bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-295: Food-based approach to cancer prevention: A phase I assessment of amorphous confections in modulating exposure and metabolism of black raspberry compounds in the oral cavity
Authors: Ahn-Jarvis Jennifer H. , Clinton Steven K. , Grainger Elizabeth M. , Simpson Christina , Gu Junnan , Teegarden Matthew D. , Riedl Kenneth M. , Knobloch Thomas J. , Weghorst Christopher M. , Schwartz Steven J. , Vodovotz Yael
Published: July 2016

Background: Oral cancer remains a major global malignancy, largely due to persistence of tobacco use worldwide. Preventive strategies focusing upon high risk individuals due to long term tobacco use or presence of pre-malignancy are needed. Based upon strong epidemiologic and laboratory evidence we have developed a black raspberry food-based product targeting this population and have tested variations in a phase I trial.

Objective:

1. To test three amorphous solids (glassy, elastic, and viscous) containing a bioactive rich black raspberry (BRB) fraction in a confectionary system for compliance.

2. To investigate the impact of amorphous structure in modulating oral exposure and metabolism of black raspberry compounds in the oral cavity as measured by differences in duration of black raspberry exposure and profile of black raspberry metabolites from saliva.

Methods: A four week, phase I, randomized, parallel study design with 60 non-smoking adults was used to investigate three amorphous forms having different release rates (prolonged, intermediate, and rapid), each at two doses (4 or 8 g BRB/day). Salivary kinetics and changes in black raspberry composition among and within individuals were assessed. HPLC with Tandem MS/MS was used to quantify and characterize black raspberry compounds from the confections and profile them in the saliva.

Results: All confections were well accepted having excellent adherence (94 ± 2%). Toxicities were limited to a grade I toxicity (NIH criteria). Oral residence time was 74% longer and saliva volume was 42% greater with glassy than the other two amorphous forms. Anthocyanin (cyanidin-3-glucoside) and ellagitannins were prevalent compounds in the saliva.

Conclusions: Three amorphous confectionary forms of a BRB food-based delivery vehicle demonstrated excellent compliance, with the glassy form showing potential for greater oral distribution, suggesting the potential for greater bioactivity. Food science and technology provides many strategies to develop novel and fully characterized food products for cancer prevention trials.

Citation Format: Jennifer H. Ahn-Jarvis, Steven K. Clinton, Elizabeth M. Grainger, Christina Simpson, Junnan Gu, Matthew D. Teegarden, Kenneth M. Riedl, Thomas J. Knobloch, Christopher M. Weghorst, Steven J. Schwartz, Yael Vodovotz. Food-based approach to cancer prevention: A phase I assessment of amorphous confections in modulating exposure and metabolism of black raspberry compounds in the oral cavity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-295.
Abstract LB-297: Antitumor immune response passively prevents and eliminates skin tumors on the mouse model of human papillomavirus cancers
Authors: Joh Joongho , Ghim Shinje , Chilton Paula M. , Park Jino , Wilcher Sarah A. , Proctor Mary L. , Jenson Alfred B.
Published: July 2016

Infection by mouse papillomavirus (PV), MmuPV1, of T cell-deficient, B6.Cg-Foxn1nu/J nude mice revealed that four, distinct squamous papilloma phenotypes developed simultaneously after infection of experimental mice. Papillomas appeared on the muzzle, vagina, and tail at or about day 42 days post-inoculation. The dorsal skin developed papillomas and hair follicle tumors (trichoblastomas) as early as 26 days after infection. When this aggressive tumor was transplanted into normal congenic strains, the transplant immediately regressed while the transplanted tumor into B6.Cg-Foxn1nu/J continued to grow. This result suggested that T-cell deficiency is critical to tumor formation. Passive transfer of hyperimmune sera from normal congenic mice immunized with MmuPV1 virus-like particles (VLPs) to T cell-deficient strains of mice prevented infection by virions of experimental mice. A cell adoption study showed that activated CD8+ populations collected during the regression process of MmuPV1 tumor explants efficiently eliminated both growing and established tumors in the model. Consequently, this study will provide an efficient immunotherapeutic strategy that can be employed to HPV-positive patients, who are at a risk of cancer development.

Citation Format: Joongho Joh, Shinje Ghim, Paula M. Chilton, Jino Park, Sarah A. Wilcher, Mary L. Proctor, Alfred B. Jenson. Antitumor immune response passively prevents and eliminates skin tumors on the mouse model of human papillomavirus cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-297.
Abstract LB-298: Gut microbiota changes in response to treatment with ursodeoxycholic acid
Authors: Caporaso J Gregory , Pearson Talima , Yellowhair Monia , Martinez Jessica , Lance Peter
Published: July 2016

Compelling evidence suggests that the gut flora influences colorectal cancer risk through direct effects on colonic bile acid composition. Bile acids are widely implicated in the etiology of colorectal cancer and the strongest evidence is for the secondary bile acid deoxycholic acid. In a study of patients with prior colorectal adenomas who were randomized to ursodeoxycholic acid (n = 188 males, 64 females), a bile acid based intervention aimed at modulating bile acid composition, or placebo (n = 162 males, 89 females), we determined effects of the intervention on the gut microbiome through 16S rRNA sequencing and bile acid composition using mass spectrometry.

We observe a consistent shift in microbial community phylogenetic composition for males (t = 5.83, p = 3.6e-8) and females (t = 3.14, p = 0.003) treated with UDCA. No effect was observed in the placebo group for either males (t = -0.08, p = 0.93) or females (t = -0.09, p = 0.92). This suggests that UDCA treatment, but not placebo treatment, is having an effect on the gut microbial communities of study participants. Interestingly, the microbiomes of the UDCA group do not change more than those of the placebo group: rather the magnitude of change is similar in the two groups, but UDCA treatment seems to drive specific microbiome changes.

We also observe significant correlations between the gut microbiome composition and bile acid composition (r = 0.31, p<0.001). Specifically we find that (prior to treatment) bile acids including CA, CDCA, and UDCA are negatively correlated with diversity (richness) and to a lesser extent the abundance of Bacteroidetes (phylum) in the gut.

These results are consistent with our previously reported observation that UDCA appears to have a greater effect in men for the prevention of colorectal adenomatous polyps, with risk-increasing effects for women. To our knowledge, this is the first study to correlate fecal bile acid levels with fecal microbial composition in humans or to assess the effect of the therapeutic bile acid UDCA on gut microbial composition. This study supports our observation that the efficacy of UDCA for the prevention of colorectal adenoma may be sex-dependent and suggests that the sex-specific effect may reflect differential effects of UDCA on the gut microbial community and the relationship between sex, the gut microbiome, and risk of colorectal adenomatous polyps.

Citation Format: J Gregory Caporaso, Talima Pearson, Monia Yellowhair, Jessica Martinez, Peter Lance. Gut microbiota changes in response to treatment with ursodeoxycholic acid. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-298.
Abstract LB-314: Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation
Authors: Lu Jianrong
Published: July 2016

The Warburg effect, which reflects cancer cells’ preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. Cancer cells restrain pyruvate flux into mitochondrial oxidative metabolism in large part by inhibiting the pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential implication of Src in tumor metabolism remained largely unclear. Here we report that active Src enzyme directly tyrosine-phosphorylates the PDH E1α subunit (PDHA1). Conversely, pharmacological Src inhibitors or depletion of Src by shRNA abolish PDHA1 tyrosine phosphorylation in cancer cells, suggesting that Src is the main kinase responsible for PDHA1 tyrosine phosphorylation. This Src-mediated modification inactivates PDH. Consistently, activation of Src attenuates PDH activity and generation of reactive oxygen species (ROS), which are byproducts of mitochondrial respiration. Src inhibitors activate PDH and increase cellular ROS levels. Importantly, expression of a tyrosine non-phosphorable PDHA1 mutant in Src-activated cancer cells restores PDH activity, increases mitochondrial respiration and oxidative stress, decreases experimental metastasis, and sensitizes cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg metabolic phenotype by inactivating PDH through tyrosine phosphorylation, and this metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. As inhibition of Src sensitizes cancer cells to pro-oxidants, combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.

Citation Format: Jianrong Lu. Oncogenic Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-314.
Abstract LB-328: Subtypes of urothelial carcinoma of the urinary bladder defined by genomic alteration combinations predict clinical characteristics
Authors: Khan Alyna , Fichtenholtz Alex , Ross Jeffrey , Frampton Garrett , Neumann Eric , Ali Siraj M. , Stephens Phil J.
Published: July 2016

Introduction: At least 70,000 patients will be diagnosed with bladder urothelial carcinoma (UC) in the United States this year. Current pathologic staging divides UC into muscle invasive (MIBC) and non-muscle invasive bladder cancer (NMIBC). Existing molecular classifications reveal a heterogeneous mutational landscape especially in the MIBC group, with studies finding that UC breaks down to anywhere from two to six classes defined by molecular features. These studies have utilized either select somatic alterations or high-dimensional mRNA expression data. Classifications of UC based on comprehensive genomic profiling (CGP) and subsequently detected somatic tumor alterations are conspicuously absent.

Methods: To create this CGP-based classification, 638 cases of mostly refractory or metastatic UC patients were assayed with CGP in the course of clinical care sequencing the coding exons of 287 cancer-related and 47 introns of 19 genes frequently rearranged in cancer and analyzing base-pair substitutions, indels, copy number alterations, and select gene fusions. Hierarchical latent class analysis (HLCA) a mixed-model classification method that finds highly statistically significant combinations of gene alterations, was applied to the resultant alteration profiles.

Results: HLCA detected the structure of somatic alteration combinations in UC, finding two main super classes driven by either CDKN2A/B co-deletion or TP53 and RB1 mutations, and subclasses further defined by altered genes in signal transduction (FGFR3, ERBB2, PIK3CA) and chromatin modifying (KDM6A, MLL2, ARID1A) pathways. These classes are predictive of clinical characteristics and tumor progression, and outperform existing molecular-based UC classifiers.

Conclusions: Identifying robust molecular subtypes of UC allows for appropriate assignment of patients to relevant clinical trials and can aid in electing suitable therapeutic strategies. Investigating the clinical context and targeted and immunotherapy implications of these subclasses will be essential for diagnostic, prognostic and therapeutic purposes.

Citation Format: Alyna Khan, Alex Fichtenholtz, Jeffrey Ross, Garrett Frampton, Eric Neumann, Siraj M. Ali, Phil J. Stephens. Subtypes of urothelial carcinoma of the urinary bladder defined by genomic alteration combinations predict clinical characteristics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-328.
Abstract LB-330: Somatic copy number alterations at oncogenic loci show diverse correlations with gene expression
Authors: Roszik Jason , Wu Ching Jiun , Siroy Alan E. , Lazar Alexander J. , Davies Michael A. , Woodman Scott , Kwong Lawrence N.
Published: July 2016

Somatic copy number alterations (SCNAs) affecting oncogenic drivers have a firmly established role in promoting cancer. However, no agreed-upon standard exists for calling locus-specific amplifications and deletions in each patient sample. Here, we report the correlative analysis of copy number amplitude and length with gene expression across 6,109 samples from The Cancer Genome Atlas (TCGA) dataset across 16 cancer types. Using specificity, sensitivity, and precision-based scores, we analyzed over 30 recurrently focally altered loci that had sufficient pan-cancer penetrance for robust statistical assessment. We were able to assign optimized amplitude and length cutoffs for nine recurrent SCNAs affecting known oncogenic drivers, using mRNA expression as a functional readout. These cutoffs captured the majority of SCNA-driven, highly-expression-altered samples. The majority of oncogenes required only amplitude cutoffs, as high amplitude samples were almost invariably focal; however, CDKN2A and PTEN uniquely required both amplitude and length cutoffs as primary predictors. For PTEN, these extended to downstream AKT activation. In contrast, the remaining 20+ assessed SCNA genes, particularly ones located peri-telomerically or in fragile sites, showed poor expression-copy number correlations. Finally, we describe several novel associations between copy number and gene expression that have implications for how SCNAs are assessed as harboring candidate cancer driver genes. Overall, our analyses identify optimized amplitude and length cutoffs as efficient predictors of gene expression changes for specific oncogenic SCNAs, yet warn against one-size-fits-all interpretations across all loci. Our results have implications for cancer data analyses and the clinic, where copy number and mutation data are increasingly used to personalize cancer therapy.

Citation Format: Jason Roszik, Ching Jiun Wu, Alan E. Siroy, Alexander J. Lazar, Michael A. Davies, Scott Woodman, Lawrence N. Kwong. Somatic copy number alterations at oncogenic loci show diverse correlations with gene expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-330.
Abstract LB-338: Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing
Authors: Fox Edward J.P. , Schmitt Michael W. , Reid-Bayliss Kate S. , Beckman Robert A. , Loeb Lawrence A.
Published: July 2016

The accumulation of somatic mutations is a defining hallmark of cancer. The genomes of solid tumors contain thousands of mutations that are present in most or all of the malignant cells in that tumor. In addition to these clonal mutations, subclonal mutations - those occurring only in a fraction of malignant cells - likely contribute to the phenotypic and morphologic heterogeneity of cancer cells within a tumor. These sub-populations may be the source for the rapid emergence of therapeutic resistance. The extent of subclonal mutations in cancer, however, has been difficult to quantify, as the high error rate of next-generation sequencing precludes reliable detection of mutations present in fewer than 5% of cells. Here, we apply the highly accurate Duplex Sequencing methodology to quantify the extent of subclonal mutations in 15 colorectal cancers (CRC) and paired normal mucosa. We also quantify the clonal somatic mutation load by exome sequencing. By sequencing known CRC driver and non-driver genes (depth >5,000X and accuracy >10-7), we find that colorectal cancers without known DNA repair deficits harbor an extensive complement of subclonal mutations, suggesting that mutational diversity of CRCs has been greatly underestimated. We show that normal colonic mucosa also accumulates substantial numbers of subclonal mutations, predominantly CG>TA transitions at CpG dinucleotides, in an age-dependent manner. However, the burden of tumor-associated subclonal mutations does not correlate with age and has a distinct spectrum (relative increase in TA>CG transitions) indicating different mechanisms of mutation accumulation are operative in normal and tumor tissue. The frequency of tumor cells harboring unique subclonal mutations is so high that it is likely that every possible neutral somatic point mutation is present by the time a tumor is clinically detectable This could account for the high frequency by which tumors become resistant to chemotherapeutic agents.

Citation Format: Edward J.P. Fox, Michael W. Schmitt, Kate S. Reid-Bayliss, Robert A. Beckman, Lawrence A. Loeb. Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-338.
Abstract LB-342: HDAC inhibition promotes tubulin-independent cancer cell migration
Authors: Hessler Lindsay K. , Boggs Amanda E. , Whipple Rebecca A. , Vitolo Michele I. , Chakrabarti Kristi R. , Bhandary Lekhana , Thompson Keyata N. , Martin Stuart S.
Published: July 2016

Breast cancer remains the most common cancer and second-leading cause of cancer-related death in women, with metastatic disease carrying a particularly poor prognosis. Despite advances with chemotherapeutic drugs aimed at tumor growth, we do not fully understand the effects of these drugs on the metastatic process. Histone deacetylase inhibitors (HDACi) are novel epigenetic therapies that induce cancer cell death through various mechanisms, including apoptosis, cell-cycle arrest and antiangiogenesis. Clinical trials investigating HDACi use in solid tumors are ongoing but have yielded mixed results. To date, very few studies have examined how HDACi influence the metastatic potential of breast tumor cells.

Since HDAC enzymes act on both histone and non-histone targets, HDACi drugs cause dramatic increases in non-histone protein acetylation, including acetylation of alpha-tubulin. A well-known marker of stable microtubules, tubulin acetylation increases in metastatic breast tumors and predicts poor patient survival. However, the effects of HDACi on tubulin-related cytoskeletal dynamics of tumor cells have not been previously examined. The current study investigates whether the use of HDACi in breast cancer cells could promote metastatic phenotypes.

Clinically-relevant HDAC pan-inhibitors that target multiple Class I HDAC enzymes (Entinostat) or both Class I and Class II (FDA-approved Vorinostat) yielded strong and rapid increases in the migration of both MCF-7 and Bt-549 breast cancer cells. In addition, Vorinostat and Entinostat were each able to strongly induce histone acetylation, while only Vorinostat induced tubulin acetylation. To determine if the increased tubulin acetylation induced by HDACi drugs was sufficient to induce tumor cell migration, we used an isotype-specific HDACi (Tubastatin) that selectively targets the Class II HDAC6 and therefore can increase tubulin acetylation. At doses which strongly induce tubulin acetylation, Tubastatin did not increase tumor cell migration or other tubulin-dependent cancer cell processes, including reattachment and microtentacle formation. Vorinostat and Entinostat therefore induce tumor cell migration through a tubulin-independent mechanism, indicating that more precise targeting of HDAC enzymes could help avoid therapeutic approaches that induce metastatic phenotypes.

Citation Format: Lindsay K. Hessler, Amanda E. Boggs, Rebecca A. Whipple, Michele I. Vitolo, Kristi R. Chakrabarti, Lekhana Bhandary, Keyata N. Thompson, Stuart S. Martin. HDAC inhibition promotes tubulin-independent cancer cell migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-342.
Abstract LB-345: Acetylenic tricyclic bis-(cyano enone) interacts with cysteine residues of actin and inhibits non-small cell lung cancer cell migration
Authors: Chan Eddie , Saito Akira , Honda Tadashi , Di Guglielmo John
Published: July 2016

During epithelial-to-mesenchymal transition (EMT), epithelial cells lose their cell-cell junctions, apical-basal polarity, and reorganize their actin cytoskeleton. These changes, among others, increase the motility of individual cells and promote a highly invasive phenotype. The actin cytoskeleton is also key in cell migration and invasion, as the polymerization of actin at the leading edge provides the necessary driving force for translocation and protrusions. Therefore, the actin cytoskeleton is a potential target for inhibiting tumour progression. In this study we characterized a novel tri-cyclic synthetic triterpenoid derivative, TBE-31, in its ability to associate with actin and inhibit cell migration. Using a pull-down approach, we demonstrate that TBE-31 binds directly to actin. Furthermore, TBE-31 inhibited branched and linear actin polymerization in vitro, and stress fibre formation in cultured cells. Actin cytoskeleton reorganization and stress fiber formation was also inhibited in TGFβ-dependent EMT of non-small cell lung cancer cells. We next used SwissDock software to investigate the potential molecular interaction between TBE-31 and actin. Swissdock predicted that TBE-31 would have a high affinity for binding to the same cleft as Cytochalasin D, a bona-fide actin polymerization inhibitor. As triterpenoids associate with cysteine residues in target proteins, we generated cysteine to alanine mutants of actin and verified TBE-31 binding using pull-down assays. We identified that cysteine 374 is important for TBE-31 interaction with actin. Finally, we observed that TBE-31 inhibited fibroblast and non-small cell lung tumour cell migration with an IC50 of 1.0 and 2.5 μM, respectively. Taken together, our results suggest that TBE-31 targets actin polymerization to alter cell morphology and inhibit cell migration.

Citation Format: Eddie Chan, Akira Saito, Tadashi Honda, John Di Guglielmo. Acetylenic tricyclic bis-(cyano enone) interacts with cysteine residues of actin and inhibits non-small cell lung cancer cell migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-345.
Abstract LB-362: A six-gene classifier stratifies low-grade glioma patients with wild-type IDH
Authors: Huebner Alexander , Oehlke Oliver , Juratli Tareq A. , Meng Wei , Ibrahim Ahmed , Li Bin , Erny Daniel , Robe Pierre , Krex Dietmar , Schackert Gabriele , Prinz Marco , Grosu Anca , Chakravarti Arnab
Published: July 2016

Gliomas are the most common primary brain tumors presenting a heterogeneous group of malignancies. Particularly, there is a significant heterogeneity in outcomes of patients with grade II and grade III gliomas. There has been recent progress in reclassifying glomas by integrating molecular signatures such as IDH mutation status, 1p/19q co-deletion and alternative telomer maintenance to the established histopathological classification scheme. Patients with IDH wild-type (WT) gliomas are found to have the worst prognosis. Currently there is no prognostic or predictive biomarker within this group of patients.

To this end, the goal of the current study was to develop a gene classifier for identifying a prognostic/predictive biomarker model for grade II and grade III gliomas with IDH WT, which would have the potential of identifying patient groups with distinct degrees of risk for disease progression, treatment options, and survival outcome. Our approach was to identify a robust list of candidate genes using multiple datasets and create a single score classifier based on the expression of identified genes. We analyzed multiple datasets comprising a total of 756 glioma patients using a meta-analysis approach which identified six prognostic genes. A linear model consisting of these six genes was trained in an institutional cohort by employing RNAseq and qRT-PCR techniques to measure the gene expression and validated in an independent grade II/III glioma set (TCGA LGG).

The classifier performed significantly in both the institutional cohort of 85 grade II/III glioma patients (HR, 29.94; 95% CI, 3.96-226.36; p = 0.001) and in the TCGA LGG dataset consisting of 416 glioma patients (HR, 4.03; 95% CI, 1.82-8.92; p = 0.001, for low versus high risk group). Multivariate Cox regression analysis validated the risk classifier independent of other clinical factors. After analyzing patient populations separately, based on IDH mutation status, we discovered that the classifier performed with high significance in the patients with IDH WT both in the institutional cohort and the TCGA LGG dataset (HR, 1.93; 95% CI, 1.24-3.02; p = 0.004 and HR, 1.99; 95% CI, 1.38-2.87; p < 0.001 respectively) reliably predicting the clinical outcomes.

Citation Format: Alexander Huebner, Oliver Oehlke, Tareq A. Juratli, Wei Meng, Ahmed Ibrahim, Bin Li, Daniel Erny, Pierre Robe, Dietmar Krex, Gabriele Schackert, Marco Prinz, Anca Grosu, Arnab Chakravarti. A six-gene classifier stratifies low-grade glioma patients with wild-type IDH. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-362.
Abstract PL02-01: Isogenic tumors can utilize heterogeneous mechanisms of nutrient uptake
Authors: Thompson Craig B. , Palm Wilhelm , Ye Jiangbin , Pavlova Natalya N. , King Bryan
Published: July 2016

An emerging feature of cancer cell metabolism is the ability to acquire the anabolic precursors necessary to support cell viability and growth from a nutrient-poor environment. Cell proliferation studies undertaken under nutrient-limiting conditions have led us to define two distinct pathways by which tumor cells gain a competitive advantage over their nontransformed counterparts. One pathway is defined by enhanced capture of existing glucose and amino acids through nutrient-selective transporters. The key mediators of this pathway are AKT and its downstream effector, mTORC1. The other pathway depends on the uptake and degradation of extracellular proteins and lipids. Oncogenic forms of RAS are potent activators of this pathway. Many tumors appear capable of using both nutrient uptake pathways and can switch between them depending on extracellular nutrient conditions. Implications of these findings for tumor heterogeneity and therapeutic responsiveness will be discussed.

Citation Format: Craig B. Thompson, Wilhelm Palm, Jiangbin Ye, Natalya N. Pavlova, Bryan King. Isogenic tumors can utilize heterogeneous mechanisms of nutrient uptake. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL02-01.
Abstract PL04-03: Heterogeneity, drug resistance, and clonal evolution in colorectal cancers
Authors: Bardelli Alberto
Published: July 2016

When metastatic cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? To address this question a deeper understanding of the evolutive nature of cancer cells is necessary. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor's evolution the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. Another approach is to unleash the ability of the immune system to recognize drug resistant cells. We tested this possibility in syngeneic mouse models of CRC sensitive to targeted therapies. Our findings indicate that manipulation of the mutational loads can trigger prolonged therapeutic responses that are not observed when cancer cells are challenged with targeted drugs alone. We postulate that rationally combined targeted and immuno-therapies can restrain tumor evolution, and can limit the emergence of drug resistance thus leading to long-term responses.

Citation Format: Alberto Bardelli. Heterogeneity, drug resistance, and clonal evolution in colorectal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL04-03.
Abstract SY10-01: How aneuploidy drives cancer
Authors: Davoli Teresa , Uno Hajima , Xu Andrew , Mengwasser Kristen , Sack Laura , Park Peter J. , Elledge Stephen J.
Published: July 2016

Aneuploidy has been recognized as a hallmark of cancer for over 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. We developed Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8200 tumor-normal pairs we provide statistical evidence suggesting many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. These genes represent the vast majority of cancer drivers and the genetic networks they drive are a focus of future cancer system biological approaches to cancer research. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and the potency of TSGs (STOP genes), OGs and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity. We are now assessing how aneuploidy drives cancer and the potency with which it does so. We have found that aneuploidy predicts survival better than mutational drivers and as well as existing clinical parameters in many cases. We have also discovered that different classes of aneuploidy drive transcriptional programs for two hallmarks of cancer and will present data supporting these observations and their implications.

Citation Format: Teresa Davoli, Hajima Uno, Andrew Xu, Kristen Mengwasser, Laura Sack, Peter J. Park, Stephen J. Elledge. How aneuploidy drives cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY10-01.
Abstract SY12-01: PI 3-kinase and cancer metabolism
Authors: Cantley Lewis C.
Published: July 2016

In general cancer cells produce higher levels of reactive oxygen species (ROS) than normal cells due to increased rates of metabolism and defective mitochondria. In order to survive under conditions of high ROS, cancer cells typically turn on pathways for generating NADPH and glutathione to bring ROS levels back to homeostasis. Activating mutations in PIK3CA or loss of PTEN or activating mutations in KRAS can stimulate glucose uptake and metabolism and pathways for generating NADPH and glutathione to suppress ROS. A detailed understanding of the biochemical mechanisms by which cancer cells suppress excess ROS may suggest new therapies for inducing synthetic lethality in tumors that evolve in specific mutational backgrounds. Our research using human cancer cell lines and genetically engineered mouse models suggests new approaches for killing cancer cells by targeting metabolic pathways for ROS suppression that allow cancer cells to survive.

Citation Format: Lewis C. Cantley. PI 3-kinase and cancer metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY12-01.
Abstract SY15-01: SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities
Authors: Roberts. Charles W.M.
Published: July 2016

Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least nine different SWI/SNF subunits, collectively identified in twenty percent of all cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription.

My laboratory began studying the SWI/SNF complex when SNF5 (SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to tumor suppression over fifteen years ago when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT we have shown that these cancers are diploid and have remarkably simple genomes. We now study the complex using mouse models, cell lines and primary human tumor samples. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented including our recent efforts that identify EZH2 and polycomb complexes as potential therapeutic vulnerabilities in these cancers.

Citation Format: Charles W.M. Roberts. SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY15-01.
Abstract SY15-02: Identification of novel oncogenic mechanisms in brain tumors with quiet genomes through mapping the enhancer landscape
Authors: Erkek Serap , Pajtler Kristian W. , Johann Pascal D. , Northcott Paul A. , Chavez Lukas , Kool Marcel , Pfister Stefan M.
Published: July 2016

Malignant pediatric brain tumors, including ependymoma, medulloblastoma and atypical teratoid/rhabdoid tumors, frequently demonstrate a very “quiet” genome with very few nonsynonyomous single nucleotide variants or indels and a stable copy number profile. The recent advance of integrative genomics approaches from primary tumor tissue including whole-genome sequencing, RNA sequencing, whole-genome bisulfite sequencing, and ChIP sequencing for core histone marks and important transcription factors and chromatin configuration have enabled the discovery of new tumor-driving pathways and potentially druggable alterations in these cancers with quiet genomes. This knowledge after functional validation in vitro and in vivo provides critical insight in the search for the cell of origin in these tumors, the understanding of underlying pathomechanisms, and the identification of new treatment options.

Citation Format: Serap Erkek, Kristian W. Pajtler, Pascal D. Johann, Paul A. Northcott, Lukas Chavez, Marcel Kool, Stefan M. Pfister. Identification of novel oncogenic mechanisms in brain tumors with quiet genomes through mapping the enhancer landscape. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY15-02.
Abstract SY18-02: Immunogenomics and precision cancer medicine
Authors: Van Allen Eliezer
Published: July 2016

The expansion of precision cancer medicine through robust interrogation of cancer genomes at the point of care has enhanced patient stratification and treatment selection strategies in numerous cancer types. In parallel, the rise of multiple immunotherapies, such as immune checkpoint blockade, has significantly improved clinical outcomes for multiple patient populations. The intersection of clinical cancer genomics and immuno-oncology has created an opportunity to learn how the tumor and germline genomes impact immune checkpoint blockade response, and how the immune system can be leveraged with knowledge of the cancer genome to more effectively stratify patients and tailor immune-specific therapies. Here, we describe the landscape of genomic correlates of immune checkpoint blockade, and examine how emerging genomic studies of immunotherapy responders and non-responders may inform patient selection strategies for clinical trial design. Furthermore, we explore how knowledge of the cancer genome and prioritization of neoantigens that arise from somatic mutations may impact personalized cancer vaccine development. Finally, we examine emerging data on genomic resistance to immunotherapies and the implications for combination treatment strategies. Broadly, the convergence of comprehensive clinical genomics and immuno-oncology treatment strategies may inform precision medicine for immunotherapies across cancer types.

Citation Format: Eliezer Van Allen. Immunogenomics and precision cancer medicine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY18-02.
Abstract SY28-01: Immunotherapy in combination with neoadjuvant therapy and immune-related adverse events
Authors: Smyth Mark J. , Liu Jing , Blake Stephen J. , Teng. Michele WL
Published: July 2016

Immunotherapy has recently entered a renaissance phase with the approval of multiple agents for the treatment of cancer. Immunotherapy stands ready to join traditional modalities, including surgery, chemotherapy, radiation, and hormone therapy, as a pillar of cancer treatment. Although immunotherapy has begun to have success in advanced cancer treatment, its scheduling and efficacy with conventional therapies, such as surgery, has not been systematically examined. Here, we have used two models of spontaneously metastatic breast cancers in mice to compare the therapeutic power of neoadjuvant versus adjuvant immunotherapies in the context of primary tumor resection. Therapies, including Treg depletion, anti-PD-1 or anti-PD1/anti-CD137 combinations were evaluated. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8+ T cells immediately prior to and post surgery may provide a predictor of outcome. New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAEs) in humans. Prolonged T regulatory cell (Treg) depletion in tumor bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab treated patients, while transient Treg depletion and anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily provoked following treatment with additional immunomodulatory antibodies. This platform has been used to compare a number of promising immunotherapies.

Citation Format: Mark J. Smyth, Jing Liu, Stephen J. Blake, Michele WL Teng. Immunotherapy in combination with neoadjuvant therapy and immune-related adverse events. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY28-01.
Abstract SY31-03: The future of combinations of immunomodulators with local radiation: toward a personalized immunotherapy approach
Authors: Demaria Sandra
Published: July 2016

We have shown in multiple preclinical tumor models that ionizing radiation therapy can convert tumors refractory to immune checkpoint inhibitors and other immune modulators into responsive ones. Importantly, the elicited antitumor T cells rejected not only the irradiated tumor but also nonirradiated spontaneous metastases or synchronous palpable tumors (abscopal effect), demonstrating the potential of radiation to generate systemically effective antitumor immune responses.

Investigations into the mechanisms underlying a successful response have highlighted a complex interaction between radiation and anti-CTLA-4 occurring at the priming and effector phase of the antitumor immune response. These data support a model whereby the irradiated tumor becomes a “live attenuated vaccine” resulting in marked expansion of a limited number of distinct T-cell clones within the tumor.

Our data also suggest that generation of an in situ tumor vaccine by radiation is regulated by the intrinsic tumor immunogenicity, the host immune system, and the radiation regimen employed. The interaction of these three compartments determines the levels of immune modulating mediators in the tumor microenvironment, including interferon type I, transforming growth factor-b, and adenosine, which in turn control the number and state of activation of intratumoral dendritic cells, and the magnitude of the induced T-cell response. Thus, while radiation offers the promise of a simple treatment to achieve individualized vaccination against each patient's own tumor, success is likely to be achieved by a personalized combination of the most effective radiation regimen and immune modulator(s).

We have recently shown in non-small cell lung cancer patients with chemotherapy-refractory metastatic disease that the synergy of radiotherapy and anti-CTLA-4 can be translated in the clinic (NCT02221739). Analysis of tumor and peripheral blood from responding and non-responding patients are beginning to provide clues to potential biomarkers and underlying mechanisms of response. Overall, local radiotherapy is showing the potential to be an ideal partner for immunotherapy. Because of its universal use in cancer treatment it is tempting to test standard of care radiotherapy in combination with any immunotherapy. However, rational use of radiation regimens and targeting of specific immune suppressive factors preexisting or elicited by radiation in a given tumor will be needed to truly reveal radiation's role in personalized immunotherapy.

Citation Format: Sandra Demaria. The future of combinations of immunomodulators with local radiation: toward a personalized immunotherapy approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY31-03.
Abstract SY42-01: Emerging epigenetic targets in high-risk pediatric solid tumors
Authors: Stegmaier Kimberly
Published: July 2016

Pediatric cancers are typically characterized by simple genomes and key initiating events driven by aberrancy of a transcription factor or chromatin modifier. One such example is the most common extracranial solid tumor in children, neuroblastoma. Amplification of the transcription factor encoding gene MYCN is present in ∼50% of high-risk neuroblastomas, representing the best-characterized genetic marker of poor survival in these pediatric patients. We have focused on the discovery of new therapeutic strategies to targeting this recalcitrant subtype of neuroblastoma using chemical and functional genomic approaches. First, we identified BET bromodomain inhibitors as highly active in MYCN-amplified neuroblastoma in an unbiased screen of 673 diverse cancer cell lines and validated this finding using genetic suppression with shRNA and chemical inhibition with multiple BET inhibitors. Mechanistically, BET inhibitors suppress the MYCN transcriptional program and the expression of MYCN itself. Extending these studies in vivo, both to patient derived xenografts (PDX) and to genetically engineered mouse (GEM) models of MYCN-driven neuroblastoma, we demonstrated remarkable efficacy. However, this single agent approach was not curative, suggesting the need for combination therapies. In order to address this issue, we performed both gain-of-function (ORF) and loss-of-function (CRISPR/Cas9) screening of neuroblastoma cell lines treated with BET bromodomain inhibitors at an IC90 to identify potential mechanisms of resistance to treatment and to nominate targetable pathways for combination therapy. Three key pathways emerging at the intersection of these screens are under evaluation and will be presented. In parallel, we have performed a genome-wide CRISPR screen in a panel of 8 neuroblastoma cell lines, 7 of which are MYCN amplified, to identify new dependencies. In comparing neuroblastoma cell lines to over 70 non-neuroblastoma cancer cell lines, several known neuroblastoma dependencies were confirmed, including MYCN, ALK, and PHOX2B. Importantly, novel dependencies were revealed. Validated new dependencies will also be the topic of this presentation.

Citation Format: Kimberly Stegmaier. Emerging epigenetic targets in high-risk pediatric solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY42-01.