bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1386: Predictive markers of efficacy for an angiopoietin-2 targeting therapeutic in xenograft models
Authors: Triana-Baltzer Gallen B. , Pavlicek Adam , Goulart Ariadne , Huang Hanhua , Woodnutt Gary , Levin Nancy 
Published: August 2012

Abstract
The clinical efficacy of anti-angiogenic therapies has been difficult to predict, and in this era of personalized medicine biomarkers that can predict effect are sorely needed. CVX-060 is an angiopoietin-2 (Ang2) targeting therapeutic, consisting of two peptides that bind Ang2 with high affinity and specificity, covalently fused to a scaffold antibody. The resulting therapeutic has shown promising activity in a phase 1 clinical trial, with several phase 2 clinical programs in progress/planning. In order to optimize the use of this compound in the clinic a set of predictive biomarkers are desired. Here we describe the construction of a predictive model based on the efficacy of CVX-060 in 13 conventional xenograft models, focusing on renal and ovarian cancer. Pretreatment size tumors from each of the models were profiled for the levels of ∼25 protein markers of angiogenesis, SNP haplotype in 5 angiogenesis genes, and somatic mutation status for ∼12 genes implicated in tumor growth and/or vascularization. The markers chosen for evaluation were accumulated from angiogenesis literature and a differential gene expression analysis of CVX-060 treatment-induced changes. CVX-060 efficacy was determined as tumor growth inhibition (TGI%) at termination of each study. A predictive statistical model was constructed based on the correlation of these efficacy data with the marker profiles, and the model was subsequently tested via prospective analysis in 7 additional models The results of this work reveal a range of CVX-060 efficacy in xenograft models of diverse tissue types (0-49% TGI, median = 38%). Notably, we define a subset of 5-7 proteins, the levels of which are predictive of TGI by Ang2 blockade. The majority of these proteins are proximal to the target of CVX-060 and the direction of the associations is such that better efficacy correlates with high levels of target and low levels of compensatory/antagonizing molecules. The SNPs and somatic mutations examined here did not correlate with TGI. Our study describes a systematic approach to the problem of identifying predictive markers of anti-angiogenic affect, and demonstrates the significant ground work necessary to reveal treatment-sensitive predictive markers which can be quantitatively defined. This effort has revealed a set of predictive markers for CVX-060 efficacy that will be further evaluated in ongoing clinical trials.
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 1386. doi:1538-7445.AM2012-1386
Abstract 1395: Docetaxel pretreatment is associated with increased incidence of CNS-metastases in a murine model of HER2-positive breast cancer
Authors: Mischo Axel , Harter Patrick , Mueller Klaus , Kleber Sascha , Zachskorn Cornelia , Renner Christoph , Steeg Patricia S. , Mittelbronn Michel , Pestalozzi Bernhard C. 
Published: August 2012

Abstract
Breast cancer is the most frequent neoplasm in females as it affects 1:10 women. In populations of early breast cancer subsequent brain metastases develop in 5%, while in metastatic breast cancer (mBC), the incidence of CNS-metastases reaches 10-16% [Ann Oncol 2006; 17:935]. The incidence is particularly high (30%-50%) in patients (pts) with HER2-positive mBC [Ann Oncol 2008; 19:1837]. Similarly, the incidence of CNS-metastases is high in pts treated with taxanes for mBC [Ann Oncol 2001; 12:353]. Therefore, we aimed to investigate the role of taxanes on CNS metastases in a murine breast cancer model using the MDA-MB-231BR cell line which has a tropism to metastasize into the CNS upon intracardiac injection [J Natl Ca Inst 2008;100:1092]. Groups of Balb/c nude mice were injected intravenously with docetaxel at a dose of 10mg/kg every 2 weeks for 5 injections (long tax, N=17) or with only 2 similar injections (short tax, N=16) or no injection (control, N=14). Two weeks later MDA-MB-231 BR tumor cells (500′000 cells in 0.1mL PBS) were injected into the left ventricle. Four weeks after that, animals were sacrificed for collection of organs and analysis by histology. The main finding was that metastatic foci were significantly increased in long-tax mice (median number of foci 52, range 0-76) compared to control mice (median number of foci 20, range 0-52; p=0.015). In short-tax animals an intermediate incidence of foci was found (median 30, range 0-79), with a trend, but not a significant difference compared to untreated animals (p=0.7) Histologically we observed a mainly perivascular intraparenchymal infiltration pattern while superficial metastases or a spread to the cerebrospinal fluid was only rarely seen. We therefore assessed changes of the blood-brain barrier (BBB) by ultrastructural approaches. However, we have not found obvious differences in the BBB configuration after taxane treatment. In summary, our results provide evidence that taxane treatment might facilitate spread of breast cancer cells into the CNS, however underlying mechanisms remain to be determined.
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 1395. doi:1538-7445.AM2012-1395
Abstract 1411: Calcium-depending formation of bone metastases in patients with renal cell carcinoma
Authors: Schneider Elke , Roos Frederik , Hampel Christian , Thüroff Joachim W. , Brenner Walburgis 
Published: August 2012

Abstract
Introduction: Although a number of molecules have been implicated in the process of formation of cancer metastases, the organ-selective nature of cancer cells is still poorly understood. Renal cell carcinoma (RCC) often metastasize into bones, a calcium enriched tissue. We analyzed the influence of the calcium sensing receptor (CaSR) in RCC and an enhanced extracellular calcium concentration in processes of metastatic spread. Material and Methods: In 33 matched RCC specimens, 11 non-metastasized, 11 metastasized into the lung and 11 metastasized into bones five years after nephrectomy, CaSR was quantified by RT-PCR and Western blot analyses. To investigate the influence of enhanced extracellular calcium on the formation of metastases, primary RCC cells were isolated from patients developing bone, lung and no metastasis five years after nephrectomy (each 3 cell lines). Cell proliferation after calcium treatment (2.5, 5 and 10 µM) was quantified by BrdU incorporation. Cell migration was determined in a Boyden chemotaxis assay with calcium as chemotactical agent (10 µM). Expression and activity of intracellular signal transduction mediators were analyzed by a human phospho kinase array and Western blot analyses. Results: Compared to non-metastasizing RCC, CaSR mRNA expression was 10.8-fold increased and CaSR protein level was 1.5-fold increased in tumor specimens of patients developing bone metastases. In primary RCC cells with a high bone metastastic potential CaSR expression was 3.7-fold higher compared to non-metastasizing RCC cells. Calcium treatment of bone-metastasizing RCC cells, but not of non-metastasizing cells, induced a concentration dependent enhancement of proliferation. In a Boyden chamber experiment with calcium as chemo attractant, RCC cells from patients with bone metastases showed a 9.4-fold higher migratory potential compared to cells from patients without metastases. In lung metastatic RCC cells migration was only 1.7-fold enhanced. The enhanced proliferation and migration of cells with high potential to build bone metastases seem to be caused by an activation of Akt and a highly increased integrin alpha 5 expression. Additionally, the tumor suppressor PTEN was markedly reduced in tumors metastasizing into bones and after calcium treatment, promoting tumor progression. Conclusion: Our results indicate that formation of bone metastases of RCC is caused by an enhanced expression of the CaSR. Extracellular calcium has a promoting effect on cell migration and proliferation of bone metastasizing RCC cells via Akt signalling and integrin alpha 5.
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 1411. doi:1538-7445.AM2012-1411
Abstract 1412: Progesterone and calcitriol attenuate inflammatory cytokines CXCL1 and -2 in endometrial and ovarian cancer cells
Authors: Kavandi Leyla , Collier Michael A. , Nguyen Huyen , Syed Viqar 
Published: August 2012

Abstract
Chronic inflammation has been shown to play a critical role in growth of cancers. NF-κB is a transcriptional factor that regulates diverse biological processes, including cell proliferation, survival and inflammation. We have previously shown inhibition of endometrial and ovarian cancer cell growth with progesterone and calcitriol. In the present study, we evaluated the effect of progesterone and calcitriol on the expression of inflammatory genes. Using RT-PCR array of inflammatory cytokine and receptor genes, we found two inflammatory cytokines, CXCL1 and -2 (GRO-A and -B), downregulated by both treatments. PCR array results were validated by Western blotting. Knockdown of NF-kB resulted in a reduced expression of CXCL1 and -2 and the inhibitory effect of progesterone and calcitriol on the expression of cytokines was abrogated in NF-kB-silenced cancer cells. Silencing of IkBα increased the expression of CXCL1 and -2 in cancer cells, which can be attributed to the increased activation of NF-kB-p65, caused by the lack of its inhibitor. Progesterone and calcitriol-induced inhibition was abolished in IkBα-knockdown cells. Our results demonstrate that suppression of IkBα phosphorylation by progesterone and calcitriol contributes to the reduced expression of CXCL1 and -2. We investigated the effect of CXCL1 and -2 downregulation on metastasis-promoting genes and found a marked inhibition of CXCR4, COX2 and matrix metalloproteinases (MMP2 and MPP-9). Overall, our results indicate that progesterone and calcitriol downregulate NF-kB in cancer cells, leading to the suppression of metastasis, thus providing the molecular basis for the treatment of endometrial and ovarian cancer patients with progesterone and calcitriol.
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 1412. doi:1538-7445.AM2012-1412
Abstract 1414: Regulation of tumor cell trafficking by chromogranin A
Authors: Dondossola Eleonora , Crippa Luca , Colombo Barbara , Ferrero Elisabetta , Corti Angelo 
Published: August 2012

Abstract
Chromogranin A (CgA) is an acidic glycoprotein present within secretory vesicles of many normal and neoplastic endocrine and neuroendocrine cells. CgA is abnormally released in circulation in patients with neuroendocrine and non neuroendocrine tumors, as in a subpopulation of patients with non small cell lung cancer (NSCLC), with important prognostic implications. We have previously demonstrated that CgA can preserve the barrier function of the vascular endothelium. This prompted us to investigate the role of circulating CgA on metastasis development and tumor self-seeding, the ability of tumor cells to re-infiltrate their tumor of origin. Using mouse mammary adenocarcinoma models we observed that CgA inhibits both tumor self-seeding and organ colonization. Studies of the mechanism of action showed that CgA can inhibit the shedding of cancer cells in circulation from primary tumors, the re-infiltration of tumors and the colonization of lungs by circulating tumor cells. Pharmacological modulation of CgA further affected the development of lung colonies by tumor cells. We obtained evidences to suggest that CgA can inhibit the transendothelial migration of cancer cells, by preserving the VE-cadherin-dependent endothelial barrier function. These findings point to a role of circulating CgA as a regulator of tumor cell trafficking from tumor-to-blood and from blood-to-tumor/normal tissues. Inhibition of the multidirectional trafficking of cancer cells in normal and neoplastic tissues may represent a novel strategy to reduce cancer progression.
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 1414. doi:1538-7445.AM2012-1414
Abstract 1415: Anti-metastatic properties of tumor-entrained neutrophils
Authors: Granot Zvi , Henke Erik , Comen Elizabeth A. , King Tari A. , Norton Larry , Benezra Robert 
Published: August 2012

Abstract
Metastasis represents the final stage in cancer progression and is the primary cause of cancer related mortality. Disseminated cells that are capable of colonizing distant organs and forming metastases therefore present an important therapeutic challenge. In recent years, primary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow derived cells (BMDCs). Here, using mouse models of breast cancer, we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells. In contrast to other BMDCs that promote metastatic colonization, tumor-entrained neutrophils (TENs), but not control neutrophils, inhibit seeding of metastatic tumor cells in the lungs. TENs protect the pre-metastatic lung by initiating physical contact, generating H2O2 and killing tumor cells. While tumor secreted CCL2 has a pro-tumorigenic effect at the primary site, our data show that it is both required and sufficient for optimal anti-metastatic entrainment at the metastatic site. As tumor-secreted TGFβ blocks cytotoxicity at the primary site, TENs cytotoxicity is limited to the pre-metastatic site where TGFβ levels are low. Additionally, we find that TENs are also present in the peripheral blood of human breast cancer patients prior to surgical resection but not in healthy individuals. Several chemokines known to be increased in the circulation of breast cancer patients have the capacity to induce a cytotoxic phenotype in naïve human neutrophils, providing a possible mechanism for neutrophil entrainment in cancer patients. Taken together, our data show that while tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site.
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 1415. doi:1538-7445.AM2012-1415
Abstract 1567: mTERT genetic vaccine chemotherapy combination augment antigen-specific immune response and confer tumor protection in time dependent fashion
Authors: Ugel Stefano , Facciaponte John , Scarselli Elisa , Mennuni Carmela , Monica Nicla La , Coukos George , Facciabene Andrea 
Published: August 2012

Abstract
Successful cancer chemotherapy relies on the comprehensive elimination of tumor cells. However, at clinically tolerated doses, chemotherapeutic drugs usually fail to kill all tumor cells in vivo. Theoretically, to achieve complete eradication, partial tumor killing by chemotherapy should be accompanied by a “bystander effect” in which the immune system recognizes, attacks, and eradicates residual tumor cells. Doxorubicin) is an anthracycline antibiotic that intercalates with DNA, inhibiting its replication. It has been shown that treatment of dendritic cells with Doxorubicin increases their ability to present antigen to Ag-specific T cells in vitro and it is accompanied by upregulation of the Ag-processing machinery (APM) proteins and costimulatory molecules. The telomerase reverse transcriptase, TERT, is an attractive target antigen for cancer vaccine because its expression is reactivated in a conspicuous fraction of human tumors. Critical to the success of combination therapy using TERT vaccine and chemotherapy drugs is a positive (synergistic) interaction between chemotherapy drugs and immune effectors mechanisms. Indeed, activation of antitumor immune responses by vaccine could be antagonized by chemotherapy, if the selected drug exerts immune antagonistic effects. Understanding the dose and the schedule of administration of Doxil (pegylated Doxorubicin) is critical for the design of rational combinations of vaccine and chemotherapy. To test the interactions between TERT vaccine and Doxil we performed a series of experiment using six different therapeutic schedules of Doxil/TERT administration. Interestingly, only two of the Doxil/TERT vaccine combinations resulted in a significant tumor growth inhibition delay which was also accompanied by increase in anti-TERT T cell response. This data unveil new facets of “Chemo immune adjuvancy” of Doxorubicin, and demonstrate how the in vivo efficacy of this combination is impacted by the dosing schedule
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 1567. doi:1538-7445.AM2012-1567
Abstract 1596: Effect of combined treatment with ursolic acid (UA) and resveratrol (Res) on skin tumor promotion by TPA
Authors: Cho Jiyoon , Rho Okkyung , Carbajal Steve , Junco Jacob , Slaga Thomas J. , DiGiovanni John 
Published: August 2012

Abstract
In recent years, emerging evidence suggests that cancer chemopreventive agents when combined might be more effective than when given alone. Both UA and Res have been shown to reduce inflammation and tumor development in various tissues. In mouse skin, both compounds have been shown to block skin tumor promotion by TPA and reduce TPA-induced inflammation. In this study, we have further evaluated the effect of UA and Res on skin tumor promotion with emphasis on examining combinations of these agents. For these experiments, UA, Res and combinations of UA + Res were applied topically (various doses) prior to TPA treatment on mouse skin. The combination of UA + Res showed additive and possibly synergistic inhibition of TPA-induced epidermal hyperproliferation as assessed by both epidermal hyperplasia and BrdU labeling index. The effect of UA, Res and the combination of UA + Res on epidermal signaling pathways was also evaluated. The combination of UA + Res significantly inhibited activation of epidermal Akt, NF-κB, p38 MAPK, and JNK in response to TPA treatment compared to the treatment with the individual compounds. The combination of UA + Res also dramatically reduced the induction of epidermal Cox-2 by TPA. Notably, combined treatment with UA and Res induced a dramatic increased phosphorylation of AMPK-α suggesting that AMPK activation may also play a critical role in the ability of the combination to alter skin tumor promotion. Combination treatment during skin tumor promotion showed greater inhibition of tumor multiplicity than with either agent alone. In further experiments, the effect of UA, Res and UA + Res on proliferation of bulge-region keratinocyte stem cells (KSCs) was evaluated. Both UA and Res treatment inhibited TPA-induced proliferation and migration of bulge-region KSCs. Furthermore, the combination of UA + Res appeared to be more effective at blocking proliferation of these cells from the hair follicle when compared with the single compound-treated groups. Taken together, these data suggest that the combination of UA + Res has either additive or synergistic inhibitory effects on keratinocyte proliferation (including KSCs) and various signaling pathways. These effects may explain the greater inhibition of skin tumor promotion by the combination of UA and Res.
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 1596. doi:1538-7445.AM2012-1596
Abstract 1677: Associations between cigarette smoking with incident colorectal cancer by p53 protein expression in a population-based cohort of older women
Authors: Tillmans Lori , Vierkant Robert , Wang Alice , Samadder N. Jewel , Lynch Charles , Anderson Kristin , French Amy , Haile Robert , Harnack Lisa , Potter John , Slager Susan , Smyrk Thomas , Thibodeau Stephen , Cerhan James , Limburg Paul 
Published: August 2012

Abstract
Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53 protein, encoded by the TP53 tumor suppressor gene that is commonly mutated in CRC, is important in cell cycle arrest needed to repair DNA damage or induce apoptosis to prevent tumor propagation. In this prospective cohort study, we examined CS-associated CRC risks by p53 protein expression level in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (never, current, former), average number of cigarettes per day (1-19, 20-39, &gt; 40) and cumulative pack-years (1-19, 20-39, &gt; 40). P53 protein expression was determined by immunohistochemistry on tissue microarrays. Tumor cores were scored by combining both staining intensity and percent of cells stained to determine negative, low or high p53 protein expression levels. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Of the 732 available CRC cases, 486 (66%) had complete CS and p53 data. Associations between CS and CRC subtypes defined by p53 expression level are shown in the Table. Conclusions: These data demonstrate no clear heterogeneity of CS with CRC subtypes defined by p53 expression levels among older women.

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 1677. doi:1538-7445.AM2012-1677