tbuckley/cabot-search huggingface dataset:
Abstract 2891: Retinoic acid directs breast cancer cell state changes through regulation of TET2-aPKC pathway
Authors: Meng-Ju Wu, Chun-Ju Chang
Journal: Cancer Research (2017)

Abstract The key molecular mechanism governing the cancer cell state (stem cell-like state vs. differentiation state) to control the cancer stem cell (CSC) pool remains elusive. This study provides the first evidence showing that all-trans retinoic acid (ATRA) induces the interaction and chromatin recruitment of a novel RARB-TET2 complex to epigenetically activate a specific cohort of gene targets, including MiR-200c. TET2-activated miR-200c further targets and suppresses aPKC, a cell polarity protein that plays a pivotal role in directing asymmetric division of mammalian stem cells to sustain the stem cell pool. Our data reveals that pharmacological concentration of ATRA effectively down-regulates aPKC through activation of miR-200c, leading to a decrease of the stem cell-like populations from non-tumorigenic mammary epithelial cells and non-aggressive breast cancer cells. However, aggressive breast cancer cells that manifest TET2-miR200c dysregulation sustain a CSC pool highly resistant to ATRA, where inhibition of aPKC directs the resistant CSCs to the luminal cell-like state and sensitization to Tamoxifen, resulting in abrogation of mammary tumor growth and progression. Together, these findings elucidate a novel RARB-TET2-miR200c-aPKC signaling pathway that directs cancer cell state changes and also provide previously unidentified therapeutic implications for aPKC inhibitors in diminishment of breast CSCs to eradicate breast cancer. Citation Format: Meng-Ju Wu, Chun-Ju Chang. Retinoic acid directs breast cancer cell state changes through regulation of TET2-aPKC pathway [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 2891. doi:10.1158/1538-7445.AM2017-2891
Abstract 312: Anti-proliferative effects of cinnamon extract in colon cancer
Authors: Patrick P. Carriere, Hina Mir, Neeraj Kapur, Clarence E. Clark, Shailesh Singh
Journal: Cancer Research (2017)

Abstract Colon cancer is the third most lethal cancer worldwide, and is estimated to cause 49,190 cancer-related deaths in the U.S. in 2016 alone. Current treatments for colon cancer are limited in their capacity to target tumor cells employing adaptive mechanisms necessary for survival and proliferation, often resulting in poor prognosis. Therefore, it is critical to develop novel target-specific therapeutic approaches with minimal cytotoxicity to normal cells, in order to mitigate potential side effects. Proanthocyanidins represent a subclass of flavonoids, which have been widely investigated for their chemopreventive and therapeutic potential. Cinnamtannin B-1 (CTB-1) is a proanthocyanidin shown to have anti-cancer effects in several cancers, but its anti-cancer potential in colon cancer has not been tested. Hence, the focus of this study was to determine the anticancer effects of CTB-1 in colon cancer. Our results show that CTB-1 treatment significantly decreases the cell viability and proliferation of DLD-1 and COLO 201 human colon cancer cells in a time and dose-dependent manner. In addition, CTB-1 treatment modulated the cell cycle progression of colon cancer cells via G2/M arrest, coupled with a reduction of cells in the S phase. The expression and/or phosphorylation of key molecules involved in apoptosis and cell cycle progression were also modulated in response to CTB-1 treatment. Collectively, these findings, for the first time, shed light on the anti-proliferative effects of CTB-1 in colon cancer, and further demonstrate its potential as a novel therapeutic/preventive agent. Citation Format: Patrick P. Carriere, Hina Mir, Neeraj Kapur, Clarence E. Clark, Shailesh Singh. Anti-proliferative effects of cinnamon extract in colon 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 312. doi:10.1158/1538-7445.AM2017-312
Abstract 2926: Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis
Authors: Antony Prabhu, Pravin Kesarwani, Shiva Kant, Stewart Graham, Prakash Chinnaiyan
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) represents an archetypal example of a heterogeneous malignancy, harboring regions of invasion, necrosis, and vascularization. To begin to understand the diverse molecular consequences of this complex tumor ecology, we analyzed RNA-seq data generated from commonly identified intratumoral structures in GBM that were isolated and enriched using laser capture micro-dissection. Structures included the infiltrative, leading edge, central tumor core, and cellular regions in areas of necrosis. From this RNA-seq database consisting of 119 structural regions from 37 individual tumors generated from ~12,000 hematoxylin and eosin histologic images, we validated significant intra-tumoral heterogeneity in GBM, with cells derived from the infiltrating leading edge almost exclusively harboring the proneural molecular subtype, while cells in regions of necrosis displaying the mesenchymal subtype. In addition, we made the striking observation that when evaluating the tumors transcriptional profiles in the context of their derived structural regions, there was a relative small amount of inter-tumoral heterogeneity in GBM, with significant clustering of transcriptional profiles of specific structural regions from different tumors. To begin to understand the specific molecular events driving regional growth and their contributory role in gliomagenesis, we analyzed the transcriptional programs in the context of evolutionary progression. This level of analysis identified numerous pathways associated with neuronal receptor signaling, autophagy, and fatty acid metabolism as early events in tumorigenesis. Traditional cancer related signaling pathways emerged as key mediators driving progression, with glioma and p53 signaling ranking highest on the list. As the tumor progressed to harbor regions of necrosis, in addition to expected changes in VEGF and tumor signaling, we uncovered global metabolic changes associated with progression, with metabolic pathways comprising 10 of the top 20 pathways unique to this region. Collectively, these findings suggest that the observed intra-tumoral heterogeneity in GBM may be a conserved, predictable consequence to its complex microenvironment and therapeutic strategies rationally designed to target these unique, unequivocally present tumor cell biomes may lead to therapeutic gains in this otherwise fatal malignancy. Citation Format: Antony Prabhu, Pravin Kesarwani, Shiva Kant, Stewart Graham, Prakash Chinnaiyan. Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis [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 2926. doi:10.1158/1538-7445.AM2017-2926
Abstract 1044: Development of a miRNA-based signature to predict human cancer metastasis
Authors: Lian Willetts, Konstantin Stoletov, Juan Jovel, Emma Woolner, John D. Lewis
Journal: Cancer Research (2017)

Abstract Metastasis is the primary cause of death for cancer patients, and invasive cancer cell migration is required at multiple steps during metastasis (e.g. intravasation and extravasation). Since microRNAs (miRNAs) have been implicated as key regulators of metastatic spread of cancer cells, we sought to develop a miRNA signature that can be used to predict cancer metastasis. We hypothesized that the miRNAs that are functionally required for invasive cell migration could serve as biomarkers to predict human cancer metastasis. We developed an intravital imaging-based approach combined with NGS to screen for miRNAs that are required for invasive cell migration of human HT1080 fibrosarcoma cells. The screen-identified miRNAs were validated in a panel of in vitro and in vivo assays for invasive migration. Microarray analysis identified genes downregulated in transfected HT1080 cells. Publically available databases were used to correlate the expression of screen-identified miRNAs and the progression of multiple human cancers. We used a qRT-PCR approach combined with machine learning to develop a miRNA signature to predict metastasis in a 66-patient cohort of prostate cancer. We identified over twenty novel miRNAs that regulate directional cancer invasion. Microarray analysis in HT1080 cells revealed that the altered expression of metastasis-regulating miRNAs is associated with 50% reduction in gene expression of migration and adhesion gene network components such as integrin a4, CDC42, and transgelin). We evaluated the potential of screen-identified miRNAs to serve as biomarkers to predict cancer metastasis. Using publically available databases, we found that majority of screen-identified miRNAs are dysregulated in multiple human cancer types (e.g. prostate, breast, ovarian and lung) and the expression of these miRNAs correlate directly with patient disease progression. We analyzed the expression of the top two screen-identified miRNAs in plasma samples from the PCa patient cohort. A signature was generated using a weighted K-nearest neighbor algorithm that provided a ROC area under the curve of 0.79 for predicting metastatic disease. We identified a panel of novel metastasis-regulating miRNAs that is functionally involved in human cancer metastasis. These miRNAs have the potential to serve as both biomarkers to predict metastasis and potentially as therapeutic targets to block metastasis. Citation Format: Lian Willetts, Konstantin Stoletov, Juan Jovel, Emma Woolner, John D. Lewis. Development of a miRNA-based signature to predict human cancer metastasis [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 1044. doi:10.1158/1538-7445.AM2017-1044
Abstract #3014: Effects of smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers
Authors: Steven Carmella, Menglan Chen, Shaomei Han, Joni Jensen, Anna Briggs, Dorothy Hatsukami, Stephen Hecht
Journal: Cancer Research (2009)

Tobacco carcinogen and toxicant biomarkers, quantitative measurements of exposure and fate of specific tobacco carcinogens and toxicants, could in principle become an important part of a risk algorithm to identify smokers susceptible to lung cancer and are also important for the evaluation and potentially the regulation of new and existing tobacco products. Our goal is to develop a panel of tobacco carcinogen and toxicant biomarkers applicable in these activities. One validation criterion for a tobacco carcinogen or toxicant biomarker is its relationship to tobacco use. This can be determined by assessing the decrease in a biomarker level when people stop using the product. Therefore, in this study, we evaluated the relationship to cigarette smoking of eight tobacco carcinogen and toxicant biomarkers: 1-hydroxypyrene (1-HOP), a metabolite of pyrene and a widely accepted biomarker of exposure to carcinogenic polycyclic aromatic hydrocarbons; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), an established biomarker of exposure to the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 6 mercapturic acids (MA) derived from: 1,3 butadiene (MHBMA and DHBMA), acrolein (HPMA), crotonaldehyde (HBMA), benzene (SPMA), and ethylene oxide (HEMA) . Smokers provided 24h urine samples twice while still smoking and then on days 3, 7, 14, 21, 28, 42, and 56 after quitting. Seventeen subjects (11 female) completed the study. Their mean age (± S.D.) was 43.9 ± 11.0 years (range 23 - 58). Sixteen were Caucasian and one was of mixed racial heritage. They had been smoking an average of 17.3 ± 12.3 years and smoked 21.8 ± 6.7 cigarettes per day. MAs were quantified by a newly developed combined LC-negative ion-APCI-MS/MS method, total NNAL by GC-nitrosamine selective detection, and 1-HOP by LC-fluorescence. Baseline values of the biomarkers could be split into three groups: low, medium, and high. NNAL, 1-HOP, and SPMA comprised the low group (1-3 nmol/24h), HEMA and MHBMA the medium group (30 - 50 nmol/24h), and DHBMA, HPMA, and HBMA the high group (2600 - 11,000 nmol/24h). Levels of all MAs except DHBMA decreased rapidly after smoking cessation. In each case, the mean reduction of the MA from baseline was approximately 80% (P  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3014.
Abstract 1423: Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell lung cancer
Authors: Xiaozhen Liu, David Bouck, Khristofer Garcia, Jonathan Blank, Hugues Bernard, Allison Berger, Mike Kuranda, Erik Koenig, Eric Lightcap
Journal: Cancer Research (2017)

Abstract Platins are one of the most widely used classes of chemotherapeutic drugs. Although used as part of first-line standard of care regimens for advanced non-small cell lung cancer (NSCLC), their effectiveness remains limited, with a 5-year survival rate of 18%. Therefore, combination therapy to overcome resistance and improve survival is needed. Pevonedistat (TAK-924/MLN4924) is an investigational first-in-class Nedd8-activating enzyme (NAE) inhibitor that blocks activation of the cullin family of E3 ubiquitin ligases by preventing cullin conjugation with Nedd8, a ubiquitin-like protein. In vitro, pevonedistat is synergistic with carboplatin in a cell viability assay in 6 out of 20 NSCLC cell lines either with or without paclitaxel. In vivo studies using patient-derived xenograft (PDX) models showed a combination effect in a carboplatin-insensitive but not carboplatin-sensitive model. To evaluate the mechanism of the synergy between pevonedistat and platinum, RNAi of 320 DNA-damage response genes was performed in 4 cell lines in vitro. Depletion of genes involved in TC-NER (transcription-coupled nucleotide excision repair) and ICR (interstrand crosslink repair) reduced the synergy between pevonedistat and platinum, with the contribution of each pathway varying by cell line. Since TC-NER and ICR are also involved in the repair of DNA damage by platins, the results suggest that delaying completion of platin induced DNA repair by pevonedistat results in enhanced cell death. Pevonedistat may impede TC-NER by inhibition of neddylation of the E3 ubiquitin ligase CUL4-RBX1-DDB1-ERCC8, thereby possibly providing a direct reversal of resistance to platins. Citation Format: Xiaozhen Liu, David Bouck, Khristofer Garcia, Jonathan Blank, Hugues Bernard, Allison Berger, Mike Kuranda, Erik Koenig, Eric Lightcap. Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell 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 1423. doi:10.1158/1538-7445.AM2017-1423
Abstract 5041: Translational pharmacokinetic-pharmacodynamic xenograft model for TAK-931, a small molecule cell division cycle 7 (CDC7) kinase inhibitor
Authors: Charles Locuson, Mayank Patel, Akihiro Ohashi, Kenichi Iwai, Tadahiro Nambu, Toshiyuki Takeuchi, Akifumi Kogame, Douglas Bowman, Stephen Tirrell, Huifeng Niu, Cindy Xia
Journal: Cancer Research (2017)

Abstract TAK-931 is a small molecule inhibitor of the cell division cycle 7 (CDC7) kinase. As a serine/threonine kinase that contributes to DNA replication and the DNA damage response, CDC7 is hypothesized to be a promising cancer drug target. CDC7 inhibition with TAK-931 has demonstrated antiproliferative activity with cancer cell lines and tumor growth inhibition (TGI) in murine ectopic xenograft models. Herein, the analysis of multiple models to characterize pharmacokinetic (PK) and pharmacodynamic (PD) relationships with xenograft TGI is described. TAK-931 treatment-induced TGI was dose schedule-independent and could be described using plasma drug concentrations or tumor PD inhibition. However, the efficacious doses were at least 10-fold higher for the PK-TGI relationship than for the PD-TGI relationship. This discrepancy was used to select a dynamic PK-PD-TGI modeling approach to project the minimal efficacious dose (MED) and minimal biological active dose (MBAD) for TAK-931 due to the large differences in time-concentration profiles predicted for humans versus mice. The Phase I human trial is on-going and will be used to verify the dynamic PK-PD-driven modeling approach for the CDC7 inhibitor. Citation Format: Charles Locuson, Mayank Patel, Akihiro Ohashi, Kenichi Iwai, Tadahiro Nambu, Toshiyuki Takeuchi, Akifumi Kogame, Douglas Bowman, Stephen Tirrell, Huifeng Niu, Cindy Xia. Translational pharmacokinetic-pharmacodynamic xenograft model for TAK-931, a small molecule cell division cycle 7 (CDC7) kinase inhibitor [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 5041. doi:10.1158/1538-7445.AM2017-5041
Abstract 5642: Quantitative comparison of hydrocortisone and prednisone in the postoperative hormone therapy of hypercortisolism
Authors: Kunlong Tang, Yuting Huang, Shangwen Dong, Peng Gao
Journal: Cancer Research (2017)

Abstract Tumors and several types of malignancies including lung cancer, pancreatic cancer, pituitary tumor, and most often adrenal adenoma, may cause hypercortisolism, which requires glucorticoid (GC) replacement following adrenalectomy and/or surgical resection of the tumor. Based on our previous report of a simplified GC therapy scheme and the perioperative observation, we further investigated its efficacy and safety up to 6 months post-surgery in this retrospective cohort study. All patients received no GC before surgery. The i.v. doses of hydrocortisone (HC) were 100 mg during surgery, 100 mg bid on day 0 and day 1, followed by 100 mg qd on the morning of day 2 post-surgery. Patients were grouped by oral reception of either HC or prednisone since day 2. The doses and the withdrawal schedule are shown in Table. We found in adrenal adenoma patients, the adrenocorticotropic hormone (ACTH) levels were normal, and sufficient to stimulate the recovery of the dystrophic adrenal cortex, thus exogenous supplemental ACTH might not be necessary. By 6 months post-surgery, prednisone and HC exhibited similar efficacy in correcting hypertension, hyperglycemia, and hypokalemia (p&amp;gt;0.05). Most patients lost weight. Both groups reported significant improvement in a subjective evaluation questionnaire. HC showed advantages over prednisone in improving liver function (p=0.035), but also caused significant leg edema (p=0.034). Both groups developed adrenal insufficiency (AI) during GC withdrawal, with no significant difference regarding the incidence rate or severity. Most AI symptoms were relieved by resuming the prior oral doses, while the severe cases were treated in hospital. No particular variable was identified as risk factor for AI. The withdrawal process may last longer time for HC than prednisone. HC may be prioritized for patients with hyperglycemia or abnormal liver function, while prednisone may reduce the incidence of leg edema. hydrocortisoneprednisonepathology2220adrenal adenoma14/2216/20Cushing's Disease8/224/20oral glucorticoid schemedose on day 240 mg, tid10 mg, tidwithdrawal20 mg/week5 mg/weekaverage length (month)6.64.9correction of symptomshypertension10/1512/19hyperglycemia6/117/10hypokalemia12/1211/11abnormal liver panel7/82/7 *weight loss20/2217/20adrenal insufficiency10/227/20severe case1/101/7leg edema6/220/20 * Note: This abstract was not presented at the meeting. Citation Format: Kunlong Tang, Yuting Huang, Shangwen Dong, Peng Gao. Quantitative comparison of hydrocortisone and prednisone in the postoperative hormone therapy of hypercortisolism [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 5642. doi:10.1158/1538-7445.AM2017-5642
Abstract 5178: CB002, a novel p53 pathway-restoring compound that induces apoptosis through the pro-apototic protein NOXA
Authors: Liz J. Hernandez Borrero, Shengliang Zhang, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract P53 is a transcription factor that becomes stimulated upon genotoxic and cellular stress signals ultimately leading to the transcriptional activation of genes involved in processes such as DNA repair, cell cycle arrest, and apoptosis etc. TP53 is the most commonly mutated tumor suppressor and this is associated with cancer initiation, cancer progression and therapy resistance. P53-targeted therapy has proven to be challenging because direct functional restoration of p53 as a transcription factor has been difficult to achieve. We haven taken a different approach by investigating small molecules that functionally restore the p53-signaling pathway instead of direct p53 targeting. To date there is no approved drug that restores the p53 pathway in cancer cells with mutant p53. Therefore, we performed a high-throughput screen to identify such molecules. We identified a family of small molecules, CB002 and its structural analogs, as candidates for restoration of the p53 pathway in p53-null and mutant p53-expressing cancer cells. CB002 was specific in causing apoptosis in colorectal cancer cells and not in normal human fibroblasts cells as indicated by a Sub-G1 assay. Utilizing the xCELLigence RTCA DP system and CIM-Plate we show that CB002 treatment decreases the ability of colorectal cancer cells to migrate. The ability of CB002 to restore the p53 pathway was validated by studying the activation of p53 target genes p21, DR5, and NOXA in various cancer cell lines and expression of well-established apoptotic markers. Stable knockdown of NOXA completely abrogated the expression of cleaved PARP and reduced Sub-G1 cells, implicating the relevance of NOXA as a key mediator of cell death induction by CB002. We are currently exploring the mechanism by which NOXA induces apoptosis, as preliminary results suggest that degradation of Mcl-1 is not required for CB002 mediated cell death. In addition, we are evaluating the ability of CB002 structural analogs in decreasing the stability of mutant p53 using a larger panel of p53 mutants, as CB002 appears to target R175H p53 mutants. Our data supports the continued investigation of CB002 as a p53 pathway-restoring compound that may be further developed as a cancer therapeutic for p53-null tumors as well as tumors with p53 mutations. Citation Format: Liz J. Hernandez Borrero, Shengliang Zhang, David T. Dicker, Wafik S. El-Deiry. CB002, a novel p53 pathway-restoring compound that induces apoptosis through the pro-apototic protein NOXA [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 5178. doi:10.1158/1538-7445.AM2017-5178