bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-204: Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential
Authors: Justilien Verline , Regala Roderick P. , Tseng I-Chu , Walsh Michael P. , Batra Jyotica , Radisky Evette S. , Murray Nicole R. , Fields Alan P. 
Published: August 2012

Abstract
Matrix metalloproteinase 10 (Mmp10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many members of which have been implicated in tumor progression, invasion and metastasis. However, emerging evidence suggests a possible role for Mmps in tumor initiation. Here we reveal an unexpected role for Mmp10 in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mouse lung cancer cell cultures enriched in stem-like cells grow as undifferentiated tumor “oncospheres” that express elevated levels of the cancer stem cell markers Aldh1, CD133, Nanog, Notch3, Notch 4, Hey 1 and Hey 2. These cells also express elevated levels of Mmp10 mRNA and secrete elevated levels of Mmp10 protein. Functionally, these lung CSCs exhibit self-renewal, the ability to clonally expand, enhanced transforming potential in vitro, and enhanced tumorigenic properties when injected orthotopically into the lungs of syngeneic mice. RNAi-mediated knockdown of Mmp10 in these cells leads to a loss of stem cell marker gene expression and a dramatic inhibition of oncosphere growth, clonal expansion, transformed growth in vitro, and lung tumor formation and metastasis in vivo. In contrast, oncospheres implanted into syngeneic non-transgenic or Mmp10−/− mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human tumors demonstrates that Mmp10 is elevated in many human tumor types including lung, head and neck, esophageal, colon, breast, melanoma, bladder, cervical, ovarian, prostate and brain. Furthermore, gene set enhancement analysis (GSEA) demonstrates that elevated Mmp10 expression correlates with tumor metastasis and with cancer stem-like genomic signatures in human lung tumors. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells.
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 LB-204. doi:1538-7445.AM2012-LB-204
Abstract LB-216: Receptor targeted (CD206) Tc99m tilmanocept localization in sentinel nodes in breast cancer and melanoma is concordant with preoperative imaging and a reduction in missed disease
Authors: Cope Frederick O. , Metz Wendy , Abbruzzese Bonnie , Shuping Jo , Hartman Richard , King Dennis , Christman Lori , Blue Michael 
Published: August 2012

Abstract
Purpose: Tilmanocept is wholly synthetic molecule composed of a dextran-10 backbone with both multiple mannose side moieties (for receptor biding) and DTPA (for chelation of divalent cations). Tilmanocept is designed as a high affinity ligand for the human mannose binding receptor (CD206) of reticuloendothelial cells (RECs), and more specifically, those RECs that reside in tumor-draining lymph nodes. Tilmanocept is designed to provide high sensitivity and specificity for intraoperative lymphatic mapping in melanoma, breast cancer, head/neck squamous cell carcinoma, and other solid tumors. This study was designed to evaluate the correlation of preoperative imaging using Tc99m tilmanocept and intraoperative tumor bed-adnexed node findings, along with metatstatic disease finding for Tc99m tilmaocept with its “truth” comparator, Lymphazurin. Results/Conclusions: The results of combined prospective phase 3 clinical trials in breast cancer and melanoma indicate that there is a near 99% correlation between the preoperative imaging (lymphoscintigraphy) based on the use of the CD206 targeted Tc99m tilmanocept and the intraoperative/surgical findings of tumor-adnexed lymph nodes. Additionally, these findings provide exceptional guidance for nodal extraction in contrast to the “truth” mapping agent Lymphazurin, where Tc99m provides a significantly lower failed detection rate leading to a ∼10 percent improved staging rate for breast cancer and mealnoma patients (less missed disease and appropriate post-surgical treatment program).
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 LB-216. doi:1538-7445.AM2012-LB-216
Abstract LB-218: Immune response assessment in a phase II trial of AE37 HER2 peptide vaccine
Authors: Hale Diane F. , Vreeland Timothy J. , Dabney Raetasha S. , Clifton G Travis , Sears Alan K. , Pappou Efi , Anastasopoulou Eleftheria , Ardavanis Alexandros , Ponniah Sathibalan , Papamichail Michael , Perez Sonia , Shumway Nathan , Peoples George E. , Mittendorf Elizabeth 
Published: August 2012

Abstract
Introduction: AE37 is the Ii-Key hybrid of the HER2 derived peptide AE36 (776-790). A phase I trial administering AE37 with the immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T cells with HER2 specific anti-tumor activity. Here we present an analysis of our immunologic testing of our prospective, randomized, single-blinded, phase II trial of the AE37+GMCSF vs. GMCSF alone for the prevention of breast cancer recurrence. Methods: After completion of indicated standard therapy; disease-free, node positive or high risk node negative breast cancer patients were randomized to receive either AE37+GMCSF (VG) or GMCSF (CG) in 6 monthly intradermal inoculations. Patients were enrolled with any level of HER2 expression (IHC 1+ 2+ or 3+). Specific immunologic responses to both AE36 and AE37 were evaluated. In vitro responses were measured using [3H]-thymidine incorporation assay and in vivo responses using delayed-type hypersensitivity (DTH) reactions. T regulatory cells (Tregs) were measured throughout vaccination series. Data was analyzed using Pearson chi-squared tests. Results: To date 217 patients have enrolled (VG=109, CG=108). HER2 over-expression was present in 54 (49.5%) VG and 51 (47.2%) CG, p=0.783. VG had 59 (51.4%) ER positive and CG had 58 (53.7%, p=0.985). The in vitro proliferation responses with a stimulation index (SI) ≥2 were classified as high responders VG 36 (33.0%) vs CG 8 (7.4%, p&lt;0.001), SI 1.5-2 were classified as low responders VG 19 (17.4%) vs CG 16 (14.8%, p=0.600) or SI &lt;1.5 as non responders VG 54(49.5%) vs CG 84(77.8%, p&lt;0.001). The in vivo DTH reactions measured in 149 (VG n=86, CG n=63) were stratified as responders with ≥5mm (VG 74(86.0%) vs CG 17(27.0%) p&lt;0.0001) or non responders with &lt;5mm (VG 12 (14.0%) vs CG 46(73.0%) p&lt;0.001). Tregs responses were measured in 107 patients (VG n=56, CG=51) and categorized according to percent change from pre-vaccination baseline as an increase &gt;110% (5(8.9%) VG vs 10 (19.6%) CG, p=0.112), no change 90-110% (10 (17.9%) VG vs 13 (25.5%) CG, p=0.337), or decrease &lt;90% (41 (73.2%) VG vs 28 (54.9%), p=0.048). Conclusion: VG patients had significant immunologic responses compared to CG. VG had a statistical decrease in Tregs compared to CG. Monitoring immunologic tests and Tregs throughout the vaccination process may stratify patients into responders and non responders and thus assist in identifying patients that will have recurrence.
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 LB-218. doi:1538-7445.AM2012-LB-218
Abstract LB-224: A randomized phase 2 study of two doses of itraconazole in men with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Antonarakis Emmanuel S. , Heath Elisabeth I. , Smith David C. , Rathkopf Dana , Blackford Amanda L. , Danila Daniel C. , King Serina , Frost Anja , Ajiboye A. Seun , Zhao Ming , Mendonca Janet , Kachhap Sushant K. , Rudek Michelle A. , Carducci Michael A. 
Published: August 2012

Abstract
BACKGROUND: The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling, and delays tumor growth in murine prostate cancer xenograft models. Unlike ketoconazole, it does not suppress androgen synthesis. METHODS: A phase 2 study of oral itraconazole in men with mCRPC was conducted at 4 sites. Men were randomized to low dose (LD) or high dose (HD) itraconazole (200 or 600 mg/day) until disease progression or unacceptable toxicity. The primary endpoint was PSA progression-free survival (PPFS) at 24 wk (PSA progression = 25% PSA rise above baseline/nadir); a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints were progression-free survival (PFS) at 24 wk (progression = clinical/radiographic progression or death, but not rising PSA); median PFS; median PPFS; and max PSA decline. Exploratory outcomes included CTC enumeration, analysis of adrenal androgens (serum testosterone and DHEA), VEGF analysis, and GLI1 expression in skin biopsy samples. RESULTS: The HD arm enrolled to completion (N=29), but the LD arm closed early (N=17) due to a prespecified futility analysis. Table 1 shows efficacy results. In addition, 3/5 men (60%) in the HD arm and 2/3 men (67%) in the LD arm with unfavorable (≥5) CTCs at baseline converted to favorable (&lt;5) CTC counts with treatment. Itraconazole did not reduce serum testosterone or DHEA levels. It had no effect on circulating VEGF levels. In skin biopsies, downmodulation of GLI1 was seen in 33% and 68% of men in the LD and HD arms, respectively. Median PPFS was superior in men who achieved GLI1 downmodulation compared to those who did not (P=.028). Toxicities with itraconazole included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia/hypertension/edema. CONCLUSIONS: Only the HD arm met its primary endpoint. Itraconazole 600 mg/day may have activity in men with mCRPC that is not mediated by androgen suppression, and may correlate with GLI1 downmodulation.
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 LB-224. doi:1538-7445.AM2012-LB-224
Abstract LB-23: Ras signaling interrupts TGF-beta-induced KLF5 acetylation to alter the KLF5-Smads transcriptional assembly in epithelial cells
Authors: Guo Peng , Xing Changsheng , Dong Xue-Yuan , Dong Jin-Tang 
Published: August 2012

Abstract
β (TGF-β) suppresses early stage tumorigenesis but promotes late stage tumor progression. While also presenting dual roles in tumorigenesis, KLF5 in the acetylated form is essential for TGF-β to properly regulate gene transcription in the inhibition of cell proliferation. The Ras oncogenic signaling not only converts TGF-β from a tumor suppressor to a tumor promoter but also uses KLF5 as a functional effector. One intriguing question is whether and how Ras signaling uses the KLF5 transcription factor to modulate TGF-β function. In this study, we addressed this question by examining whether and how Ras signaling alters TGF-β-induced KLF5 acetylation and the assembly of the p300-KLF5-Smads transcriptional complex in gene regulation. We found that Ras inhibited TGF-β-induced KLF5 acetylation and interfered with TGF-β in p15 induction and Myc repression. In addition, TGF-β-induced Smad3 phosphorylation at the C-terminal region was necessary for TGF-β to induce KLF5 acetylation, and Ras interrupted this phosphorylation. Ras signaling further interrupted the interactions among p300, KLF5 and Smad4, as well as the binding of the p300-KLF5-Smads complex onto the TGF-β-responsive promoter elements for both p15 and Myc. Without TGF-β, however, Ras signaling increased KLF5 acetylation, enhanced the p300-KLF5 interaction, and promoted the binding of the KLF5 transcriptional complex onto the TGF-β-responsive promoter elements. These findings suggest that KLF5 mediates the crosstalk between TGF-β and Ras signaling, and that suppression of TGF-β-induced KLF5 acetylation by Ras signaling alters TGF-β-induced assembly of p300-KLF5-Smads complex onto gene promoters, thus switching the function of TGF-β in gene regulation.
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 LB-23. doi:1538-7445.AM2012-LB-23
Abstract LB-239: ROCK1 inhibition reduces tumor collagen content in the KPC model for PDAC
Authors: Whatcott Clifford J. , Lobello Janine , Watanabe Aprill , Sepulveda Mario , Von Hoff Daniel D. , Han Haiyong 
Published: August 2012

Abstract
ROCK1 is a multifunctional member of the AGC (protein kinase A/G/C) kinase family that has been implicated in the modulation of stress-fiber assembly, cell contraction, apoptosis, and in the migration and invasion of multiple cancer cell types. It has been reported that ROCK1 plays an important role in the activation and function of pancreatic stellate cells, including in the formation of desmoplasia in pancreatic ductal adenocarcinoma (PDAC)(Masamune, 2003, Br J Pharmacol, 140:1292). Desmoplasia and its effects are thought to contribute to poor drug delivery in PDAC treatment. We therefore hypothesized that ROCK1 inhibition may reduce desmoplasia and enhance drug efficacy in PDAC treatment. We previously reported that ROCK1 is overexpressed in human pancreatic tumor cells and amplified in a small subset of PDAC patient samples. In this study we report that the ROCK inhibitor, fasudil, reduced collagen mRNA levels by 3.9-fold in cultured pancreatic stellate cells derived from PDAC tissues treated at 100µM. We also observed a 3.0-fold reduction in collagen protein expression in co-cultured tumor and stellate cells at the same concentration of fasudil. Similar reductions were observed in immunofluorescence analysis of co-cultured tumor and stellate cells treated with fasudil. We next sought to determine if ROCK1 inhibition would result in a reduction in collagen expression in the the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model for PDAC. KPC mice were treated orally, b.i.d., with 100mg/kg fasudil and by i.p. with gemcitabine (q3dx4) at 80mg/kg. Tumors in KPC mice treated with the combination of fasudil and gemcitabine showed a marked reduction in overall tumor collagen content when compared to vehicle-treated mice as measured by a pentachrome staining. Histochemical analysis of tumors also showed reductions in the overall proliferation of the pancreatic stellate cell compartment. Ongoing efforts are being made to assess whether this treatment regimen may enhance gemcitabine efficacy in the KPC mice. These results indicate that ROCK1 is a potential therapeutic target in pancreatic cancer, and may provide an effective means to enhance current treatment regimens.
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 LB-239. doi:1538-7445.AM2012-LB-239
Abstract LB-243: Cetuximab and Artesunate synergistically inhibit the invasion and distant metastasis of non-small cell lung cancer
Authors: Rasheed Suhail Ahmed , Mudduluru Giridhar , Patil Nitin , Leupold Jörg Hendrik , Effert Thomas , Allgayer Heike 
Published: August 2012

Abstract
Cancer is a complex disease and multi step process evolving from malfunctions of molecules and their complex networks which regulate this process. The blockage of the cancer signalling network is crucial in the cancer treatment. In some cases, single drug therapy might not be comprehensive enough to inhibit the activity of secondary signals, feedback regulations and resistance to particular molecules, due to their abundant expression or activity. An understanding of these complex phenomena in cancer therapy for the benefit of patients is essential, especially since it bears the chance to establish novel concepts of combination drug therapy. In the present study, we have tried to find a compound combination to overcome resistance towards Cetuximab, which blocks ligand binding to the epidermal growth factor receptor (EGFR), in non-small cell lung cancer (NSCLC). The anti-malarial drug Artesunate (ART) has been shown to have a profound cytotoxic action against cancer cell lines, and we recently showed its anti-metastatic action in NSCLC. Initial screening experiments in NSCLC cell lines showed that Cetuximab sensitivity is positively correlated with the E-cadherin expression, whereas ART sensitivity was negatively associated with EGFR expression. A549 (high E-cadherin and EGFR, sensitive to Cetuximab alone and not sensitive to ART alone) and H1299 (no E-cadherin and medium EGFR, resistant to Cetuximab alone and sensitive to ART alone) were chosen as model cell lines for this study. Cell proliferation and colony formation assays were performed either with Cetuximab/ART alone or with the combination of both. Interestingly, Cetuximab alone was not able to reduce cell proliferation and colony formation significantly in comparison to ART. In contrast to that combination of both of the drugs able to reduce these phenomena significantly even more than ART alone (p≤0.05). Combination isobologram analysis for ART and Cetuximab showed a significantly reduced proliferation rate in both the tested cell lines. In vivo, chorioallantoic membrane (CAM) metastasis assays revealed that combinatorial treatment of the cells with both drugs significantly reduced primary tumor growth of A549 (p=0.01) and H1299 (p=0.02) cells, in contrast to the treatment by Cetuximab alone. Our findings suggest that ART is resensitizing Cetuximab resistant NSCLC cells for treatment with this antibody. Currently, our study will be completed by experiments to identified major molecules and signalling cascades mediating compound interaction and re-sensitization.
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 LB-243. doi:1538-7445.AM2012-LB-243
Abstract LB-249: Characterization of a novel potent and selective CDK4/6 inhibitor and a resistance mechanism
Authors: Dai Kang , Li Cong , Liang Lingming , Rong Minqing , Orf Jessica , Keegan Kathy , Li Zhihong , Fu Jiasheng , Ma Ji , Carlson Tim , McGee Larry , Medina Julio , Kamb Alexander , Wickramasinghe Dineli 
Published: August 2012

Abstract
CDK4 and CDK6 are two highly related cyclin D-dependent cell cycle regulatory kinases. CDK4/6 activity promotes G1 to S phase transition by phosphorylating the retinoblastoma (Rb) tumor suppressor protein. Here, we report the characterization of a potent, selective and orally-available small molecule inhibitor of CDK4/6 for treating Rb-positive cancer. The inhibitor was over 1000-fold more potent in inhibiting CDK4 than CDK1. It also showed Rb-dependent anti-proliferative activity both in cancer cell lines and in xenograft tumor models. A greater degree of variation in sensitivity to the inhibitor was observed in colon cancer cell lines compared to the other cell lines tested. To understand this difference in sensitivity, we isolated CDK4/6 inhibitor-resistant colon cancer cells by growing sensitive cells in the presence of the inhibitor. Gene expression in the parental and the resistant cells was analyzed and compared. Cyclin E1, a CDK2 cyclin, was found to be the most significantly overexpressed gene in the resistant cells. Consistent with this, CDK2-associated cyclin E1 protein and CDK2 kinase activity were also significantly increased in the cells. These results suggest that high expression of cyclin E1 may make tumors less sensitive to CDK4/6 inhibition and could be a potential sensitivity marker for patient selection for treatment with a CDK4/6 inhibitor.
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 LB-249. doi:1538-7445.AM2012-LB-249
Abstract LB-251: Manipulation of macrophage phenotype enhances the apoptotic response to chemotherapy in mesothelioma
Authors: Broaddus V. Courtney , Battula Sailaja , Barbone Dario , Blakely Collin , Sugarbaker David J. , Bueno Raphael , Coussens Lisa M. 
Published: August 2012

Abstract
Macrophages within the tumor microenvironment (TME) may contribute to tumor chemoresistance. We have found that macrophages constitute a significant percentage of the infiltrating leukocytes in mesothelioma, a highly chemoresistant tumor. We asked whether reprogramming of macrophage phenotype from a Th2 (pro-tumor) to a Th1 (anti-tumor) phenotype would alter the mesothelioma chemoresponsiveness. To address this, we used 3D organotypic models of mesothelioma growth: 1) multicellular spheroids, with mesothelioma cells grown alone or co-cultured with macrophages derived from peripheral blood monocytes, and 2) primary tumor fragment spheroids derived from small fragments of freshly isolated human mesothelioma. Macrophages were incubated with Th1 (LPS & IFNγ) or Th2 (IL-4 &IL-13) cytokines prior to co-culture with mesothelioma spheroids, followed by exposure to standard-of-care chemotherapy, cisplatin plus pemetrexed. Gene expression was evaluated in macrophages to affirm Th1-type (TNF, IL-12, IFNα) versus Th2-type (CD206, IL10) programming. In both spheroid approaches, Th1-type macrophage programming significantly increased the apoptotic response of mesothelioma cells to chemotherapy. Moreover, when CSF1R signaling in macrophages was inhibited by incubation with a small molecular weight kinase antagonist, GW2850, chemoresponsiveness was significantly increased as evidenced by increased presence of apoptotic tumor cells in spheroids. Enhanced chemoresponsiveness of mesothelioma tumor cells was dependent on presence of macrophages because incubation of tumor cells with Th1-type cytokines or GW2850 in the absence of macrophages was without effect. We conclude that manipulating the TME may be a promising therapeutic approach in mesothelioma. This work was supported by a DOD Mesothelioma Program grant PR80717 to Broaddus and Coussens and a T32 Training Grant to Battula and Blakely.
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 LB-251. doi:1538-7445.AM2012-LB-251