bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract CT082: Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026
Authors: Peters Solange , Creelan Benjamin , Hellmann Matthew D. , Socinski Mark A. , Reck Martin , Bhagavatheeswaran Prabhu , Chang Han , Geese William J. , Paz-Ares Luis , Carbone David P.
Published: July 2017

Background: CheckMate 026 is a randomized trial of nivolumab monotherapy versus platinum doublet chemotherapy in patients with untreated stage IV or recurrent non-small cell lung cancer (NSCLC) and ≥1% programmed death-1 ligand 1 (PD-L1) tumor expression. Nivolumab was not associated with improved progression-free survival (PFS) versus chemotherapy in patients with ≥5% PD-L1 expression, however, nivolumab had a favorable safety profile compared with chemotherapy and overall survival (OS) was similar between treatment arms. In an exploratory analysis, we assessed whether patients with high tumor mutation burden (TMB) may derive enhanced benefit from nivolumab compared with platinum doublet chemotherapy.

Methods: TMB scores for missense, somatic mutations were determined in patients with sufficient samples for whole exome sequencing of tumor and matched whole blood DNA. For the initial analyses, patients were equally divided into groups based on TMB tertile distribution. Patients in the low, medium, and high TMB tertiles had 0-99, 100-242, and ≥243 mutations, respectively.

Results: Of 541 randomized patients, 312 (57.7%) had evaluable data to determine TMB. The percentage of patients with high TMB was lower in the nivolumab arm than in the chemotherapy arm (29.7% vs 39.0%). Baseline characteristics, PFS, and OS in patients evaluable for TMB were similar to all randomized patients. In patients with high TMB, PFS was improved (median PFS of 9.7 vs. 5.8 months; HR, 0.62; 95% CI, 0.38 to 1.00) and objective response rate was higher with nivolumab versus chemotherapy (46.8% vs 28.3%). OS in patients with high TMB was similar between the 2 treatment arms, which may be attributable in part to a 65% crossover rate to nivolumab in the chemotherapy arm for this subgroup.

Conclusions: This is the first pivotal randomized phase 3 trial to incorporate an analysis evaluating TMB and clinical benefit with programmed death-1 inhibitor therapy. The findings of this exploratory retrospective analysis suggest that nivolumab improves ORR and PFS compared with platinum doublet chemotherapy in patients with high TMB.

Citation Format: Solange Peters, Benjamin Creelan, Matthew D. Hellmann, Mark A. Socinski, Martin Reck, Prabhu Bhagavatheeswaran, Han Chang, William J. Geese, Luis Paz-Ares, David P. Carbone. Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026 [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 CT082. doi:10.1158/1538-7445.AM2017-CT082
Abstract CT102: Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort
Authors: Odia Yazmin , Schulte Jessica , Iwamoto Fabio
Published: July 2017

Tumor-treating fields (TTF) are approved for use in patients with glioblastomas at recurrence (2011) or adjuvant setting (2016) due to survival benefit in various trials. Since 12/2012, 46 patients were treated with TTF for de novo or recurrent gliomas at Columbia University. Rates and outcomes of combination with immunotherapy were analyzed, given the recent preclinical data of synergism between TTF and PD1 targeted therapy. The impact of compliance was also analyzed in multivariable analyses in this retrospective cohort.

Of 44 treated patients, 18 (41%) were women and 2 (5%), 4 (9%) and 36 (86%) had WHO grade II, III and IV gliomas. Median age at diagnosis was 56 (23-84) years. TTF was used at recurrence in 38 (86%), with a median of 2 (0-4) prior recurrences. Prior therapies included bevacizumab (22, 50%), surgery [25/44 (57%) gross total], radiation and temozolomide. Median TTF therapy duration was 1.8 (0.1-20.3) months. Only 2 (5%) experienced skin toxicity requiring interruptions. Compliance goal of 75% was met by 11/44 (25%) glioma patients. Concurrent systemic therapy was used in 35 (80%), including temozolomide (12, 27%), nitrosourea (2, 5%), bevacizumab (17, 39%), immunotherapy (26, 59%) or other (5, 11%).

Objective response rate (ORR) based on RANO was noted in 25/42 (60%) of all gliomas and 21/38 (55%) of glioblastomas, At interim follow-up, progression free (PFS) and overall (OS) survival were 2.7 and 6.9 months, respectively. PFS was significantly increased among glioblastoma patients treated with concurrent immunotherapy (PFS: 3.3 vs. 1.95, p=0.0364). Long-term follow-up PFS and OS will be re-analyzed, along with the potential confounding impact of compliance rates.

TTF improves survival for patients with glioblastomas. Immunotherapy shows promise for various tumor histologies. The possible synergism between these modalities in preclinical studies and this retrospective glioma series warrants further study in randomized controlled gliomas trials. We propose a single-arm phase II trial of concurrent PD1 inhibitor and TTF for patients with bevacizumab-naïve glioblastoma at second or third recurrence. OS is the primary endpoint; secondary endpoints include PFS, ORR, predictive value of PDL1 expression, and impact of compliance. Results from the EF-14 trial will serve as a historical control.

Citation Format: Yazmin Odia, Jessica Schulte, Fabio Iwamoto. Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort [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 CT102. doi:10.1158/1538-7445.AM2017-CT102
Abstract CT134: Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma
Authors: Weiss Glen J. , Waypa Jordan , Coats Jessica , Blaydorn Lisa , McGahey Kayla , Sangal Ashish , Whitehead Robert P. , Khemka Vivek
Published: July 2017

Background: Pembrolizumab (P) is a checkpoint inhibitor that blocks the interaction between programmed cell death protein 1 on T-cells and PD-L1 and PD-L2 on tumor cells. We conducted a single center phase Ib/II study of gemcitabine, nab-paclitaxel, and P (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) (NCT02331251).

Methods: PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% were eligible and received gemcitabine and nab-paclitaxel on days 1 and 8 and P 2 mg/kg on day 1 every 21 days until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months.

Results: 17 pts with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Any grade drug-related treatment adverse events (AEs) occurred in 100% of patients; the most common (>20% pts) were anemia, thrombocytopenia, hypoalbuminemia, ALT and ALK elevation, fatigue, rash, nausea, vomiting, diarrhea, fever, insomnia, and edema in limbs. Grade 3 events (>10% pts) were hyponatremia, thrombocytopenia, and neutropenia (2 case each, 11.8%). Dose-limiting toxicities occurred only in previously treated PDAC (grade 3 thrombocytopenia; grade 3 fatigue and thrombocytopenia) and the cohort was subsequently divided into chemo naïve and previously treated pts. The recommended phase II dose (RP2D) for chemo naïve PDAC was gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. Of the 8 evaluable chemo naïve PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 2 PR on treatment for ~11 and 15 months and there are 3 pts still too early to assess. The primary endpoint of >15% complete response was not met. The best response for previously treated pts was SD. For chemo naïve and previously treated PDAC, the 6-month survival rate is 89% (with 3 pts still on study less than 3 months) and 40%, respectively. The median PFS and OS is 5 and 10.3 months and 2.1 and 4.1 months for chemo naïve and previously treated pts, respectively.

Conclusions: GNP can be safely given to chemo naïve PDAC pts. Efficacy appears to be similar to slightly improved over previously reported results for standard weekly x 3 every 28 day gemcitabine and nab-paclitaxel dosing.

Citation Format: Glen J. Weiss, Jordan Waypa, Jessica Coats, Lisa Blaydorn, Kayla McGahey, Ashish Sangal, Robert P. Whitehead, Vivek Khemka. Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT134. doi:10.1158/1538-7445.AM2017-CT134
Abstract CT141: Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy
Authors: Rulseh Aaron , Šroubek Jan , Klener Jan , Vymazal Josef
Published: July 2017

Introduction: Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy.

Materials and Methods: Tumor treating fields (TTFields) therapy is a novel treatment technique that has recently shown significant prolonged progression free survival and overall survival innewly diagnosed GBM. This therapy is approved for the treatment of newly diagnosed and recurrent GBM and is based on the principle that low intensity, intermediate frequency alternating electric fields (100 to 300 kHz) have an anti-mitotic effect in specific cell types. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest.

Results: Our center was the first in the world to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals (10 GBM and 10 RGBM) in 2004 and 2005, and 4 of the original 20 patients are still alive today (2 GBM, 2 RGBM), in good health and no longer receiving any treatment roughly 12 years after initiating TTField therapy, with no clinical or radiological evidence of recurrence. Two of the 4 surviving patients exhibited radiological signs of tumor growth initially, before the tumor regressed in size after a median of 4 months of continuous treatment.

Conclusions: Our results indicate that TTField treatment may be remarkably successful for both newly diagnosed and recurrent GBM patients. Further investigation is needed to identify any unique characteristics of these patients. We recommend that TTField treatment should be applied for a sufficient amount of time, and that initial radiologic progression following treatment initiation should not be considered a reason to discontinue treatment.

Citation Format: Aaron Rulseh, Jan Šroubek, Jan Klener, Josef Vymazal. Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy [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 CT141. doi:10.1158/1538-7445.AM2017-CT141
Abstract CT161: METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC
Authors: Mehta Minish P. , Gondi Vinai , Brown Paul D.
Published: July 2017

BACKGROUND

Tumor Treating Fields (TTFields) are noninvasive regional antimitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly diagnosed glioblastoma patients.

TRIAL DESIGN

270 patients with 1-10 brain metastases (BM) from NSCLC will be randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2nd cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2st cerebral progression.

Objectives: To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population.

Endpoints: Time to 1st cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary).

Main eligibility criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, no electronic implantable devices in the brain.

Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day will be applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease.

Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.

Citation Format: Minish P. Mehta, Vinai Gondi, Paul D. Brown. METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC [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 CT161. doi:10.1158/1538-7445.AM2017-CT161
Abstract DDT01-01: The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma
Authors: Hughes Paul E.
Published: July 2017

Mcl-1 is a prosurvival member of the Bcl-2 family of proteins, which regulate programmed cell death via protein-protein interactions between prosurvival and proapoptotic members of the family. A variety of studies have demonstrated that Mcl-1 is a key prosurvival factor for many human cancers, making it a highly desirable target for therapeutic intervention. However, targeting Mcl-1 to induce tumor cell death has been an exceptional challenge for the development of drug-like small molecule inhibitors due to the high-affinity interaction of Mcl-1 with proapoptotic binding partners and the lack of an obvious small molecule binding pocket. In this presentation we will describe the application of structural analysis and molecular modeling to the optimization of an HTS screening hit that culminated in the identification of a clinical candidate, AMG 176. In addition, we will present data demonstrating that AMG 176 is a potent, highly selective, and reversible Mcl-1 inhibitor. Mechanism-of-action studies revealed that AMG 176 induces a rapid and irreversible commitment to apoptosis in tumor cells via the disruption of protein-protein interactions with proapoptotic members of the Bcl-2 family. Furthermore, the extensive profiling of a large and diverse tumor cell line panel revealed that lines derived from hematologic malignancies, such as multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma, are particularly sensitive to Mcl-1 inhibition with the expression of Bcl-xL inversely correlating with response. In addition, cell line profiling data revealed an activity profile distinct from a selective Bcl-2 inhibitor, further underscoring the unique therapeutic opportunity for an Mcl-1 inhibitor. Synergistic combinations were identified with therapies selectively targeting Bcl-2, the MAPK pathway, and proteasome inhibitors. In vivo, AMG 176 demonstrated robust inhibition of tumor xenograft growth with a clear PK/PD relationship, exhibiting on-mechanism activity as measured by Bak and caspase activation on a discontinuous dosing schedule of once or twice weekly. An ongoing phase 1 clinical trial is currently evaluating AMG 176 in multiple myeloma.

Citation Format: Paul E. Hughes. The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma [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 DDT01-01. doi:10.1158/1538-7445.AM2017-DDT01-01
Abstract LB-002: Optimizing immunogenicity prediction of neoepitopes
Authors: Kosaloglu-Yalcin Zeynep , Lanka Manasa , Sidney John , Vaughan Kerrie , Greenbaum Jason , Sette Alessandro , Peters Bjoern
Published: July 2017

Epitopes that arise from a somatic mutation, so called neoepitopes, are now known to play a key role in cancer immunology and immunotherapy. Recent advances in high-throughput sequencing have made it possible to identify all mutations and thereby all potential neoepitope candidates in an individual cancer. It has however become evident that the vast majority of these neoepitope candidates do not induce a T cell response when tested in vivo or in vitro, i.e. they are not immunogenic. Especially in patients with a high mutational load, usually hundreds of potential neoepitopes are detected, highlighting the need to further narrow down this candidate list. Several studies have used different combinations of immunoinformatic tools such as MHC binding predictions to prioritize the initial set of neoepitopes candidates. The tools to use and thresholds to apply for this prioritization has so far been largely based on experience with epitope identification in other settings such as infectious disease and allergy. To establish the appropriate tools and thresholds in the cancer setting, we here curated a set of immunogenic neoepitopes from the published literature and performed detailed analyses to detect what features discriminate immunogenic neoepitopes from a background set of mutated peptides. We experimentally measured the HLA binding affinity of all curated immunogenic neoepitopes. In doing so, we aimed to identify the optimal affinity threshold to effectively identify immunogenic neoepitopes. As a next step, we sought to assess the added value of different immunoinformatics tools, including various HLA binding prediction algorithms, processing prediction, stability prediction, and immunogenicity prediction, to most effectively detect immunogenic neoepitopes. The obtained results are now going to be used to facilitate the development of more accurate prediction algorithms.

Citation Format: Zeynep Kosaloglu-Yalcin, Manasa Lanka, John Sidney, Kerrie Vaughan, Jason Greenbaum, Alessandro Sette, Bjoern Peters. Optimizing immunogenicity prediction of neoepitopes [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 LB-002. doi:10.1158/1538-7445.AM2017-LB-002
Abstract LB-003: Racial differences of intron retention and DNA methylation in breast cancer
Authors: Kim Dongwook , Shivakumar Manu , Lee Youngji , Olopade Olufunmilayo , Kim Dokyoon , Lee Younghee
Published: July 2017

Regulation of gene expression by DNA methylation in gene promoter regions is well-studied; however, the effects of methylation in the gene body (i.e., exons and introns) on gene expression are comparatively understudied. Recently, hyper-methylation has been implicated in the inclusion of alternatively spliced exons; moreover, exon recognition can be enhanced by recruiting the methyl-CpG-binding protein (MeCP2) to hyper-methylated sites. In this study, we examined whether or not the level of methylation of an intron is correlated with how frequently that intron is retained during splicing using DNA methylation and RNA sequencing data from breast cancer tissue samples in The Cancer Genome Atlas (TCGA). We found that hypo-methylation of introns is correlated with higher levels of intron expression in mRNA and that most novel cancer-specific mRNA isoforms are due to intron retention. The methylation level of an intron is inversely correlated with its retention in mRNA transcripts from the gene in which it is located. Furthermore, we observed significant racial differences in the methylation level of retained introns: In samples from African-American donors, retained introns were not only less methylated compared to Caucasian donors, but also were more highly expressed. This underscores the need for Understanding racial epigenetic differences and their correlation with breast cancer is an important step toward achieving personalized cancer care.

Citation Format: Dongwook Kim, Manu Shivakumar, Youngji Lee, Olufunmilayo Olopade, Dokyoon Kim, Younghee Lee. Racial differences of intron retention and DNA methylation in breast 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 LB-003. doi:10.1158/1538-7445.AM2017-LB-003
Abstract LB-005: Precise and rapid detection of gene fusions and microbial pathogens in next-generation sequencing data with sequence bloom trees
Authors: Lehnert Erik D. , Freeman Eric , Salzman Julia
Published: July 2017

Public archives of sequencing data continue to grow at a rapid pace. (Re)analysis of large datasets can be both expensive and resource-intensive, and users are often only interested in the sample prevalence of a small subset of sequences. We have implemented a Sequence Bloom Tree data structure for the TCGA RNA-seq datasets, allowing researchers to rapidly test samples for the presence of sequences of interest. We demonstrate the ability to rapidly identify samples containing viral transcript sequences, estimate the sample prevalence of gene fusions and novel splice variants, and infer the presence of HeLa-cell contamination in a subset of TCGA data. We have implemented post-querying controls to mitigate false positives arising from the presence of genes with highly similar sequences. The tools are described using Common Workflow Language, allowing researchers to reproducibly generate and query the dataset.

Citation Format: Erik D. Lehnert, Eric Freeman, Julia Salzman. Precise and rapid detection of gene fusions and microbial pathogens in next-generation sequencing data with sequence bloom trees [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 LB-005. doi:10.1158/1538-7445.AM2017-LB-005
Abstract LB-010: Modeling the impact of mutations in ubiquitin pathway genes across human cancers
Authors: Osmanbeyoglu Hatice U. , Leslie Christina
Published: July 2017

A number of ubiquitin pathway genes show a strikingly high frequency of somatic alterations across diverse human cancers. While several ubiquitin ligase genes with recurrent mutations or copy number alterations been studied in individual cancers, their role in many malignancies remains poorly understood. To better model the impact of ubiquitin pathway alterations, we developed a computational strategy for exploiting parallel phosphoproteomics and mRNA sequencing data for large tumor sets to link dysregulation of upstream signaling pathways with altered transcriptional response through the transcriptional circuitry. Our modeling allows us to interpret the impact of mutations and copy number events in terms of altered signaling and transcription factor (TF) activity. We used a multi-task learning strategy to jointly train phosphoprotein-TF interaction models across 10 human cancers for which large reverse-phase protein array and RNA-seq data sets are available through TCGA. We then applied a novel algorithmic approach to extract networks of signaling proteins and TFs whose inferred activities are correlated across tumors and whose dysregulation is associated with specific somatically altered ubiquitin pathway genes. Our analysis revealed both known and novel interactions of ubiquitin ligase genes with signaling pathways and transcriptional programs in a pan-cancer context.

Citation Format: Hatice U. Osmanbeyoglu, Christina Leslie. Modeling the impact of mutations in ubiquitin pathway genes across human cancers [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 LB-010. doi:10.1158/1538-7445.AM2017-LB-010
Abstract LB-012: Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions
Authors: Papineni Rao V. , Umar Shahid , Goltsov Alexey , Ahmed Ishfaq
Published: July 2017

We earlier showed with Systems Biology approach that the genotoxic stress response evoked by cancer, infection, and radiation injury have similarities, particularly at the gastrointestinal tract. This was made possible using biophotonics, and show promise in drug screening opportunities using each of these pathologies as a surrogate model for one another. Using similar molecular Imaging methodology, we showed for the first time binding of osteoporosis drug bisphosphonate to prostate and ovarian cancer tumors and potential drug repurposing candidature. Recently, we presented similar drug re-tasking potential of 2-Deoxyglucose (2-DG) in anti-infection. Here, our data demonstrating mitigation of citrobacter rodentium infection by dietary treatment by 2-DG (0.4%), were analyzed with the bisphosphonate anti-infection response to enteric bacterial pathogens data reported elsewhere. Based on these results, a systems approach analysis is developed and presented demonstrating cross-talk and communication between different cells and integrated responses to pathogens and disease by 2-DG and bisphosphonate in anticancer and anti-infection actions. A role in EGFR signaling and modulation in the infiltration immune response cells by these two dissimilar compounds play a profound bridging event in anticancer and anti-infection activities. These system biology strategies will provide opportunities for drug repurposing in personalized cancer therapy and in anti-microbial management during cancer treatment. Also pave way for safer drugs in prevention and therapy of HER family-driven cancers.

Citation Format: Rao V. Papineni, Shahid Umar, Alexey Goltsov, Ishfaq Ahmed. Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions [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 LB-012. doi:10.1158/1538-7445.AM2017-LB-012
Abstract LB-022: PTP1B directed therapeutics for HER2 positive breast cancer
Authors: Krishnan Nava
Published: July 2017

PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, non-catalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state.

MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. Currently, we are testing MSI-1436 in a Phase 1 clinical trial in HER2-positive breast cancer patients, in collaboration with the Monter Cancer Center at Northwell Health formerly NS-LIJ.

Note: This abstract was not presented at the meeting.

Citation Format: Nava Krishnan. PTP1B directed therapeutics for HER2 positive breast 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 LB-022. doi:10.1158/1538-7445.AM2017-LB-022
Abstract LB-023: STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin
Authors: Kida Taiki , Rogoff Harry A. , Li Chiang J.
Published: July 2017

Cancer stem cells (CSCs) are considered to play an important role in cancer therapy resistance, metastasis, and recurrence. Wnt/β-catenin is one of key signaling pathways that confer cancer stemness properties to a portion of the heterogeneous cancer cell population. Dysregulation of the Wnt/β-catenin pathway may lead to accumulation of β-catenin and aberrant activation of its target gene transcription. However, it has been proven difficult to design a therapeutic targeting β-catenin. Identification of a drugguble target for the β-catenin pathway is highly desirable given the importance of β-catenin in promoting cancer stemness.

Here, we demonstrate that Serine Threonine Kinase 17A (STK17A), a novel member of the death-associated protein family of serine/threonine kinases, promotes cancer stemness phenotypes via β-catenin. Over-expression of STK17A resulted in increased anchorage-independent spherogenesis and invasive phenotype of cancer cells, whereas STK17A gene silencing reduced these malignant phenotypes. Overexpression of STK17A led to increased transcriptional activity of β-catenin and upregulation of its target genes. These changes were accompanied by increased phosphorylation of β-catenin at ser675. Cell-free in vitro kinase assay revealed that STK17A directly phosphorylates β-catenin at ser675 in an ATP-dependent manner. Moreover, BBI-503 (Amcasertib), a first-in-class cancer stemness kinase inhibitor, was found to potently inhibit STK17A, leading to inhibition of β-catenin phosphorylation at ser675. These results suggest that inhibition of STK17A is a promising approach for targeting cancer stemness.

Citation Format: Taiki Kida, Harry A. Rogoff, Chiang J. Li. STK17A, a novel serine threonine kinase, promotes cancer stemness phenotypes by phosphorylating β-catenin [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 LB-023. doi:10.1158/1538-7445.AM2017-LB-023
Abstract LB-030: Specific missense mutations in TP53 elicit contrasting biochemical and biological outcomes affecting prostate cancer progression
Authors: McCann Jennifer J. , Dean Jeffry L. , Leeuw Renee De , Schiewer Matthew J. , McNair Christopher M. , Knudsen Karen E.
Published: July 2017

Prostatic adenocarcinoma (PCa) remains the most frequently diagnosed cancer type and the third leading cause of cancer death in men in the United States. While organ-confined disease is manageable, treatment options for disseminated PCa remain limited. First-line therapy for metastatic PCa functions through targeting the androgen receptor (AR) signaling axis, as AR activity is required for tumor maintenance. However, while treatment is initially effective, these tumors invariably recur, displaying reactivation of AR signaling despite continued therapeutic targeting. Moreover, no durable treatment currently exists for this ultimately fatal disease stage, termed castrate-resistant PCa (CRPC). Significantly, recent high profile, genome-wide studies have revealed that missense mutations in the TP53 gene occur in nearly all cancer types, and these mutations frequently occur at specific TP53 “hotspots”. Interestingly, enrichment of certain hotspot p53 mutants specifically occurs in PCa. While the underlying causes of PCa-enriched mutations remain undefined, their presence elicits contrasting, pro-oncogenic biochemical and biological phenotypes. Unpublished data suggests that mutant p53 isoforms act in a mutation-specific fashion to drive PCa progression through alterations in the canonical activity of p53, identified through characterization of their related transcriptomes and cistromes. Biologically, these mutant p53 isoforms also confer differential proliferative and survival phenotypes. Moreover they act in a mutation-dependent fashion in response to castration therapy both in vitro and in vivo. Mechanistically, pro-oncogenic mutant p53 appears to manipulate both conventional and novel pathways leading to PCa progression. These findings both corroborate and expand the recent findings that mutations in p53 drive cancer progression, and further suggest a critical role for p53 mutations as regulators of disease progression in PCa.

Citation Format: Jennifer J. McCann, Jeffry L. Dean, Renee De Leeuw, Matthew J. Schiewer, Christopher M. McNair, Karen E. Knudsen. Specific missense mutations in TP53 elicit contrasting biochemical and biological outcomes affecting prostate cancer progression [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 LB-030. doi:10.1158/1538-7445.AM2017-LB-030
Abstract LB-031: Deciphering distinct roles of RASA2 in melanomagenesis
Authors: Arafeh Rand , Qutob Nouar , Emmanuel Rafi Rafi , Madore Jason , Elkahloun Abdel , Wilmott James S. James S. , Gartner Jared J. , Pizio Antonella Di , Rotkopf Ron , Dutton-Regester Ken , Hill Victoria , Pritchard Antonia , Lin Jimmy C. , Rosenberg Steven A , Khan Javed , Ben-Dor Shifra , Niv Masha Y. Masha Y. , Ulitsky Igor , Mann Graham J , Scolyer Richard A. , Hayward Nicholas K. , Samuels Yardena
Published: July 2017

Melanoma is the deadliest form of human skin cancer. The incidence of melanoma continues to rise. Recent advances in knowledge of melanoma genetics, genomics and biology has led to an optimistic view of the therapeutic outlook for melanoma patients. We analyzed sequence data from >500 melanoma genomes/exomes to identify novel tumor suppressor genes in melanoma. RASA2 was identified as the most highly somatically mutated novel tumor suppressor gene. RASA2 was mutated in 5% of melanomas and deleted in an additional 16.4% of cases. RASA2 is a GTPase Activating Protein (GAP) that regulates RAS; which is one of the most highly mutated oncogenes in melanoma but drugs targeting RAS have as yet shown poor efficacy. The role of RASA2 has not been investigated in melanoma. NF1, which encodes another RAS- specific GAP, was found to be frequently mutated in melanoma. Interestingly, mutations in RASA2 and NF1 co-occur in the same patients with high frequency. We plan to elucidate the roles of RASA2 in melanomagenesis and to understand why RASA2 and NF1 mutations co-occur despite the fact that both proteins are RasGAPs. Ras includes three isoforms: NRas, KRas and HRas. Our preliminary data show that RASA2 is more specific to NRAS and that NF1 is more specific to KRAS and HRAS. This finding highlights the existence of a paradigm of cooperativity in which combined loss of multiple negative regulators (RASA2 and NF1) of the RAS pathway is required for melanoma development. Therefore, this type of enhancement of RAS signaling is possibly selected for in some melanomas. We will apply a proteomic screen using BioID to identify RASA2 and NF1 binding partners to provide insights into the functional effects and consequences of alterations in RASA2 and NF1. We expect that these studies will not only identify the cellular components that contribute to the Ras signaling pathway but will also identify potential novel therapeutic targets.

Citation Format: Rand Arafeh, Nouar Qutob, Rafi Rafi Emmanuel, Jason Madore, Abdel Elkahloun, James S. James S. Wilmott, Jared J. Gartner, Antonella Di Pizio, Ron Rotkopf, Ken Dutton-Regester, Victoria Hill, Antonia Pritchard, Jimmy C. Lin, Steven A Rosenberg, Javed Khan, Shifra Ben-Dor, Masha Y. Masha Y. Niv, Igor Ulitsky, Graham J Mann, Richard A. Scolyer, Nicholas K. Hayward, Yardena Samuels. Deciphering distinct roles of RASA2 in melanomagenesis [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 LB-031. doi:10.1158/1538-7445.AM2017-LB-031
Abstract LB-032: Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma
Authors: Wang Qing , Zhu Jiang , Yang Hsin-Sheng
Published: July 2017

Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently down-regulated in many types of cancer including colorectal cancer. In this study, we found that knockdown/knockout of Pdcd4 increased the activity of mammalian target of rapamycin complex 2 (mTORC2). Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which was resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the sin1 5’ untranslated region (5’UTR) was fused with luciferase reporter and named as 5’Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation of 5’Sin1-Luc but not the control luciferase without the sin1 5’UTR, suggesting that sin1 5’UTR mediated Pdcd4’s inhibition on Sin1 translation. Ectopic expression of wild type Pdcd4 and Pdcd4(157-469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited the Sin1 translation, and thus inhibited mTORC2 kinase activity and invasion in colon tumor cells. By contrast, Pdcd4(157-469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and as a result failed to inhibit mTORC2 activity and invasion. In addition, treating cells with an eIF4A inhibitor also efficiently inhibits Sin1 expression and invasion. These results suggest that Pdcd4-inhibited Sin1 translation is through eIF4A, and is functionally important for suppression of mTORC2 activity and invasion. In colorectal cancer tissues, Sin1 protein but not mRNA was significantly up-regulated while Pdcd4 protein was down-regulated, suggesting that loss of Pdcd4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which Pdcd4 inhibits Sin1 translation to attenuate mTORC2 activity and thereby suppress invasion.

Citation Format: Qing Wang, Jiang Zhu, Hsin-Sheng Yang. Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma [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 LB-032. doi:10.1158/1538-7445.AM2017-LB-032
Abstract LB-035: Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis
Authors: Ro Seung-Hyun , Xue Xiang , Shah Yatrik , Lee Jun Hee
Published: July 2017

The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53's control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis.

Citation Format: Seung-Hyun Ro, Xiang Xue, Yatrik Shah, Jun Hee Lee. Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis [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 LB-035. doi:10.1158/1538-7445.AM2017-LB-035
Abstract LB-051: High LDHA expression predicts decreased survival in neuroblastoma
Authors: Dorneburg Carmen , Christner Lisa , Barth Thomas F. , Mueller-Klieser Wolfgang , Fischer Matthias , Barbara Hero , Beckers Anneleen , Speleman Frank , Debatin Klaus-Michael , Beltinger Christian
Published: July 2017

Neuroblastoma (NB) is a common pediatric malignancy that often carries a poor prognosis. Aerobic glycolysis, i.e. the Warburg effect, is a hallmark of cancers, including NB. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate. It is considered a pivotal component of the LDH tetramer, which is central in the Warburg effect. LDHA is overexpressed in many cancers. Little is known about the role of LDHA in NB. We therefore determined the expression of LDHA mRNA and protein in 651 and 112 clinically annotated patient samples, respectively. We show that enhanced mRNA expression and predominant cytoplasmic protein expression of LDHA, as detected by immunohistochemistry, is markedly associated with increased tumor aggressiveness and decreased patient survival. Surprisingly, despite the proposed pivotal role of LDHA in the Warburg effect, LDHA was dispensable for aerobic glycolysis in NB cells. Complete depletion of LDHA by CRISPR/Cas9-mediated knock-out in several NB cell lines did not decrease glucose consumption and production of pyruvate and ATP. In accordance, LDH activity was maintained despite loss of LDHA, as LDHB and LDHC were still expressed, most likely compensating for the loss of LDHA. In line with LDHA being dispensable for aerobic glycolysis in NB cells, LDHA depletion did not decrease malignant characteristics of NB cells. Thus, clonogenic growth, migration and tumorigenicity remained unaffected. Extending these findings from manifest to developing NB, we show that in the TH-MYCN NB mouse model the development of NB from normal sympathetic ganglia is not associated with increased LDHA expression. Taken together, this work establishes LDHA as a novel predictive marker in NB and calls into question the pivotal role in aerobic glycolysis attributed to LDHA.

Citation Format: Carmen Dorneburg, Lisa Christner, Thomas F. Barth, Wolfgang Mueller-Klieser, Matthias Fischer, Hero Barbara, Anneleen Beckers, Frank Speleman, Klaus-Michael Debatin, Christian Beltinger. High LDHA expression predicts decreased survival in neuroblastoma [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 LB-051. doi:10.1158/1538-7445.AM2017-LB-051
Abstract LB-056: Quantitative mass spectrometry analysis of immune checkpoint protein expression and N-glycosylation in human melanoma
Authors: Betanzos Carlos Morales , Lee Hyoungjoo , Ericsson Paula I. Gonzalez , Balko Justin M. , Johnson Douglas B. , Zimmerman Lisa J. , Liebler Daniel C.
Published: July 2017

Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed an targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from approximately 0.03 to 1.5 fmol/microgram protein and the PRM data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody. PD-1 was measured at levels up to 20-fold lower than PD-L1, but the abundances were not significantly correlated (r2 = 0.062, p = 0.264). PD-1 abundance was weakly correlated (r2 = 0.3057, p = 0.009) with the fraction of lymphocytes/histiocytes in sections. PD-L2 was measured from 0.03 to 1.90 fmol/microgram protein and the ratio of PD-L2 to PD-L1 abundance ranged from 0.03 to 2.58. In 8 samples, PD-L2 was present at more than half the level of PD-L1, which suggests that PD-L2, a higher affinity PD-1 ligand, is sufficiently abundant to contribute to T-cell downregulation. We also identified five branched mannose and N-acetylglucosamine glycans at PD-L1 position N192 in all 22 samples. Extent of PD-L1 glycan modification varied by approximately 10-fold and the melanoma with the highest PD-L1 protein abundance and most abundant glycan modification yielded a very low PD-L1 IHC estimate, thus suggesting that N-glycosylation may affect IHC measurement and PD-L1 function. Additional PRM analyses quantified immune checkpoint/co-regulator proteins LAG3, IDO1, TIM-3, VISTA and CD40, which all displayed distinct expression independent of PD-1, PD-L1 and PD-L2. Targeted MS can provide a next-generation analysis platform to advance cancer immuno-therapeutic research and diagnostics. (Supported by NIH grant U24CA159988)

Citation Format: Carlos Morales Betanzos, Hyoungjoo Lee, Paula I. Gonzalez Ericsson, Justin M. Balko, Douglas B. Johnson, Lisa J. Zimmerman, Daniel C. Liebler. Quantitative mass spectrometry analysis of immune checkpoint protein expression and N-glycosylation in human melanoma [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 LB-056. doi:10.1158/1538-7445.AM2017-LB-056