bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2369: SOX11 promotes protective microenviromental nixes in agressive MCL
Authors: Amador Virginia 
Published: August 2015

Abstract
Mantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid neoplasms and althought MCL represents only a 5-10% of all non-Hodgkins lymphomas, the aggressive clinical evolution with short responses to treatment, frequent relapses and the poor response to current therapies of the MCL patients, makes this lymphoma one of the tumors most studied internationally. Recent clinical observations have identified some patients with a more indolent form of this disease that have a long survival even without the need for treatment. Gene expression profiling (GEP) studies have identified the aberrant expression of the transcription factor SOX11 in aggressive MCL and absent in MCL with an indolent outcome, other lymphomas or normal B-cells, suggesting that SOX11 might play a relevant pathogenic role in the development and progression of this tumor. We have recently demonstrated in experimental studies that SOX11 blocks the maturation of the MCL cells and promotes the growth and angiogenesis of these tumors confirming the clinical observations that SOX11 may play an important role in the aggressive behavior of MCL. We have now generated preliminary results suggesting that SOX11 may regulate the migration and adhesion of the tumor cells increasing tumor dissemination and homing to different tissues compartments, protective microenvironment niches, the proliferation of new vessels bringing nutrients to the tumor and modulating an immature cellular status with more stemness capacity and drugs resistance known as cancer stem cell status. The understanding of these mechanisms will provide new potential candidates for therapeutic interventions.
Citation Format: Virginia Amador. SOX11 promotes protective microenviromental nixes in agressive MCL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2369. doi:10.1158/1538-7445.AM2015-2369
Abstract 2382: Exploring the relationship between reelin signaling and breast cancer metastasis
Authors: Khialeeva Elvira , Chou Joan , Carpenter Ellen M. 
Published: August 2015

Abstract
We have investigated the role of reelin signaling in the progression of metastatic breast cancer. Reelin signaling serves to position neurons in the developing central nervous system, but functions of this signaling pathway in other tissues have not been studied until recently. Our laboratory discovered that the reelin pathway is an important regulator of mammary gland development. We showed that reelin and Dab1, the intracellular adaptor protein for reelin, are required for timely development and proper morphology of the mammary gland. We also found that normal mammary epithelial cells (MECs) can respond to exogenous reelin by slowing their migration rate. Since aberration of developmental pathways is often implicated in breast cancer progression, we studied the possible roles of the reelin pathway in this process. We found that reelin signaling pathway components are differentially expressed across a variety of human breast cancer cell lines. We also showed that mouse mammary carcinoma 4T1 cells do not respond to reelin by slowing their migration, likely through downregulation of Dab1 mRNA. Orthotopic injections of 4T1 cells into Balb/C mice are used to model stage IV triple negative breast cancer, and resulted in aggressive tumors that produced numerous metastases in the lungs by 4 weeks post-injection. In order to find whether reelin signaling functions in the tumor microenvironment, we injected 4T1 cells into mice that lack reelin or Dab1 (reeler and Dab1 mutant mice). We found that 4T1 tumor growth was delayed in reeler mutants, and we are currently in the process of assessing the metastatic burden in these mice. We did not see differences in tumor growth or metastatic lung colonization in Dab1 mutant mice. These results indicate that the reelin signaling pathway may promote tumor growth via Dab1-independent, non-canonical signaling events.
Citation Format: Elvira Khialeeva, Joan Chou, Ellen M. Carpenter. Exploring the relationship between reelin signaling and breast cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2382. doi:10.1158/1538-7445.AM2015-2382
Abstract 2384: CD151-integrin complexes suppress ovarian tumor growth by repressing slug-mediated emt and canonical wnt signaling
Authors: Yang Xiuwei H. 
Published: August 2015

Abstract
The majority of human ovarian cancer is diagnosed in the late, metastatic stages and is highly resistant to current chemotherapies. The molecular and cellular mechanisms underlying the malignancy of ovarian cancer remain poorly understood. We report a surprising functional link between CD151-α31 integrin complexes and the malignancy of serous ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in approximately 90% of metastatic lesions, while it remains detectable in &gt;40% of primary ovarian tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses with multiple ovarian cancer cell lines show that knocking down CD151 or α3β1 integrin markedly enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated upon CD151 removal. Knocking down Slug partially restores CD151-α3β1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of β-catenin and Axin-2 as well as resistance to the inhibition in β-catenin-dependent transcription complexes. Taken together, our study demonstrates that CD151-α3β1 integrin complexes suppress ovarian cancer malignancy by repressing Slug-mediated EMT and canonical Wnt signaling.
Citation Format: Xiuwei H. Yang. CD151-integrin complexes suppress ovarian tumor growth by repressing slug-mediated emt and canonical wnt signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2384. doi:10.1158/1538-7445.AM2015-2384
Abstract 2394: Cancer-associated fibroblasts in invasive lobular breast carcinoma
Authors: Boelens Mirjam C. , Wientjens Ellen , Schut Eva , Klarenbeek Sjoerd , de Visser Karin E. , Jonkers Jos 
Published: August 2015

Abstract
Cancer-associated fibroblasts (CAFs) can promote breast cancer progression and therapy response through paracrine and juxtacrine signaling pathways. CAFs are abundantly observed in especially the invasive lobular carcinoma (ILC) subtype of breast cancer. Surprisingly, there is nothing known about the function of these CAFs in ILC. Given the fact that human ILC is generally resistant to standard chemotherapy, we believe that the cause of this therapy resistance lies into the active crosstalk between CAFs and tumor cells leading to a more progressive and resistant phenotype. Therefore, we aim to discover the exact function of CAFs in ILC as well as their drugable targets.
In order to reliably study the role of CAFs in ILC, we generated a genetically engineered mouse model for ILC based on the tissue-specific loss of E-cadherin and PI3K signaling pathway activation, two hallmarks of human ILC. This clinically relevant mouse model spontaneously developed tumors that grow as typically invasive ‘indian files’ into a rigid extracellular matrix (ECM) that is very rich of CAFs. Uniquely, these tumors closely resemble human classical ILC, including its growth rate. Based on a mammary gland transplantation setting using fluorescent labeled hosts, we have shown that fibroblasts are recruited by ILC, both in vivo and in vitro, suggesting ILC-secreted mediators. Interestingly, in vitro inhibition of PDGFRβ (expressed by fibroblasts) can at least in part inhibit this recruitment. We are currently investigating whether inhibition of PDGFRβ in vivo can prevent the recruitment of fibroblasts and subsequently tumor development or progression. In parallel, we have isolated fibroblasts and epithelial cells from primary mouse ILCs and wild-type mammary glands to screen for other important players in the tumor-stroma crosstalk using RNA-seq and secretome proteomics. We will subsequently assess their functional significance during ILC development, progression and therapy response.
Citation Format: Mirjam C. Boelens, Ellen Wientjens, Eva Schut, Sjoerd Klarenbeek, Karin E. de Visser, Jos Jonkers. Cancer-associated fibroblasts in invasive lobular breast carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2394. doi:10.1158/1538-7445.AM2015-2394
Abstract 2403: Biopsy-free comprehensive tumor profiling of 1,000+ consecutive cancer patients using CLIA-certified commercial test and its clinical utility
Authors: Collisson Eric , Mortimer Stefanie , Sebisanovic Dragan , Mokhtari Reza , Bakhtiari Somayeh , Lopez Rene , Gadde Devi M. , Vidamo Maria M. , Patel Heena , Kermani Bahram G. , Eltoukhy Helmy , Lanman Richard B. , Talasaz AmirAli 
Published: August 2015

Abstract
Background: Genomic alterations of metastatic cancers may be discordant with alterations in primary tumors due to continuous evolution of disease and tumor heterogeneity. Current NGS approaches based on tissue biopsies can fail to capture a complete picture of the real-time cancer profile. Biopsy-free genomic profiling of circulating tumor DNA (ctDNA) can provide deep insights into the disease when biopsies are not an option.
Methods: We developed Guardant360 for comprehensive profiling of ctDNA with high sensitivity (detection in 90%+ of advanced cancer pts) and ultra-high specificity (&gt;99.9999%). Guardant360 has been validated to analyze a 69-oncogene panel covering over 120,000 bases and detects SNVs, gene amplifications, indels and genomic rearrangements, including all NCCN-guidelines recommended biomarkers. We previously reported high concordance of ctDNA profiles with concurrent matched biopsies.
Results: In our first 1,000 clinical tests (77% across breast, colorectal and lung and 23% distributed over many other indications), we successfully processed 99.8% of samples. In 3 cases, we canceled the test as we detected secondary genome carry-over (confirmed to be pregnancy or liver transplant cases). Despite the wider range of clinical stages in commercial samples, we detected ctDNA in 78%. Additionally, we identified actionable mutations with associated treatments in 74% of those cases. Clinical benefit of the test was shown in many patients. Examples: A refractory IBC patient with Her2 status change, showed strong response to Her2 TKI. Patients with quantity-not-sufficient biopsy sequencing, showed strong actionable alterations (ERBB2 amplification, BRAF mutation, EGFR activating and resistance mutations, etc)
Conclusion: Comprehensive sequencing of a patient's cancer in real -time through a simple blood test can empower oncologists to make better informed treatment decisions, especially when repeat tissue biopsy is not a desirable or viable option.
Citation Format: Eric Collisson, Stefanie Mortimer, Dragan Sebisanovic, Reza Mokhtari, Somayeh Bakhtiari, Rene Lopez, Devi M. Gadde, Maria M. Vidamo, Heena Patel, Bahram G. Kermani, Helmy Eltoukhy, Richard B. Lanman, AmirAli Talasaz. Biopsy-free comprehensive tumor profiling of 1,000+ consecutive cancer patients using CLIA-certified commercial test and its clinical utility. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2403. doi:10.1158/1538-7445.AM2015-2403
Abstract 2409: Ultrasensitive detection of genomic alterations in cell-free DNA by Droplet Digital PCR
Authors: Tam Nga Wan Rachel , Sumiyoshi Teiko , Patel Rajesh , Sarma Sundari , Kiermaier Astrid , Raja Rajiv 
Published: August 2015

Abstract
As cancer cells die, they release small pieces of DNA into the bloodstream. These molecules of DNA are called circulating tumor DNA (ctDNA). ctDNA carry somatic aberrations that are found in the originating tumor tissue and can serve as excellent biomarkers. They can be extremely valuable as tools for disease monitoring, and samples for predictive and prognostic biomarkers. However, limited quality and quantity of formalin-fixed paraffin-embedded (FFPE) tissues and circulating cell-free DNA (cfDNA) samples available from patients pose a big challenge to performing DNA quantification, mutation profiling and copy number variation analysis.
We explored the feasibility of using Droplet Digital PCR (ddPCR) technology to address this challenge. Using ddPCR, we studied the ability to perform high-sensitivity mutation analysis and accurate quantification of allele frequencies, and compared this approach to alternate methods such as next-generation sequencing (NGS). For mutation profiling, we examined a total of 22 mutation detection ddPCR assays across 7 oncogenes - KRAS, PIK3CA, EGFR, BRAF, NRAS, cKIT and AKT1. The assay sensitivity for the majority of mutation detection assays was found to be approximately 0.03%. We have identified/reconfirmed various mutations using matching FFPE/plasma samples from patients in various cancer types. Moreover, we have adapted the previously published HER2 CNV ddPCR assay to detect HER2 copy number variation in cfDNA.
We will present data showing validation of this platform using commercially available DNA control, archival FFPE tissue and cfDNA samples and demonstrate improved sensitivity and specificity. The platform is being routinely used in our labs to analyze samples from multiple clinical trials. These efforts enable the development of a non-invasive method to overcome existing challenges to provide molecular understanding of patient's tumor evolution, and aid in the development of personalized therapies for cancer patients.
Citation Format: Nga Wan Rachel Tam, Teiko Sumiyoshi, Rajesh Patel, Sundari Sarma, Astrid Kiermaier, Rajiv Raja. Ultrasensitive detection of genomic alterations in cell-free DNA by Droplet Digital PCR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2409. doi:10.1158/1538-7445.AM2015-2409
Abstract 2411: Non-invasive analysis for T790M mutations of EGFR using a selective amplification method
Authors: Nishikawa Shingo , Kimura Hideharu , Koba Hayato , Yoneda Taro , Sone Takashi , Booth Chris , Webb Andrew , Kasahara Kazuo 
Published: August 2015

Abstract
Epidermal growth factor receptor (EGFR) T790M mutation is associated with EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance in non-small cell lung cancer (NSCLC). However, tissue availability limits the genotyping of EGFR T790M mutation in a clinical setting. The aims of this study are to develop a blood-based, non-invasive approach to detecting the EGFRT790M mutation in advanced NSCLC patients, using PointMan™ EGFR DNA Enrichment Kit, which is a novel method for selective amplification of genotype specific sequences.
Methods: Blood samples were collected from NSCLC patients with activating EGFR mutations, who were resistant to EGFR-TKIs treatment. EGFR T790M mutations in plasma DNA were detected using the kit. The concentrations of plasma DNA were determined using quantitative real-time PCR.
Results: 21 (87.5%) of the patients had EGFR T790M mutations in their plasma DNA as detected using the kit. In all 6 cases detected T790M mutations from tumor tissues, the T790M mutations ware detected also in plasma DNA. The concentrations of plasma DNA were higher in patients with T790M mutations than without the mutations.
Conclusions: The PointMan™ is an easily and useful method for determining the plasma EGFR T790M mutation status.
Citation Format: Shingo Nishikawa, Hideharu Kimura, Hayato Koba, Taro Yoneda, Takashi Sone, Chris Booth, Andrew Webb, Kazuo Kasahara. Non-invasive analysis for T790M mutations of EGFR using a selective amplification method. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2411. doi:10.1158/1538-7445.AM2015-2411
Abstract 243: Expression of T-cell checkpoint ligands on circulating tumor cells is modulated following treatment of patients with an anti-tumor DNA vaccine
Authors: Rekoske Brian T. , Olson Brian M. , McNeel Douglas G. 
Published: August 2015

Abstract
Background: We have previously demonstrated in a murine tumor model that treatment with a DNA vaccine could lead to increased PD-1 expression on antigen-specific CD8+ T cells, led to upregulated levels of PD-L1 on tumors, and that the anti-tumor efficacy of the vaccine was enhanced when combined with PD-1/L1 blockade. We therefore examined whether prostate cancer patients previously treated with a DNA vaccine similarly upregulated these immunosuppresive ligands on their tumor cells, or the corresponding receptors on tumor-specific CD8+ T cells, and if augmented Th1-type immune responses were detectable following in vitro stimulation with checkpoint blockade.
Methods: Circulating tumor cells (CTCs, CD45-/EpCAM+) from 16 prostate cancer patients with castrate-resistant disease, and antigen-specific (tetramer+) CD8+ T cells from those patients that were HLA-A2+ (6/16), were analyzed for their expression of various checkpoint ligands (PD-L1, galectin-9, HVEM) or receptors (PD-1, TIM-3, LAG-3, BTLA, CD160) using flow cytometry before and after treatment with a DNA vaccine encoding prostatic acid phosphatase (PAP). Immune responses to the PAP target antigen were measured in vitro for cytokine secretion via ELISA, or by a trans-vivo DTH-footpad assay, in the presence or absence of PD-1/L1 blockade.
Results: Patients that developed either long-term immune responses or changes in PSA doubling time following vaccination had significantly higher levels of PD-L1 and HVEM, and lower levels of galectin-9, on their post-treatment CTCs than patients who did not develop responses. No significant changes in PD-1 or other regulatory receptors were detectable on tetramer+ CD8+ T cells. However, at least 25% of patients following immunization had augmented PAP-specific cytokine secretion in vitro when combined with PD-L1 blockade. PD-1 regulated PAP-specific responses were also observed in patients using the trans vivo DTH assay.
Conclusions: These results demonstrate that the development of an anti-tumor immune response via DNA vaccination can lead to changes in checkpoint ligand expression on tumor cells and checkpoint-regulated immune responses. This suggests that combining DNA vaccines with blockade of one or more of these checkpoint pathways could produce enhanced anti-tumor responses in patients with prostate cancer.
Citation Format: Brian T. Rekoske, Brian M. Olson, Douglas G. McNeel. Expression of T-cell checkpoint ligands on circulating tumor cells is modulated following treatment of patients with an anti-tumor DNA vaccine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 243. doi:10.1158/1538-7445.AM2015-243
Abstract 2434: The anticancer activity of Japonicone A is mediated by inhibiting NFAT1-MDM2 pathway
Authors: Voruganti Sukesh , Qin Jiang-Jiang , Wang Wei , Zhang Ruiwen 
Published: August 2015

Abstract
NFAT1 plays a crucial role in cancer development and progression and has been suggested as a novel target for cancer therapy. We recently report NFAT1 promotes the expression of the MDM2 oncogene, independent of p53. The present study was designed to elucidate the mechanisms of action for a newly identified NFAT1 inhibitor, Japonicone A (JapA), and demonstrate the value of targeting NFAT1-MDM2 signaling in cancer therapy. JapA was identified as a novel NFAT1 inhibitor from our initial screening of a natural product library. Its effects on NFAT1 expression and stability were analyzed in several human breast cancer cell lines with different genetic background, including MCF-7 (estrogen receptor (ER) positive and p53 wild-type), MCF-7 p53−/− (ER positive and p53 knockout), MDA-MB-231 (triple negative and p53 mutant), and MDA-MB-468 (triple negative and p53 mutant) cell lines. The effects of JapA on NFAT1 expression were also determined in MCF-7 and MDA-MB-231 xenograft tumors in vivo. To further demonstrate the specificity of JapA in targeting NFAT1-MDM2 pathway and the importance of NFAT1-MDM2 inhibition in JapA's anticancer activity, MCF7 NFAT1 overexpression (OE) and knockdown (KD) cell lines, as well as pharmacological activators and inhibitors of NFAT1 signaling were used in this study. Our results indicated that JapA showed a significant, specific inhibition of NFAT1 in breast cancer cells in vitro and in vivo. It induced NFAT1 protein ubiquitination and proteasomal degradation, and inhibited NFAT1 nuclear translocation. JapA also disrupted the binding of NFAT1 to the MDM2 P2 promoter, leading to the inhibition of MDM2 transcription. Furthermore, the inhibition of NFAT1 and the NFAT1-MDM2 signaling are critical for JapA's anticancer activity, as shown in NFAT1 OE and KD cell lines. In conclusion, JapA represents a new class of NFAT1 inhibitor. It exerts its anticancer activity through inhibiting NFAT1 and the NFAT1-MDM2 pathway, providing evidence for the value of NFAT1 as a novel target in developing effective targeted therapy for cancers. (Supported by NIH R01 CA112029, R01 CA121211, and R01 CA186662)
Citation Format: Sukesh Voruganti, Jiang-Jiang Qin, Wei Wang, Ruiwen Zhang. The anticancer activity of Japonicone A is mediated by inhibiting NFAT1-MDM2 pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2434. doi:10.1158/1538-7445.AM2015-2434