bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B45: Vertical inhibition of the PI3K pathway potently sensitizes diffuse large B cell lymphoma to BCL-2 antagonism
Authors: Lee Jong-Hoon Scott , Tang Sarah , Ortiz Veronica , Fruman David A. 
Published: October 2015

Abstract
The PI3K/AKT/mTOR axis is one of the most commonly mutated pathways in cancer, where aberrant activation promotes cell growth, proliferation, and survival. However, selective inhibitors targeting PI3K/AKT/mTOR have been hindered by their inability to effectively induce cell death in certain cancers. With the introduction of inhibitors that directly inhibit key pro-survival factors such as BCL-2 and BCL-XL (ABT-263 and ABT-199), the potential to achieve cancer cell death using combinations of targeted inhibitors has become a realizable goal. Here we show that selective inhibition of key components in the PI3K pathway (PI3K, AKT, or mTOR) potently sensitized a panel of DLBCL cell lines to ABT-263-induced apoptosis. While the degree of sensitization varied according to which PI3K pathway component was targeted, dual inhibition of both PI3K and mTOR consistently elicited the most potent sensitization across several cell lines. Previous work in other cancer types has linked the potency of this combination to the capacity of PI3K pathway inhibitors to reduce MCL-1 in an mTORC1-dependent manner. However, we found that this was not the case for DLBCL. For example, ABT-263 resistance induced by over-expression of MCL-1 was overcome when cells were co-treated with a dual-PI3K/mTOR inhibitor NVP-BEZ235 despite maintained expression of MCL-1. Instead, inhibition of the PI3K pathway led to a general increase in mitochondrial priming as measured by BH3 profiling. This occurred through distinct effects from both AKT and mTORC1 on the abundance of multiple BCL-2 family proteins at the mitochondria including reductions in the pro-survival proteins BCL-2, MCL-1, and BCL-XL as well as increases in Bim and Bad. In addition to these direct effects on BCL-2 family proteins, we found that inhibition of the PI3K pathway reduced expression of cancer-relevant proteins c-Myc and eIF4G as determined by reverse phase protein array. Thus, this project highlights the broad effects of dual-PI3K/mTOR inhibitors that sensitize DLBCL to apoptosis, and suggests that inhibition of the PI3K pathway has distinct effects on cell survival signaling among different cancer cell types.
Citation Format: Jong-Hoon Scott Lee, Sarah Tang, Veronica Ortiz, David A. Fruman. Vertical inhibition of the PI3K pathway potently sensitizes diffuse large B cell lymphoma to BCL-2 antagonism. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B45.
Abstract IA04: PTEN regulation and output
Authors: Parsons Ramon E. 
Published: October 2015

Abstract
PTEN is one of the most frequently mutated and epigenetically silenced tumor suppressor genes in cancer. The PTEN gene encodes intracellular (PTEN) and secreted (PTEN-L) protein isoforms that have lipid phosphatase activity. The secreted isoform has the ability to enter cells in trans. PTEN tumor suppression occurs through PI3K-dependent and independent mechanisms. Recent progress involving PTEN function, isoforms, enzyme regulation, and attempts at therapy will be presented.
Citation Format: Ramon E. Parsons. PTEN regulation and output. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA04.
Abstract IA06: PI 3-kinase and Akt at the interface of signaling and metabolism
Authors: Toker Alex 
Published: October 2015

Abstract
The PI 3-Kinase and Akt signaling pathway plays a critical role in modulating all phenotypes associated with human malignancies, including cell survival, proliferation and metabolism. Recent studies point to a major role for Akt signaling in modulating changes in metabolic pathways, although the specific mechanisms are unknown. Using unbiased metabolic profiling, we have uncovered a role for oncogenic PI 3-K and Akt in sensing redox changes in cancer cells, specifically by up-regulating glutathione levels and enhancing glutathione biosynthetic flux. Mechanistically, this is mediated by mTORC1-mediated up-regulation of the oxidative pentose phosphate pathway and Nrf2 activation. These findings indicate a post-translational mechanism by which oncogenic Akt signaling directly activates Nrf2 in cancer. Enhanced glutathione biosynthesis provides several advantages to cancer cells, including oxidative stress resistance and anchorage-independent growth, and thus constitute a metabolic dependency that can be targeted as a therapeutic strategy within breast cancer cells driven by Akt hyperactivation. In a separate study, we show that the chemotherapy agent doxorubicin triggers rapid and sustained activation of Akt signaling in breast cancer lines. Small molecule inhibitors of PI3K or Akt block Akt signaling downstream of DNA damage and sensitize cells to the cytotoxicity of doxorubicin. We have identified MERIT40, a component of the BRCA1-A DNA damage repair complex, as a novel Akt substrate that is phosphorylated in doxorubicin-treated cells. MERIT40 phosphorylation is required for formation and stabilization of the multicomponent BRCA1-A complex in response to DNA damage and this contributes to the resolution of DNA damage. We propose that disruption of MERIT40 phosphorylation contributes to the ability of PI3K/Akt inhibitors to sensitize breast cancer cells to chemotherapy through disruption of BRCA1 A complex integrity which is required for DNA damage repair and cell survival in the DNA damage response.
Citation Format: Alex Toker. PI 3-kinase and Akt at the interface of signaling and metabolism. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA06.
Abstract IA15: New insights on the role of tumor suppressor phosphatases
Authors: Pandolfi Pier Paolo 
Published: October 2015

Abstract
Because of the critical tumor suppressive role PTEN, its multiple layers of regulation have been the subject of intense investigation. Through its ability to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) PTEN suppresses the activation of the PI3K pathway. Its loss in turn results in the aberrant hyper-activation of AKT-mTOR signaling. Deletion, silencing and mutation of the PTEN phosphatase represents one of the most frequent events in human tumorigenesis. Reductions in PTEN levels are also tremendously consequential, resulting in cancer susceptibility and overt tumorigenesis in a cell type specific manner. In keeping with this notion PTEN is also found mutated in the germ line of individuals affected by PTEN Hamartoma Syndromes, characterized by developmental defects and cancer susceptibility. INPP4b, on the other hand, is an inositol polyphosphate-4-phosphatase, type II, that dephosphorylates the phosphate group at position 4 of the inositol ring from inositol 3,4-bisphosphate. In so doing, INPP4b, like PTEN, can oppose the activation of the PI3K-Akt pathway. The INPP4b gene has been recently found frequently deleted in human cancers. On this basis we started investigating its putative tumor suppressive role both in vitro and in vivo in mouse models. Novel data emerging from the analysis of the critical role of these phosphatases in human cancer and disease pathogenesis will be presented.
Citation Format: Pier Paolo Pandolfi. New insights on the role of tumor suppressor phosphatases. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA15.
Abstract IA28: PI3K and mTOR inhibitors in lymphoid malignancies: Clinical data
Authors: Leonard John P. 
Published: October 2015

Abstract
Activation of pathways associated with PI3 Kinase and mTOR is commonly associated with a variety of lymphoid cancers, and can result in cell survival, growth and resistance to standard chemoimmunotherapeutics. Strong preclinical rationale has led to several agents that have been evaluated in clinical trials, both as monotherapy and in combination strategies. The mTOR inhibitors everolimus Iand temsirolimus have demonstrated clear clinical activity and acceptable toxicity profiles in patients with a variety of lymphoid malignancies. Temsirolimus has been approved in the European Union and several other countries outside of the US for the treatment of relapsed and/or refractory mantle cell lymphoma. This approval was based on a phase 3 randomized trial comparing temsirolimus at 2 dosing levels vs. investigator's therapy choice, which demonstrated an improvement in progression-free survival and overall response rate. Single agent activity of temsirolimus has also been demonstrated in other lymphoma subtypes such as diffuse large B cell and follicular lymphoma, and combination studies have been performed with rituximab. Everolimus has also been evaluated in mantle cell, diffuse large B cell and follicular lymphoma, as well as Hodgkin lymphoma, and clinical activity has also been noted. Combination studies with histone deacetylase inhibitors, rituximab and lenalidomide are underway. To date, activity of PI3K inhibitors appears to be most significant in lymphoid malignancies. Idelalisib, an inhibitor of the PI3K delta isoform, is FDA approved as a single agent for patients with follicular lymphoma and small lymphocytic lymphoma, and in combination with rituximab for recurrent chronic lymphocytic leukemia. Responses have been noted in mantle cell lymphoma, though durability is short. Numerous combination studies with chemotherapy and rituximab are ongoing. IPI-145 is an oral inhibitor of the delta and gamma isoforms of PI3K, and early studies have shown activity in both indolent B cell lymphomas as well as T cell histologies. The alpha and delta PI3K inhibitor copanlisib has also demonstrated early activity in a range of lymphoid histologies. The clinical activity and toxicity profile of PI3K inhibitors has suggested a significant potential role for these agents in the treatment of various lymphoproliferative cancers. Ongoing studies are evaluating potential biomarkers for response and resistance, as well as the development of rational combination approaches. Clinical findings suggest at this stage that targeting mTOR and PI3K represents a valuable therapeutic approach in lymphoma and that further investigation in this area will lead to further progress in improving patient outcomes.
Citation Format: John P. Leonard. PI3K and mTOR inhibitors in lymphoid malignancies: Clinical data. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA28.
Abstract A01: Genome-wide changes in expression of small RNAs in human testis cancer tissue
Authors: Rounge Trine Ballestad , Furu Kari , Skotheim Rolf Inge , Enerly Espen , Haugen Trine Berit , Grotmol Tom 
Published: October 2015

Abstract
Testicular germ cell tumor (TGCT) is the most common malignancy in young men in most western countries. The incidence is highest in Northern European populations, where the incidence rates have increased significantly over the past decades. Genetic predisposition and conditions during pregnancy play a central role in TGCT development, and the disease arises from primordial germ cells that develop into carcinoma in situ (CIS) lesions. These lesions may develop into cancer from puberty onwards. Like primordial germ cells, CIS cells retain a permissive chromatin structure, indicating the involvement of epigenetic components in TGCT.
To assess the role of small RNAs in testicular carcinogenesis, we quantified small RNAs (19 to 35 bp) in 25 human cancer samples with differing TGCT histology and 12 normal testis samples using small RNA sequencing. piRNA expression levels were calculated for piRNA clusters built on the small RNA dataset generated from the 37 samples. Most piRNA clusters differ substantially in expression between TGCT samples and healthy controls, indicating a common mechanism for this genome-wide effect. In addition, a total of 101 miRNAs show differential expression between healthy tissue and TGCT samples (p&lt;0.1 when adjusting for multiple testing with the Benjamini-Hochberg procedure). Twenty miRNAs have p&lt;1×10-6, including miRNAs previously implicated in TGCT development and in cisplatin sensitivity. Furthermore, clustering demonstrates unique miRNA expression in different TGCT histological subtypes. These results indicate that small RNAs could be used as TGCT markers and potentially be a powerful tool in aiding diagnosis and identification of histological subtypes in TGCT patients, as well as in development of new therapeutic interventions.
Citation Format: Trine Ballestad Rounge, Kari Furu, Rolf Inge Skotheim, Espen Enerly, Trine Berit Haugen, Tom Grotmol. Genome-wide changes in expression of small RNAs in human testis cancer tissue. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A01.
Abstract A47: Meta-analysis of MTHFR polymorphisms in lung cancer: Population health and mutations in the world
Authors: Chen Hsiao-Ling , Shiao Shyang-Yun Pamela K. , Chiang Linda H. , Kusuma Joyce 
Published: October 2015

Abstract
Purpose: The purpose of this meta-analysis is to identify the associations of methylene-tetra- hydrofolate reductase (MTHFR) gene mutations and smoking as risk factors for lung cancer (LC). LC is the leading cause of cancer-related death worldwide. To-date, population health in relations to the epigenetics pathways is not clearly understood. Inconsistent findings have been cumulated to-date on the case control studies of MTHFR gene mutations in LC around the world.
Procedure: On-line databases were searched from PubMed (PM) and PM Central databases for meta-analyses by using a combination of key words including LC, MTHFR, and case control studies. Additional studies were located by cross reference method from located studies. For this analysis, 22 studies published within the last 17 years were identified, containing both control and LC cases of human samples. These papers were reviewed and evaluated using the criteria for the quality of studies by two raters. Relative risks (RR) were calculated for increased or decreased risks for LC.
New Data Findings: Preliminary analyses included 11799 cases and 12322 controls associating MTHFR677 locus and LC in 22 studies; 6916 cases and 8526 controls for MTHFR1298 locus in 14 studies. MTHFR677 TT variant as homozygous mutation type was associated with increased LC risk for all race groups combined (pooled RR = 1.151, 95% CI = 1.045 - 1.267, p = 0.004); and also significant for subgroups of Asians (14 studies, RR = 1.080, 1.007 - 1.158, p = 0.031) and Caucasians (8 studies, RR = 1.334, 1.017-1.749, p = 0.037). Asians combined had greater mutation rates on MTHFR677 TT and TC (TT+TC=19.6+47.2=66.8% for cases and 17.8+47.3=65.1% for controls) than Caucasians (11.4+43.4=54.8% for cases and 9.2+41.9%=51.1% for controls). For association of smoking and LC risk, pooled results from 12639 cases and 11828 controls in 17 studies associating MTHFR gene and LC indicated that smoking increased LC risk (pooled RR=1.116, 1.072 - 1.162, P &lt; 0.001).
Conclusion: Meta-analyses of epigenetic risk factors associating gene mutations and health behaviors can provide useful insights to improve the quality of future cancer prevention and intervention studies. Further studies are needed to document population-based gene mutations in relation to epigenetics pathways for cancer prevention.
Citation Format: Hsiao-Ling Chen, Shyang-Yun Pamela K. Shiao, Linda H. Chiang, Joyce Kusuma. Meta-analysis of MTHFR polymorphisms in lung cancer: Population health and mutations in the world. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A47.
Abstract B02: Head and neck and esophageal cancers after liver transplant: Results from a multicenter cohort study. Italy, 1997-2010
Authors: Serraino Diego 
Published: October 2015

Abstract
Recipients of liver transplant (LT), particularly those with alcohol liver diseases (ALD), are at high risk for cancers. This study quantified the risk of head and neck (HN) and esophageal cancers in 2770 LT recipients transplanted in nine Italian centers during 1990-2010. The number of observed cancer cases in LT recipients was compared to the expected one to obtain standardized incidence ratios (SIRs) and 95% confidence intervals (CI). ALD was documented in 26.9% of the 2770 LT recipients, and 186 post-transplant cancers were diagnosed -including 33 cases of HN cancers (6 cases of tongue carcinoma; 10 cases of other carcinomas of the oral cavity; and 17 cases of larynx carcinoma) and nine cases of esophageal carcinoma. The 10-year cumulative risk for HN and esophageal carcinoma was 2.59%. Overall, HN cancers were nearly 5-fold more frequent in LT recipients than expected (SIR=4.8, 95% CI:3.3-6.8), while esophageal carcinoma was 9-fold more frequent than expected (SIR=9.1, 95% CI: 4.1-17.2). The magnitude of the risks of HN and esophageal carcinomas strongly differed according to the presence of ALD. SIRs ranged from 11.4 in LT with ALD to 2.2 for LT without ALD for all types of HN cancers, and from 23.9 to 2.9, respectively, for esophageal carcinoma. Particularly elevated SIRs in LT with ALD were noted for carcinomas of tongue (23.1, 95% CI:7.5-54.0) or larynx (12.7, 95% CI:6.3-49.2). Our findings confirmed and quantified the large cancer excess risk in LT recipients with ALD. The risk magnitude and the prevalence of ALD herein documented stress the need of timely and specifically tailored programs for the prevention and early diagnosis of cancer among LT recipients.
Citation Format: Diego Serraino. Head and neck and esophageal cancers after liver transplant: Results from a multicenter cohort study. Italy, 1997-2010. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B02.
Abstract B20: The cholesterol metabolite, 27-hydroxycholesterol induces hyperplasia in an androgen receptor-dependent manner in normal prostate RWPE-1 cells
Authors: Raza Shaneabbas , Meyer Megan , Guo Bin , Hammer Kimberly , Ghribi Othman 
Published: October 2015

Abstract
For every 6 men, 1 will be diagnosed with prostate cancer (PCa). Moreover, benign prostatic hyperplasia (BPH) also occurs in 50% of men over the age of 50. Although Androgens are known to play an important role in PCa and BPH, some evidence shows estrogens may be involved as well. Recently a cholesterol oxidized metabolite (oxysterol), 27- hydroxycholesterol (27-OHC) was found to bind to estrogen receptor(ER) and act as a selective ER modulator (SERM). 27-OHC is the most prevalent cholesterol metabolite present in the blood with levels increasing with oxidative stress and age, especially in men. The role of 27-OHC in PCa and BPH remains to be investigated. We propose that 27-OHC has deleterious effect in PCa and BPH, whereas the effect on BPH may be androgen dependent. We recently found that incubation with 27-OHC of RWPE-1 (normal epithelial) and LNCaP (cancer cells) increased cell proliferation in both cell lines. Interestingly, upon incubation of RWPE-1 and LNCaP with 27-OHC, we observed an increase in androgen receptor (AR) activity in RWPE-1, not in LNCaP. Furthermore, we found an increase in AR binding to the Androgen Response Element upon exposure of RWPE-1 to 27-OHC. We also found that upon silencing AR gene expression, 27-OHC-induced proliferation in RWPE-1 was markedly attenuated. Additionally, 27-OHC also diminished Docetaxel-mediated apoptosis in RWPE-1. Altogether, our results propose dysregulated levels of 27-OHC as a new risk factor for BPH and PCa. This indicates a novel role for 27-OHC in the etiopathogenesis of BPH and PCa.
Citation Format: Shaneabbas Raza, Megan Meyer, Bin Guo, Kimberly Hammer, Othman Ghribi. The cholesterol metabolite, 27-hydroxycholesterol induces hyperplasia in an androgen receptor-dependent manner in normal prostate RWPE-1 cells. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B20.
Abstract B39: Aspirin modifies immune cell infiltration of the colonic mucosa in Lynch syndrome: a possible mechanism for cancer prevention
Authors: Hartog Benjamin Lee , Coaker Julie , Bishop Timothy , Mathers John , Doeberitz Magnus von Knebel , Burn John , Kloor Matthias 
Published: October 2015

Abstract
The CAPP2 study showed that 600mg aspirin daily reduced the risk of colorectal cancer (CRC) in Lynch Syndrome (LS) patients. The mechanism by which this occurs is unknown. LS cancers are particularly immunogenic. Aspirin may reduce the risk of cancer in LS patients by altering the immune milieu of the colonic mucosa. We aimed to determine the density of Foxp3-positive T regulatory cells (Treg) or CD3-positive T-cells in the normal colonic mucosa of LS patients enrolled in the CAPP2 study. We then aimed to assess any links between this, aspirin use and tumour development. Serial sections (pre- and post-intervention) from normal colonic biopsies of LS patients treated with 600mg aspirin daily or placebo were immunohistochemically stained for Foxp3 and CD3. Half of the patients chosen in each treatment group developed cancer. The level of infiltration was determined by manually counting stained cells. Aspirin use increased the mean number of infiltrating Tregs from the pre- to the post-intervention biopsy (mean increase +5.33 Tregs/mm2, p=0.048) and this increase was significantly larger in the aspirin group than in the placebo group (aspirin +5.33 Tregs/mm2 v placebo -2.19 Tregs/mm2; p=0.01). There was a greater diversity of Treg counts in patients treated with aspirin compared to placebo. Total T-cell density appeared to be unaffected by aspirin. Aspirin may alter the risk of CRC development in LS patients by changing the immune infiltrate of the colon. Our results provide first evidence that aspirin influences the levels of infiltrating immune cells in the colonic mucosa of LS patients.
Citation Format: Benjamin Lee Hartog, Julie Coaker, Timothy Bishop, John Mathers, Magnus von Knebel Doeberitz, John Burn, Matthias Kloor. Aspirin modifies immune cell infiltration of the colonic mucosa in Lynch syndrome: a possible mechanism for cancer prevention. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B39.