804 ng.h/ml), tissue distribution (Vd 20.5 L/kg) and reasonable clearance (46.2 mL/min/kg). Also, pre-clinical efficacy studies of C57Bl/6 mice bearing Lewis Lung Carcinoma (LLC) xenografts demonstrated ∼80% tumor growth inhibition relative to vehicle control. Finally, micro-PET studies performed on mice bearing LLC tumors showed a significant inhibition of tumor 2-[18F]-fluoro-2-deoxy-glucose uptake. These studies demonstrate that PFK-015 is an effective inhibitor of PFKFB3, possesses compelling in vitro properties, has satisfactory PK properties in rodents, and suppresses tumor glucose metabolism and growth in an aggressive mouse model of non-small cell lung cancer. These results support further development of PFK-015 as a novel anti-cancer agent.
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 2825. doi:10.1158/1538-7445.AM2011-2825
Abstract 2827: Activity of the proprietary Hsp90 inhibitor IPI-493 in models of colorectal cancer correlates with RAS pathway activation
Authors: West Kip A. , Hafeez Nafeeza , Dougall John Mac , Normant Emmanuel , Palombella Vito , Fritz Christian 
Published: June 2012

Abstract
Heat shock protein 90 (Hsp90) plays a role in regulating the stability of key cancer-causing proteins through its role as a protein chaperone. Proteins chaperoned by Hsp90, known as client proteins, include cancer-causing forms of ALK, BCR-ABL, EGFR, FLT3, and HER2. Infinity is developing two drug candidates in its Hsp90 chaperone inhibitor program: IPI-504 (retaspimycin hydrochloride), an intravenously-administered small molecule, and IPI-493, which is administered orally. To investigate the activity of IPI-493 in colorectal cancer (CRC), we performed in vitro growth inhibition (GI) studies on a CRC cell line panel. IPI-493 demonstrated GI50s in the range of 10-100nM in cell lines harboring either kRAS or bRAF mutations. To explore the in vivo potency of IPI-493, several mutant bRAF, mutant kRAS, as well as a wild-type kRAS/bRAF xenograft models were developed. Administration of IPI-493 at 100 mg/kg three times weekly demonstrated dramatic effects in all of the mutant models tested, with tumor growth inhibition (TGI) values between 70 and 90% and regression in one mutant bRAF model. Importantly, when IPI-493 was evaluated in combination with irinotecan, the combination resulted in greater tumor regression than seen with either agent alone with complete regressions observed in 4 of 10 animals. Interestingly, in the wild-type kRAS/bRAF models, IPI-493 administration did not lead to tumor growth inhibition. These results suggest that activation of the MAPK pathway may predispose these cells to sensitivity to Hsp90 inhibition. To investigate the effect of IPI-493 on MAPK pathway activity, we performed pharmacodynamic analysis after a single dose of IPI-493 in multiple xenograft models differing in their RAF/RAS mutation status. In mutant bRAF models, pathway activity was high, and IPI-493 administration resulted in downregulation of the activity of both bRAF and MEK. In models containing no mutations in kRAS or bRAF, we detect low baseline levels of both p-bRAF and p-MEK and little effect of IPI-493 administration. When Ras pathway activity in all CRC xenografts was compared with IPI-493 efficacy, there was a clear correlation between pathway activation and tumor growth inhibition by IPI-493. Our finding that Ras pathway activation predisposes CRC cells to sensitivity to IPI-493 and our combination data with irinotecan provide a clear rationale for the evaluation of Hsp90 inhibitors in colorectal 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 2827. doi:10.1158/1538-7445.AM2011-2827
Abstract 2851: Metronomic doxorubicin blocks hypoxia inducible factor-mediated responses to hypoxia in sarcomas and augments the effects of anti-VEGF therapy
Authors: Kim Yeo-Jung , Zhang Alexia Y. , Karl Daniel , Eisenger Karin , Simon M. Celeste , Yoon Sam S. 
Published: June 2012

Abstract
Introduction: Levels of hypoxia and hypoxia inducible factors (HIFs) in human sarcomas correlate with tumor progression and metastasis. Prolonged anti-angiogenic therapy of sarcomas can inhibit tumor growth but may also increase hypoxia and HIF activation. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (dox), was recently found to block HIF binding to DNA at low metronomic doses.
Methods: 20 patients with soft tissue sarcomas were treated with anti-VEGF antibody (bevacizumab). The tumors, before and after treatment, were examined for changes in microvessel density using CD31 immunohistochemical staining and global gene expression using microarrays. Patients’ tumors were then treated with a combination of bevacizumab and radiation followed by surgical resection. Expression of specific HIF-target genes in the response to hypoxia and/or dox was examined in vitro in 4 sarcoma cell lines by q-RT-PCR. HT1080 human sarcoma xenografts and sarcomas in genetically engineered LSL-KrasG12D/+Trp53fl/fl mice were treated with anti-VEGF receptor antibody (DC101) and/or metronomic dox and analyzed for levels of hypoxia, HIFs, and HIF-target genes.
Results: Bevacizumab alone reduced microvessel density in sarcomas by a median of 53% (p&lt;0.05). Gene set enrichment analysis of microarrays found the Gene Ontology category “Response to hypoxia” (which includes HIF-1a, HIF-2a, and ARNT) was upregulated in sarcomas with a poor response to combination therapy (bevacizumab plus radiation). Dox at 1-10 uM blocked HIF induction of VEGF and CA-9 in all 4 sarcoma cell lines by 83.7-97.0% and 88.6-97.6%, respectively, while inhibition of other HIF-target genes including c-MET and FOXM1 was variable. HT1080 sarcoma xenografts and LSL-KrasG12D/+Trp53fl/fl sarcomas demonstrated increasing hypoxia with larger tumor size and with treatment with an anti-VEGFR-2 antibody (DC101). Increasing hypoxia corresponded to greater nuclear expression of HIF-1α and HIF-2α, and metronomic Dox lowered expression of HIF-depended genes by up to 92.3%. Combining VEGFR-2 antibody and metronomic Dox therapies had a synergistic effect in suppressing tumor growth.
Conclusion: Human sarcomas respond to increased hypoxia by expressing HIF-target genes which promote compensatory responses. This hypoxic response may be exacerbated by anti-VEGF therapies and promote resistance to such therapies. Low metronomic doses of dox can block activation of HIF-target genes and works synergistically with anti-VEGF therapies to inhibit tumor growth.
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 2851. doi:10.1158/1538-7445.AM2011-2851