tbuckley/cabot-search huggingface dataset:
Abstract 2184: Development and testing of nanoformulation of a vascular disrupting agent in rat glioma with MRI monitoring
Authors: Meser M. Ali, Sunalee Jayasundara, James R. Ewing
Journal: Cancer Research (2017)

Abstract Anti-angiogenesis therapy VEGF-VEGF receptors (VEGFRs) axis alone or in combination with other therapeutic agents have demonstrated mixed results, with the majority of reports indicating that glioblastoma multiform (GBM) developed resistance against anti-angiogenesis therapy as well as small molecular receptor tyrosine kinase inhibitors. This result is perhaps not unexpected, because angiogenesis is obviously complex, involving dozen of different growth factors that trigger a cascade of subsequent events. Even if a drug effectively blocks one angiogenic growth factor, such as VEGF, blood vessels may still develop via activating alternative pathways. Yet without a sufficient blood supply, cancerous tumors can't grow larger than the head of a pin and are unlikely to become lethal. Therefore, tumor vascularization is a critical process that determines tumor growth, progression and metastasis. Thus, tumor vasculature has become an emerging target for new chemotherapeutic drugs Vascular disrupting agents (VDAs) for example, combretastatin (CA4), represent a new class of chemotherapeutic agent that targets the newly formed vasculature in solid tumors. Preclinical and early phase trials have demonstrated the promising therapeutic benefits of CA4. Nevertheless, the clinical translation of CA4 has been significantly hampered due to its poor systemic bioavailability and the non-specific distribution of CA4 throughout the body when administered intravenously. Thus, it is reasonable to explore novel formulations of CA4 that overcome the limitations mentioned above. To improve bioavailability combretastatin phosphate (CA4-P) has been synthesized. But, CA4-P showed short blood half life. We have engineered dendrimer-based nano-sized CA4 conjugate which demonstrates high water solubility. Preliminary intravenous (i.v.) delivery of nano-combretastatin in an orthotropic glioma model demonstrated a necrosis at the core of the tumor leaving a rim of viable tissue. The MRI-determined tissue parameters Ktrans, blood flow (CBF), DWI, ADC map, distribution volume and tumor size indicated the effectiveness of nano-combretastatin treatment. Citation Format: Meser M. Ali, Sunalee Jayasundara, James R. Ewing. Development and testing of nanoformulation of a vascular disrupting agent in rat glioma with MRI monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2184. doi:10.1158/1538-7445.AM2017-2184
Abstract 4172: Activation of AR signaling by mifepristone enhances prostate cancer growth and impairs enzalutamide response
Authors: Haiying Zhou, Nadine Jachan, Mallika Singh, Chris Tran, Dan McWeeney, Minna Balbas, Emily Schenkein, Tatiana Zovorotinskaya, Erica L. Jackson, Julio Medina, Daqing Sun, Yosup Rew, Xiaohui Du, John Eksterowicz, Xuelei Yan, Liusheng Zhu, Qiuping Ye, Valeria Fantin
Journal: Cancer Research (2017)

Abstract Androgen receptor (AR) signaling is crucial for normal development and homeostasis of the prostate, and is a key driver of prostate cancer initiation and progression. Hormone therapies that deprive the cancer of androgen have long been a mainstay of prostate cancer treatment. More recently, anti-androgens, such as abiraterone and enzalutamide, have been approved for use in metastatic castration resistant prostate cancer (mCRPC). Evidence also suggests that AR may play an oncogenic role in certain breast cancers. Several recent publications have demonstrated that activation of the Glucocorticoid Receptor (GR) can confer resistance to enzalutamide, and GR has also been shown to provide protection from conventional chemotherapies in other solid tumor indications. Mifepristone, is a synthetic steroidal antagonist of progesterone receptor, and to a lesser extent of GR and AR. It is currently being tested in clinical trials in combination with enzalutamide in mCRPC, and in combination with chemotherapy in triple negative breast cancer (TNBC). We sought to characterize the effect of mifepristone in pre-clinical models of prostate and breast cancer. Here we show that in the absence of androgen, mifepristone acts as a partial AR agonist, and this agonism can only be partially overcome by enzalutamide. We find that in low androgen conditions, mifepristone promotes the growth of prostate cancer cells in vitro and accelerates the growth of prostate tumors in xenograft models. Moreover, when given in combination, mifepristone significantly reduces the efficacy of enzalutamide in the LN-AR xenograft model. We are currently assessing the effects of mifepristone treatment in TNBC. Our findings suggest that partial AR agonist activity of mifepristone may have a negative impact in prostate and other AR positive cancers. We have developed a GR antagonist that is devoid of AR agonism to circumvent undesired effects on proliferation and drug response. Citation Format: Haiying Zhou, Nadine Jachan, Mallika Singh, Chris Tran, Dan McWeeney, Minna Balbas, Emily Schenkein, Tatiana Zovorotinskaya, Erica L. Jackson, Julio Medina, Daqing Sun, Yosup Rew, Xiaohui Du, John Eksterowicz, Xuelei Yan, Liusheng Zhu, Qiuping Ye, Valeria Fantin. Activation of AR signaling by mifepristone enhances prostate cancer growth and impairs enzalutamide response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4172. doi:10.1158/1538-7445.AM2017-4172
Abstract 4655: Elevated level of serum miR-99a is correlated with serous epithelial ovarian cancer and can be a potential biomarker
Authors: Akihiko Yoshimura, Kenjiro Sawada, Koji Nakamura, Yasuto Kinose, Erika Nakatsuka, Seiji Mabuchi, Tadashi Kimura
Journal: Cancer Research (2017)

Abstract Objective: There is a critical need for improved diagnostic markers to detect ovarian high grade serous cancer (HGSC). microRNAs (miRNAs) stably exist in circulating blood, reflecting tissue or organ conditions and present in circulating microvesicles such as exosomes. We aimed to identify which miRNAs are highly produced from HGSCs and analyze whether serum miRNA can discriminate patients with HGSC from healthy controls. Methods: Secreted exosomes from ovarian cancer cell lines were collected and exosomal miRNAs extracted. miRNA microarray was performed and several elevated miRNAs specific to ovarian cancer cells were picked up. Among these, we focused on miR-99a. Sera were collected from 15 patients with HGSC (stage III and IV) and 10 healthy controls. Expression level of miR-99a was determined by miRNA RT-qPCR. Results: miRNA microarray revealed several miRNAs were highly expressed in exosomes in patients with HGSC. In patients, serum miR-99a levels were significantly increased (4.8 fold) compared with those of healthy controls. ROC analysis showed that at the cut-off of 1.4, the sensitivity and specificity were 73 % and 80 % respectively for detecting HGSC (AUC = 0.85). Conclusion: Exosomal miRNAs can be detected in sera of patients with HGSC and have the potential to predict ovarian cancer. Citation Format: Akihiko Yoshimura, Kenjiro Sawada, Koji Nakamura, Yasuto Kinose, Erika Nakatsuka, Seiji Mabuchi, Tadashi Kimura. Elevated level of serum miR-99a is correlated with serous epithelial ovarian cancer and can be a potential biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4655. doi:10.1158/1538-7445.AM2017-4655
Abstract 5181: Targeted knockdown of MYC in AML cells using G-quadruplex interacting small molecules
Authors: Megan A. Turnidge, Apurvi Patel, Justin J. Montoya, David W. Lee, Daniel H. Wai, Vijay Gokhale, Laurence Hurley, Robert J. Arceci, David O. Azorsa
Journal: Cancer Research (2017)

Abstract Acute Myeloid Leukemia (AML) is a disease that occurs when genomic changes alter expression of key genes, causing cells to resume an undifferentiated state, proliferate, and maintain tumor growth throughout the body. Recently, there has been an increase in efforts toward developing therapies that specifically target the protein products of these aberrantly expressed genes. However, many of the proteins are difficult to target because of structural challenges, protein overexpression that requires high drug doses, or mutations that confer resistance to therapy. One potential type of targeted therapy that circumvents these issues is the use of small molecules that stabilize DNA secondary structures called G-quadruplexes. G-quadruplexes are present in the promoters of many potential oncogenes, and have regulatory roles in their transcription. This study analyzes the therapeutic potential of compounds that target the regulatory G-quadruplex in the MYC oncogene, which is commonly misregulated in AML. Treatment of the MYC expressing AML cell lines KG-1 and UT-7epo with the compound GQC-05 resulted in decreased expression of MYC mRNA, as determined by qPCR. Moreover, GQC-05 treatment induced a more significant decrease in c-Myc protein expression than similar treatment with JQ-1(+), as shown by western blot analysis. Treatment of AML cells with GQC-05 also decreased cell viability and increased apoptosis. Concurrent treatment of AML cells with GQC-05 and JQ-1(+) showed an antagonistic effect, indicating potential competition in the silencing of MYC. These results demonstrate that targeting the MYC promoter G-quadruplex in AML cells leads to knockdown of MYC expression and induces apoptosis. These results further support the development of a novel mechanism for targeting key genetic drivers in AML, and lay the groundwork for advances in treatment of other cancers driven by G-quadruplex regulated oncogenes. Citation Format: Megan A. Turnidge, Apurvi Patel, Justin J. Montoya, David W. Lee, Daniel H. Wai, Vijay Gokhale, Laurence Hurley, Robert J. Arceci, David O. Azorsa. Targeted knockdown of MYC in AML cells using G-quadruplex interacting small molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5181. doi:10.1158/1538-7445.AM2017-5181
Serum Cholesterol Levels in Adenomatous Polyps and Cancer of the Colon
Authors: Alfred I. Neugut
Journal: JAMA (1986)

A series of recent studies has shown an association between low serum cholesterol level and cancer, particularly of the large bowel. To explore this issue, serum cholesterol measurements were collected from 244 patients with adenomatous polyps of the colon, 182 patients with Dukes' A or B colon cancer, and 688 hospital controls who were diagnosed between 1979 and 1981 at a New York City hospital. The mean serum cholesterol levels were lower for patients with cancer (207.2 mg/dL) than for controls (219.5 mg/dL), with patients with Dukes' B cancer accounting for most of the difference. Patients with adenomatous polyps (219.8 mg/dL) were similar to controls. After adjustments for nutritional status using the serum albumin level, there were no statistically significant differences among any of the groups. We conclude that the low serum cholesterol level previously associated with malignancies, and colon cancer in particular, is a consequence rather than a cause of the cancer. (JAMA 1986;255:365-367)
Abstract 4498: Targeting IRE1a-XBP1 signaling in lung cancer
Authors: Michael J. Crowley, Shira Yomtoubian, Geoffrey Markowitz, Nasser K. Altorki, Dingcheng Gao, Juan Cubillos-Ruiz, Vivek Mittal
Journal: Cancer Research (2017)

Abstract Every year 1.5 million people die from lung cancer worldwide. Approximately ~15-30% of non small cell lung cancers (NSCLC) are driven by KRAS mutations and currently possess no viable therapeutic options. As such the discovery of effective therapeutic alternatives for the treatment of KRAS driven NSCLC are sorely needed. One prospect being explored in other solid tumors, but currently unexplored in NSCLC, is targeting the endoplasmic reticulum (ER) stress response. Adverse conditions in tumors such as hypoxia, nutrient starvation and reactive oxygen species disrupt protein folding, and induce ER stress. The most evolutionarily conserved pathway by which this insult is alleviated is the IRE1α-XBP1 axis, which responds by increasing the expression of a broad range of protein folding and quality control genes. Previous work has demonstrated that several cancers utilize this pathway to promote tumorigenesis, progression, epithelial to mesenchymal transition and metastasis. A preliminary analysis of a tissue microarray containing 304 human NSCLC samples, 254 demonstrated at least some positivity and &amp;gt;50% were strongly positive for the active isoform of XBP1. Given these preliminary findings we investigated the status of IRE1a-XB1 in our murine orthotopic model and confirmed the activation of IRE1a-XBP1 signaling in tumor cells in the context of the tumor microenvironment. Furthermore, in both cell types we can see the activation of canonical downstream targets of XBP1. Utilizing the CRISPR-CAS9 system, we knocked out IRE1a in the orthotopic tumor cell line. IRE1a abrogation was confirmed by western blot, evaluating the fraction of active XBP1 after induced ER stress in vitro, and qPCR of canonical downstream targets. Additionally, this knockout did not alter proliferation or morphology in vitro. However, when tumors were grown orthotopically, Cas9-IRE1a knockouts failed to grow past 10 days, whereas Cas9-Scramble controls and the parental tumor line grew comparably until end stage. Given these preliminary findings and data from prior studies, we hypothesize that the abnormal activation of the IRE1α-XBP1 axis may influence KRAS NSCLC progression and aggressiveness and serve as a potential novel avenue for the treatment of NSCLC. After probing the impact of the underlying mechanism on tumor growth we will finally evaluate the translational utility of targeting the ER stress pathway with a small molecule inhibitor against IRE1a. Citation Format: Michael J. Crowley, Shira Yomtoubian, Geoffrey Markowitz, Nasser K. Altorki, Dingcheng Gao, Juan Cubillos-Ruiz, Vivek Mittal. Targeting IRE1a-XBP1 signaling in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4498. doi:10.1158/1538-7445.AM2017-4498
Abstract 3447: Down-regulation of long non-coding RNAMALL-2is associated with metastasis and poor survival in lung adenocarcinoma
Authors: Ha X. Dang, Nicole M. White, Emily B. Rozycki, Christopher A. Maher
Journal: Cancer Research (2017)

Abstract Lung adenocarcinoma accounts for ~40% of lung cancers and is among the deadliest cancers worldwide. Patients with metastatic lung adenocarcinoma exhibit poor outcome with the average 5-year survival of ~1%. Long non-coding RNAs (lncRNAs) have recently emerged as having critical roles in tumorigenesis. While a subset of lncRNAs have been shown to promote tumor invasion and metastasis, little is known about the role of lncRNAs in metastatic lung adenocarcinoma. Therefore, we analyzed publicly available microarray and RNA-Seq gene expression datasets that include primary and metastatic tissues. Through this meta-analysis we discovered 98 metastasis associated lncRNAs that were dysregulated in metastatic tumors compared to non-metastatic tumors (MALLs). Notably, only two lncRNAs (MALL-2 and MALL-36) were found to be down-regulated in primary tumors, relative to normal tissue, and even further down-regulated in metastatic tumors relative to primary tumors. Gene set enrichment analysis revealed that MALL-2, the most down-regulated lncRNA in metastasis, was coexpressed with protein-coding genes enriched with biological concepts associated with repressing tumor growth and metastasis. Furthermore, we found that FOXA2, a metastasis repressor gene, was highly coexpressed with MALL-2 in lung cancer. A pan-cancer analysis using ~7,000 TCGA RNA-Seq tumor samples across 20 cancer types revealed that MALL-2 was also down-regulated and coexpressed with FOXA2 in multiple cancers suggesting the conserved regulatory relationship between the two genes. We confirmed that FOXA2 expression was decreased upon knock-down of MALL-2 and silencing MALL-2 resulted in a significant increase in cellular migration in lung adenocarcinoma cell lines. Last, we found that low expression of MALL-2 was consistently associated with poor overall survival across multiple independent lung adenocarcinoma cohorts. Taken together, our integrative analysis has revealed MALL-2 that acts as a repressor of lung adenocarcinoma metastasis by regulating FOXA2 and could serve as a biomarker of lung adenocarcinoma patient outcome. Citation Format: Ha X. Dang, Nicole M. White, Emily B. Rozycki, Christopher A. Maher. Down-regulation of long non-coding RNA MALL-2 is associated with metastasis and poor survival in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3447. doi:10.1158/1538-7445.AM2017-3447
Correlation of an Aurora A single nucleotide polymorphism (SNP) with clinical responses to alisertib in patients (pts) with advanced solid tumors.
Authors: Huifeng Niu, Hyunjin Shin, Feng Gao, Jacob Zhang, Brittany Bahamon, Hadi Danaee, Bohuslav Melichar, Russell J. Schilder, Robert L. Coleman, Antoine Adenis, Kian Behbakht, Angela DeMichele, Elizabeth Claire Dees, Kimberly Perez, Ursula A. Matulonis, Dirk Huebner, Jeffrey Ecsedy
Journal: Journal of Clinical Oncology (2016)

2583 Background: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. The Aurora A gene contains two functional SNPs (codon 31 and codon 57) that modify kinase activity. We assessed prognostic and predictive value of these SNPs. Methods: We did a correlative study of the Aurora A SNPs in The Cancer Genome Atlas (TCGA) database to evaluate their association with overall survival (OS), we then further assessed their potential association with clinical responses in 2 alisertib phase 2 trials. Whole blood samples were collected prior to alisertib study commencement and pt genotypes were analyzed by PCR. In study 1 (NCT01045421), single agent alisertib was investigated in pts with advanced solid tumors; Aurora A SNP profiles of 85 pts were obtained. In study 2 (NCT01091428), a randomized trial of alisertib plus weekly paclitaxel vs paclitaxel alone in pts with advanced recurrent ovarian cancers, Aurora A SNPs were genotyped in 122 pts (62 and 60 from each arm). The link between Aurora A SNPs and alisertib efficacy outcome was assessed. Results: The correlative TCGA study suggested prognostic significance for codon 57 SNP as all pts with solid tumors that carry VV and VI alleles had a significantly reduced OS compared with II homozygous pts [p < 0.0001, HR = 1.9 (VI) and 1.8 (VV)]. In study 1, pts with the VV allele at codon 57 (n = 53, 62%) had a significantly longer mPFS (p = 0.0213) in response to alisertib than pts with the IV and II alleles (n = 32, 38%). In study 2, pts with the VV allele at codon 57 receiving alisertib+paclitaxel (n = 47) had significantly improved mPFS (229 d) vs paclitaxel alone (n = 32; 117 d) (p = 0.0593, HR = 0.618). For the ITT population, improvement in mPFS was not statistically significant (230 vs 154 d) (p = 0.1534, HR = 0.74). In paclitaxel arm, pts with the VV variant had reduced mPFS vs ITT pts (117 vs 154 d), which was consistent with the VV variant being a poor prognostic biomarker as shown in TCGA. Higher kinase activity of Aurora A VV at codon 57 may explain the association with poor survival, chemo-resistance and better response to alisertib. Conclusions: Aurora A VV SNP at codon 57 may serve as a biomarker to predict disease outcome and response to alisertib. Clinical trial information: NCT01045421 and NCT01091428.
Utility of Progression-Free Survival at 24 Months (PFS24) to Predict Subsequent Outcome for Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Enrolled on Randomized Clinical Trials: Findings from a Surrogate Endpoint in Aggressive Lymphoma (SEAL) Analysis of Individual Patient Data from 5853 Patients
Authors: Matthew J Maurer, Thomas M. Habermann, Qian Shi, Norbert Schmitz, David Cunningham, Michael Pfreundschuh, John F. Seymour, Ulrich Jaeger, Corinne Haioun, Hervé Tilly, Herve Ghesquieres, Francesco Merli, Marita Ziepert, Raoul Herbrecht, Jocelyne Flament, Tommy Fu, Christopher Flowers, Fang-Shu Ou, Daniel Sargent, Bertrand Coiffier
Journal: Blood (2016)
Abstract 2309: Acetylation of survivin represses transactivation of STAT3 to induce sodium butyrate-induced apoptosis in human mucoepidermoid carcinoma cell lines
Authors: Sung-Dae Cho
Journal: Cancer Research (2017)

Abstract Sodium butyrate (NaBu) is one of histone deacetylase inhibitors and possesses anticancer activity. Here, the aim of this study is to determine the molecular mechanism by which NaBu controls apoptosis in MC3 and YD15 human mucoepidermoid carcinoma (MEC) cell lines. NaBu caused growth inhibition and induced apoptosis in both cell lines accompanied by the acetylation of histone proteins H2A and H3. NaBu clearly increased survivin and cleaved caspase 3 evidenced by human apoptosis array and it regulated survivin molecule at a post-transcriptional level. NaBu caused nuclear translocation of survivin protein and increased survivin acetylation in both cell lines. In addition, STAT3 and survivin were co-localized in nucleus by NaBu resulting in the decrease in the expression level of Bcl-XL mRNA which is one of STAT3 downstream molecules. In addition, NaBu induced caspase-dependent apoptosis in human MEC cells. Taken together, these results suggest that NaBu is a potent apoptosis inducer in human MEC cell lines through survivin-STAT3 signaling cascades and these findings provide the basis of its clinical application for the treatment of human MEC. This abstract is supported by SNU Invitation Program for Distinguished Scholar and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A12055874) Citation Format: Sung-Dae Cho. Acetylation of survivin represses transactivation of STAT3 to induce sodium butyrate-induced apoptosis in human mucoepidermoid carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2309. doi:10.1158/1538-7445.AM2017-2309