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Background: ARID1A mutations (ARID1Amut) occur in up to 30% of metastatic bladder cancers (mBC) and have been associated with poorer response to standard treatments and shorter overall survival. We previously identified bromodomain and extraterminal (BET) protein inhibition as a potential treatment paradigm for mBC, with particular potency of BET inhibitors (BETi) in cells lines containing ARID1A inactivating mutations (ARID1Amut). BETi prevents BET protein bromodomains from interacting with acetylated histone lysine tails and promoting transcription of multiple oncogenes. Our previous data shows that treatment with the pan-BETi OTX-015 reduces ARID1B expression, and significantly reduces both gene and protein expression of RAD51/RAD51 in ARID1Amut cells compared to ARID1A wild type (ARID1AWT), suggesting impaired DNA damage repair function. Here we evaluate the phenotypic effects of BETi on proliferation and migration in preclinical models of BC. Methods: To evaluate OTX-015-induced changes to gene expression, 5637 (ARID1AWT) and HT1197 (ARID1Amut) cells were treated with 1 μM OTX-015 for 48-h. RNA was extracted and sent to Novogene for bulk RNA-seq. Differential expression was quantified using DESeq2, and gene enrichment was analyzed using GSEA. 5637 and HT1197 cells were treated with 1 or 5 μM OTX-015 for 48-h, and colony forming potential was assessed by crystal violet staining after 10 days. Cells were treated with the same treatment schema as above, and a wound-healing assay evaluated wound closure over 48-h. Differences in the percent area of wells covered with colonies and relative wound closure were assessed by FIJI v.2.9.1. Results: BET inhibition of ARID1Amut HT1197 cells lead to a significant decrease in the pathway enrichment for G2/M checkpoint (NES=-2.78, q Conclusions: These preliminary data highlight how OTX-015 potently inhibits proliferation and migration in ARID1Amut cells. These data will be confirmed in isogenic cell lines harboring inactivating ARID1A mutations, and support future mechanistic exploration (e.g., BETi-mediated cell cycle dysregulation) in ARID1Amut bladder cancer. Citation Format: Ryan M. Kemper, Manfred Meng, Jeffrey S. Damrauer, William Y. Kim, Daniel J. Crona. OTX-015 inhibits proliferation and migration in ARID1A-mutated bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6281.

Background: Bladder cancer (BC) is a common and deadly disease. Inactivating ARID1A mutations occur in up to 30% of metastatic BC tumors, making it the most commonly mutated epigenetic gene and the 4th most commonly mutated gene overall in BC. ARID1A mutations are associated with decreased response to therapy and poor prognosis; thus, there is a need to develop therapies specifically targeting ARID1A mutant tumors. Using the UNC EpiG Diamond compound library, a set of well-annotated small molecule probes targeting chromatin regulatory proteins, we determined that inhibitors of bromodomain and extraterminal (BET) proteins potently inhibit the viability of BC cells. Here, we tested the hypothesis that ARID1Amut cells are particularly sensitized to the pan-BET inhibitor OTX-015. Methods: AR1D1A-competent (ARID1AWT) 5637 and ARID1A-mutated (ARID1Amut) HT1197 cells were treated with eight ascending concentrations of OTX-015 (0.1 nM-100 µM), and cell viability was measured using CellTiter-Glo™ after 72-120-hour incubations. IC50 values were calculated using a four-parameter non-linear regression model. Gene expression of BET inhibitor target genes, MYC, ARID1B, and RAD51, were evaluated by RT-PCR after a 48-hour incubation, normalized to an SDHA housekeeper and compared to a 0.1% DMSO control. CellTiter-Glo™ and RT-PCR experiments were conducted in technical and biologic triplicates. Western blotting evaluated OTX-015 effects on c-MYC, BAF250B (encoded by ARID1B), and RAD51 protein expression after 72-hour incubation. Results: OTX-015 was 8-times more potent in ARID1Amut HT1197 cells at 120 h than in ARID1AWT 5637 cells (IC50: 0.12 μM vs. 1.0 μM). OTX-015 treatment (1 µM) significantly reduced ARID1B and RAD51 mRNA expression versus 0.1% DMSO control (83% and 86% reduction, respectively, both P Conclusions: These preliminary results support future lines of inquiry into the molecular mechanisms that underlie sensitization of ARID1Amut cells to BET protein inhibition. Citation Format: Ryan M. Kemper, Heemaja Mewada, Jeffrey S. Damrauer, Brian Hardy, Stephen F. Frye, Kenneth H. Pearce, Jesse Raab, William Y. Kim, Daniel James Crona. ARID1A mutated bladder cancer cells are sensitized to BET protein inhibition with OTX-015 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3267.

The UC-GENOME study was designed to capitalize on The Cancer Genome Atlas (TCGA) findings in real world patients with metastatic urothelial carcinoma (UC) with co-equal aims: 1) to provide targeted DNA sequencing for potential clinical decision making at no cost to patients; and 2) to create a clinically annotated biorepository (including tissue, plasma, and PBMCs) for collaborative research. Patients with metastatic UC (n=209, median age 68 y, 74% male) were accrued at 8 academic medical centers between 2016-2019. We report on the first analysis of the targeted DNAseq (n=191) and total RNAseq (n=176) from FFPE specimens (n=169 overlap). Recurrently mutated genes were observed in a similar frequency to TCGA, including TP53 (54%), KMT2D (30%), ARID1A (26%) and FGFR3 (18%). Somatic variant patterns were correlated with previously annotated mutational signatures (COSMICv3), revealing a subset of tumors enriched for APOBEC signatures. Molecular subtypes were defined using the Bladder Cancer Molecular Taxonomy Group's consensus subtyping schema (Ba_Sq=54 [31%], Stroma-rich=64 [36%], LumP=26 [15%], LumU=24 [14%], LumNS=4 [2%], NE=4 [2%]). To further understand the tumor immune features and whether they correlate with durable clinical response, tumor microenvironment deconvolution was performed by applying MiXCR and immune gene signatures. An inflamed phenotype and enhanced T cell receptor richness but not clonality was observed within Ba_Sq and Stroma-rich subtypes, which also had the highest disease control rate (CR/PR + SD ~75%) to immunotherapy. The Stroma-rich subtype had the highest disease control rate (~88%) to chemotherapy. Future efforts will leverage the clinical, DNA and RNAseq data along with other biobanked specimens for collaborative research initiatives. Citation Format: Jeffrey S. Damrauer, Jeff Klomp, Wolfgang Beck, Mi Zhou, Elizabeth Plimack, Matthew Galsky, Petros Grivas, Noah Hahn, Peter O'Donnell, Gopa Iyer, David I. Quinn, Katherine A. Hoadley, William Y. Kim, Matthew I. Milowsky. Urothelial cancer-GENOmic analysis to improve patient outcomes and research (UC-GENOME): a bladder cancer advocacy network (BCAN) led collaborative research study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2188.

Tumor progression is the process by which cancer cells acquire increasingly aggressive characteristics, including resistance to therapies and an increased propensity to metastasize. The combination of these two processes results in recurrence of tumors in distant sites, and is chiefly responsible for cancer mortality. For instance, tumor recurrence is the leading cause of death from breast cancer. Recurrent breast cancers are thought to arise from a population of residual cells that survive treatment and persist, often in a dormant state, for years or decades before resuming proliferation. Primary breast tumors are heterogeneous, harboring different subclones of (epi)genetically distinct cells, and tumor recurrence may result from the progressive outgrowth of aggressive subclones. As a consequence, understanding the clonal dynamics of dormancy and recurrence is essential for developing strategies to prevent or treat recurrence. However, studying these processes in patients is challenging, given the difficulty in identifying residual disease and obtaining recurrent tumors. To overcome these obstacles, we have used DNA barcoding to study the clonal dynamics of breast cancer recurrence in inducible genetically engineered mouse models. These models exhibit key features of breast cancer progression as it occurs in women, including the survival of cancer cells following therapy and their eventual spontaneous recurrence. In these models doxycycline (dox) administration induces expression of an oncogene (e.g., HER2/neu, Wnt1, or Myc), leading to mammary tumor formation. Subsequent withdrawal of dox induces oncogene downregulation and complete tumor regression, mimicking targeted therapies. However, a cluster of residual cells survives oncogene downregulation and resides in a dormant, nonproliferative state in the mammary gland, and these cells eventually reinitiate proliferation to form a recurrent tumor. Using these models, we find that breast tumors can follow two distinct evolutionary routes to recurrence. Approximately half of the recurrent tumors exhibit a striking clonal dominance in which one or two subclones comprise the vast majority of the tumor. These clonal recurrent tumors exhibit evidence of de novo acquisition of Met amplification, and are sensitive to small-molecule Met inhibitors. The other half of recurrent tumors exhibit marked polyclonality, with thousands of subclones and a clonal architecture very similar to primary tumors. These polyclonal recurrent tumors are not sensitive to Met inhibitors, but have acquired dependence upon an epigenetic pathway for their growth and survival and are sensitive to drugs targeting this pathway. These results suggest that tumor recurrence can proceed via multiple independent routes, producing recurrent tumors with distinct clonal dynamics, genetic alterations, and drug sensitivities. This abstract is also being presented as Poster B45. Citation Format: Jeffrey Damrauer, James V. Alvarez. Clonal dynamics during breast cancer dormancy and recurrence [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR09.

Introduction: High-grade, muscle-invasive bladder cancer has recently been shown to harbor intrinsic molecular subtypes with distinct biologic features. Current murine models of bladder cancer, including the prominent carcinogen induced model MB49, do not account for subtype specific characteristics, leaving a gap in available tools for understanding subtype specific differences in bladder cancer. We have developed and validated immunocompetent, subtype specific models of bladder cancer, and we have used these models to assess differential responses to immune checkpoint inhibition. Methods: Two distinct models of murine bladder cancer were developed in a C57BL/6 background. The UPPL models were generated through Pten/Trp53 conditional knockout in Uroplakin3a expressing cells. BBN models were generated through exposure of wild-type C57BL/6 mice to the carcinogen N-Butyl-N-(4-hydmoxybutyl)nitrosamine and subsequent generation of cell lines from spontaneous tumors. RNAseq was performed on several BBN and UPPL tumors and cell lines, with findings validated with flow cytometry and T/B cell receptor (TCR/BCR) amplicon sequencing of tumor infiltrating lymphocytes (TILs). Results: BBN and UPPL models reflected characteristics of human basal and luminal bladder cancers, respectively. BBN (basal) models demonstrated higher immune gene signature expression, with concordantly higher numbers of TILs compared to the UPPL (luminal) model (p < 0.0001). Two BBN and two UPPL models were assessed for response to anti-PD-1 therapy in vivo as syngeneic tumors grown in wild type C57BL/6 mice. One of the BBN lines (BBN963) demonstrated robust control of tumor growth in some animals, including multiple complete responses (p = 0.0003), but also tumors that progressed, leading us to characterize BBN963 as a mixed response model. The marked response to PD-1 blockade in BBN963 was associated with significantly higher sharing of TCR CDR3 sequences among TILs compared to sequences of the other tumors (p = 0.003). In addition, analysis of BBN963 tumors by flow cytometry demonstrated naïve and memory T cell phenotypes correlated with increased and decreased tumor sizes, respectively. Closer examination of individual BBN963 tumor responses to PD-1 blockade revealed distinct responder and non-responder infiltrating immune cell phenotypes. Responders demonstrated a less diverse B cell repertoire (p = 0.0043) with increased BCR CDR3 sequence sharing (p < 0.0001). Discussion: We have developed two unique classes of murine bladder cancer lines, UPPL and BBN, with gene expression and TIL profiles that closely correlate with human luminal and basal bladder cancers, respectively. The BBN and UPPL subtype specific models can serve as a tool for elucidating bladder cancer responses to immunotherapy. The mixed response of BBN963 tumors to PD-1 blockade should be an asset for assessing pathways mediating response to checkpoint blockade as well as the value of combination therapy. [C.S., R.S, B.V, W.K contributed equally to this work] Citation Format: Christof C. Smith, Ryoichi Saito, Lisa M. Bixby, Takanobu Utsumi, Jordan Kardos, Shengjie Chai, Sara E. Wobker, Bhavani Krishnan, Jeffrey S. Damrauer, Jonathan S. Serody, David Darr, Benjamin G. Vincent, William Y. Kim. Development of subtype specific mouse models of bladder 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 1654. doi:10.1158/1538-7445.AM2017-1654

Introduction: In 2014, TCGA's Bladder Cancer Working Group presented a preliminary integrated molecular analysis of 131 muscle-invasive urothelial carcinomas (Nature 507:315, 2014). We now report on the entire cohort of 412 fresh-frozen, chemotherapy-naïve tumors. Included in the analysis were paired blood and/or tumor-adjacent tissue samples. This is the largest sequencing project on bladder cancer to date. After strict clinical and pathologic quality control, tumors were analyzed for DNA copy number variants, somatic mutations, DNA methylation, mRNA, microRNA and (phospho-) protein expression, transcript splicing, gene fusions, viral integration, APOBEC mutagenesis, pathway perturbation, clinical correlates, and histopathology. Results: There was a high overall somatic mutation rate (8.0/Mb), with a median of 245 and mean of 348 coding-region mutations per sample. That is the third highest mutation rate among the cancer types profiled by TCGA (after cutaneous melanoma and non-small cell lung cancers). We identified 54 genes as significantly mutated, compared with 32 in the original report on 131 tumors. TP53 mutations were the most common (49%), and also quite common were mutations in a number of chromatin-modifying genes, including MLL2 (29%), KDM6A (26%), ARID1A (25%), MLL3 (19%), EP300 (15%), CREBBP (12%), and MLL (11%). Other cancer-related genes showing frequent mutations included PIK3CA (22%), RB1 (17%), FGFR3 (14%), STAG2 (14%), ATM (14%), ELF3 (12%), FAT1 (12%), SPTAN1 (12%), ERBB2 (12%), ERBB3 (11%), ASXL2 (10%), ERCC2 (9%), CDKN1A (9%), TSC1 (8%), CDKN2A (7%), RHOB (6%), NFE2L2 (6%), PARD3 (6%), FAM47C (5%), RBM10 (5%),HRAS (5%), KRAS (4%), and PTEN (3%). High mutation burden was associated with improved outcome (p = 0.0004). APOBEC mutagenesis explained 70% of the mutation burden and was associated with survival. Gene silencing by promoter hypermethylation was identified in 167 genes with at least 5% frequency in the cohort. The previously identified four mRNA expression subtypes were again found in the complete set of 412 tumors, and the proportions of samples in each subtype were similar to the previous proportions. Reverse-phase proteomic array analysis of 344 of the samples revealed clusters associated with diagnostic subtype, pathological stage, and grade but not with smoking history or non-muscle invasive status. Conclusions: This integrated molecular analysis of 412 TCGA tumor samples largely validates and considerably extends observations from the initial cohort of 131 patients. The larger cohort significantly increased our power to detect lower-frequency aberrations that were not identified in the original cohort. The results provide a robust basis for further functional studies of bladder cancer biology and also provide additional incisive information for the identification of molecular targets for therapy. Citation Format: John N. Weinstein, Seth P. Lerner, David J. Kwiatkowski, Gad Getz, Jaegil Kim, Hikmat A. Al-ahmadie, Andrew D. Cherniack, Guangwu Guo, Rehan Akbani, Katherine A. Hoadley, William Y. Kim, Gordon Robertson, Andrew J. Mungall, Toshinori Hinoue, Peter W. Laird, Jonathan E. Rosenberg, Joaquim Bellmunt, Dean F. Bajorin, Margaret B. Morgan, Chad J. Creighton, Dmitry Gordenin, Joshua M. Stuart, Xiaoping Su, Michael C. Ryan, Jeffrey S. Damrauer, Wei Zhang, Yuexin Liu, Yiling Lu, Nikolaus Schultz, Raju Kucherlapati, Gordon B. Mills, Donna E. Hansel, Brian D. Robinson, Bodgen A. Czerniak, Victor E. Reuter. Comprehensive molecular characterization of 412 muscle-invasive urothelial bladder carcinomas: final analysis of The Cancer Genome Atlas (TCGA) project. [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 128.

In 2014, as part of The Cancer Genome Atlas (TCGA) Project, we reported molecular profiling of 131 chemotherapy-naive, muscle-invasive urothelial bladder cancers for DNA copy number variants (CNVs), somatic mutations by whole exome sequencing (WES), DNA methylation, mRNA expression, microRNA expression, protein expression and phosphorylation, transcript splicing, gene fusion, viral integration, pathway perturbation, clinical correlates, and histopathology (TCGA Research Network, Nature 507:315, 2014). Since that time, the number of tumors (from 19 tissue source sites) profiled comprehensively has doubled, and the final analyzed cohort will total 412 by February 2015. Unsupervised consensus clustering for the data from miRNAseq on the first 310 tumor samples shows five robust clusters, with miR-99a, miR-100, and miR-200 family members differentially abundant across the clusters. mRNA clusters I-IV remained stable as well. For the 266 tumour samples for which we have both miRNA and mRNA data, potential miRNA-mRNA targeting relationships supported by functional validation publications include miR-100-5p targeting FGFR3. The data also highlight the miR-200 family, miR-29abc, miR-17-92 and 106b-25 complexes, as well as miR-34a, miR-155, and miR-21. At this time, mutation analysis of WES data has been completed for 238 samples (including the first 131). Seven additional significantly mutated genes (using MutSig) have been identified: ASXL2 (11%), HSP90AA1 (7%), PSIP1 (5%), ZFP36L2 (5%), ZNF513 (5%), PTEN (4%), CEBPB (2%) (mutant frequency in parentheses). A sample with a POLE exonuclease domain mutation (P286R) exhibited an ultra-mutant phenotype (mutation rate ∼100 per MB). Many of the 38 (total) SMGs have not previously been described in bladder cancer. Combining copy number variation and somatic mutation data, 69% of tumors harbor one or more potentially actionable targets. Three mutation clusters were identified and characterized as: 1) “Focally amplified” - enriched in focal copy number alterations (e.g., 3p loss/PPARG) and MLL2 mutations; 2) Enriched for TP53 and RB1 mutations, E2F3 amplifications; and 3) Papillary histology, FGFR3 mutant CDKN2A-deficient. This work was supported by the following grants from the United States National Institutes of Health: U54HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025 and P01 CA120964, as well as multiple other funding sources for the individual authors. Citation Format: John N. Weinstein, Jaegil Kim, Chad J. Creighton, Rehan Akbani, Katherine A. Hoadley, William Y. Kim, Margaret B. Morgan, Toshinori Hinoue, Andrew Cherniack, Xiaoping Su, Andrew J. Mungall, Michael C. Ryan, Dean F. Bajorin, Jonathan E. Rosenberg, Bogdan Czerniak, Donna Hansel, Victor E. Reuter, Brian D. Robinson, Hikmat A. Al-Ahmadie, Jeffrey S. Damrauer, Wei Zhang, Yuexin Liu, Dmitry R. Gordenin, Joshua M. Stuart, Nikolaus Schultz, Gordon Robertson, Steven JM Jones, Raju R. Kucherlapati, David J. McConkey, Peter W. Laird, Gordon B. Mills, David J. Kwiatkowski, Seth P. Lerner, TCGA Bladder Cancer Working Group, TCGA Research Network. Progress in The Cancer Genome Atlas bladder cancer project. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2969. doi:10.1158/1538-7445.AM2015-2969

Urothelial carcinoma (UC) is a major cause of morbidity and mortality for which there are no approved molecularly targeted agents and few good treatment options beyond cisplatin-based chemotherapy. As part of The Cancer Genome Atlas (TCGA) Project, we analyzed 131 chemotherapy-naive, muscle-invasive UC tumors for somatic mutations, DNA copy number variants (CNVs), mRNA and microRNA expression, protein expression and phosphorylation, DNA methylation, transcript splicing, gene fusion, viral integration, pathway perturbation, clinical correlates, and histopathology (TCGA Research Network, Nature, in press). Whole-exome sequencing showed 29 recurrently mutated genes. Potential therapeutic targets include altered PIK3CA, ERBB2, FGFR3, TSC1, and ERBB3, plus mutated chromatin-regulating genes MLL, MLL2, MLL3, CREBBP, CHD7, SRCAP, ARID1A, KDM6A (UTX), and EP300. There were 22 arm-level CNVs and 27 focally amplified or deleted regions. CDKN2A was deleted in 47%. Low-pass whole genome sequencing identified FGFR3-TACC3 fusions. Viral DNA was identified in 6% (CMV, HHV6B, HPV16, BK polyoma), and viral transcripts were identified in 4% (CMV, BK polyoma, HPV16). . mRNA-seq identified 4 tumor clusters. Cluster I shows papillary morphology and FGFR3 dysregulation. Clusters I and II express high HER2 (ERBB2) and estrogen receptor beta signaling signature, sharing features with Luminal A breast cancer. Cluster III shows similarities to Basal-like breast and squamous cell head and neck carcinomas. . Integrated analyses confirm alteration of multiple pathways, including cell cycle regulation (93%), kinase and PI3-K signaling (72%), and epigenetic regulation (histone-modifiers: 89%; SWI/SNF nucleosome remodeling complex: 64%). Recurrent alterations in the PI3-kinase/AKT/mTOR pathway (42%) and RTK/RAS pathway (44%) are potentially actionable. . Overall, this study and others have identified multiple druggable targets in UC. FGFR3 is activated by mutation, gene fusion, and overexpression, suggesting clinical trials of FGFR3 inhibitors. PI3-kinase/mTOR/AKT/TSC1 pathway alterations are frequent, and mutation in TSC1 has been associated with response to mTOR inhibitors. ERBB2 amplifications and activating mutations may be targetable with agents such as trastuzumab, trastuzumab-DM1, lapatinib, and neratinib. The frequent alterations in epigenetic regulatory pathways suggest trials of agents such as the bromodomain inhibitors. The project is now being updated on the basis of data on 117 additional tumors. Citation Format: John N. Weinstein, Jaegil Kim, Chad J. Creighton, Rehan Akbani, Katherine A. Hoadley, William Y. Kim, Margaret B. Morgan, Toshinori Hinoue, Andrew Cherniack, Xiaoping Su, Andrew J. Mungall, Michael C. Ryan, Jonathan E. Rosenberg, Dean F. Bajorin, Bogdan Czerniak, Donna Hansel, Victor E. Reuter, Brian D. Robinson, Hikmat A. Al-Ahmadie, Jeffrey S. Damrauer, Wei Zhang, Yuexin Liu, Dmitry Gordenin, Joshua M. Stuart, Nikolaus Schultz, Gordon Robertson, Raju Kucherlapati, Peter W. Laird, Gordon B. Mills, David J. Kwiatkowski, Seth P. Lerner, representing TCGA's Bladder Cancer Working Group. Comprehensive characterization of urothelial bladder cancer: a TCGA Project update. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 987. doi:10.1158/1538-7445.AM2014-987