Citations

Abstract Enzymatic degradation of hyaluronan (HA), a key component of the extracellular matrix (ECM), can enhance tumor perfusion, improve delivery of chemotherapeutics, and enhance the effects of anti-tumor agents. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational therapeutic agent under clinical development for the treatment of patients with solid tumors that may accumulate HA. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Twenty-six patients with advanced solid tumors were enrolled in a Phase 1 multi-center trial. Patients received weekly or twice weekly doses of IV PEGPH20 (0.5 - 5 μg/kg) for the first 4-week cycle, followed by once-weekly dosing for the subsequent 4-week cycles. Serial blood samples were drawn from each patient, and plasma concentrations were measured by an ultrasensitive hyaluronidase activity assay to assess PEGPH20 pharmacokinetics (PK). Plasma levels of HA catabolites were measured using a quantitative HPLC method to characterize PEGPH20 pharmacodynamics (PD). Other measures of PD activity were evaluated in selected patients, including DCE-MRI, DW-MRI, 18FDG-PET, textural analysis on CT, and histochemical staining of HA in tumor biopsies collected both before and after PEGPH20 treatment. Peak plasma PEGPH20 concentrations increased with dose, and plasma pharmacokinetics (PK) were well described by a linear PK model. Pre-treatment plasma HA levels were typically <1 μg/mL and increased in a dose-dependent fashion after PEGPH20 treatment. Increased plasma HA corresponded with decreased HA staining in patients with available tumor biopsies. DCE-MRI analysis indicated early (24-48 hr) and rapid increase in tumor perfusion compared to baseline in 4 patients with serial MRI assessments. Pharmacodynamic activity was also demonstrated when pre-treatment 18FDG-PET scans were compared with images collected at scheduled times after PEGPH20 dosing. Reduction in FDG uptake exceeding 25% was demonstrated in 3 of 4 patients after one cycle of treatment, consistent with a partial metabolic response. These data are consistent with the mechanism of action reported in preclinical models, and results support continued evaluation of PEGPH20 in combination with anti-tumor agents via modification of the ECM. Citation Format: Ping Jiang, Daniel C. Maneval, Ramesh K. Ramanathan, Jeffrey R. Infante, Mitesh Borad, Alberto Bessudo, Patricia LoRusso, Barry J. Sugarman, Deborah Carson, Marie A. Printz, Curtis B. Thompson, Paneer Selvam, Joy Zhu, Ronald Korn, H Michael Shepard, Gregory I. Frost. Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2013-3375

Abstract Gold nanoparticles (AuNPs) have been widely studied for use in disease therapeutics as targeting and imaging agents, drug delivery vehicles and as self-therapeutics. When AuNPs interact with the biological milieu they form a corona layer, which is predominantly composed of proteins. The outer “soft” layer is dynamic and here proteins are free to exchange over time. The inner “hard” layer on the other hand consists of proteins firmly bound to the NP surface. The Vromans effect predicts that given a limited surface area, low affinity, high abundance proteins, that first attach to the surface, are over time replaced by high affinity, low abundance proteins. Our aim was to enrich low abundance proteins on the AuNP surface to probe for differentially expressed proteins that are not detected by traditional methods of protein identification. We studied the binding of ovarian cell lysates (cancerous and non cancerous) to 10 nm sized positively and negatively charged AuNPs. The formation of corona around the AuNPs was characterized by dynamic light scattering and zeta potential measurements. The composition of the protein corona was identified using mass spectrometry. Proteins were also identified from the cell lysate pool to serve as a control to assess protein enrichment on NP surface. Using this approach, Hepatoma Derived Growth Factor (HDGF) was identified as a low abundance protein that was detected by mass spectrometry in cancer cells only after enrichment on the surface of positively charged AuNPs. HDGF is overexpressed in multiple ovarian cancer cells lines and knock down using siRNA shows decrease in cell proliferation, G2/M arrest and apoptosis. This suggests an important role of HDGF in the tumorigenicity of ovarian cancer, which could serve as an important therapeutic target for the disease. Citation Format: Karuna Giri, Rochelle Arvizo. Detecting low abundance therapeutic targets for ovarian cancer using engineered gold nanoparticles. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3215. doi:10.1158/1538-7445.AM2013-3215

Abstract MOTIVATION: Transcriptome sequencing (RNA-seq) is the most economical and information-rich next generation sequencing technology to study genomic medicine. Genomic features such as gene expression, transcript expression, fusion transcripts, long non-coding RNAs and expressed single nucleotide variants (eSNVs) can be obtained from RNA-seq data. There are several computational workflows to obtain gene counts, transcript counts and fusion gene candidates, but not a comprehensive system to identify expressed SNVs from RNA-sequencing data. METHODS: We have developed a novel computational system (The eSNV-Detect) with parallel alignment strategies to identify expressed SNVs accurately from tumor transcriptome sequencing data. Sequence-based features like reads supporting reference allele, alternate allele, ratio of alternate reads to total read depth, base qualities, mapping qualities, forward strand and reverse strand supporting reads etc. along with a variety of databases such as dbSNP, 1000 genome, 5400 exome, refGene, avsift, ljb_phylop from UCSC were used to call SNVs from RNA-sequencing data. For the expressed SNVs detected in tumors, we can also identify the amino acid change and classify the protein domains using our method. RESULTS: We have applied the eSNV-Detect method to call novel expressed SNVs in two tumors (one HER2 positive and one ER positive breast tumor). BWA and Bowtie were used to align the two breast tumors. Several filtering criteria's were applied to the tumors to remove any known (germ line) or low confidence SNVs. We randomly selected 83 and 31 eSNVs for the HER2 and ER positive tumors respectively and performed Sanger sequencing validation in tumor and matched normal tissues of the tumor. We were able to validate 81 out of 83 eSNVs in the HER2 tumor sample, and 29 out of 31 eSNVs in the ER positive tumor sample. Of the eSNVs that we validated 39/81 and 10/31 were localized to functional protein domains in HER2 and ER positive tumors respectively. We are also in the process of validating eSNVs detected from RNA-seq with the tumor and blood exome sequencing data we have for the same patients. Citation Format: Xiaojia Tang, Saurabh Baheti, Khader Shameer, Kevin J. Thompson, Jean-Pierre Kocher, Edith A. Perez, Aubrey E. Thompson, Krishna R. Kalari. The eSNV-Detect: a computational system to identify expressed single nucleotide variants from tumor transcriptomes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3185. doi:10.1158/1538-7445.AM2013-3185

Abstract High-throughput data is increasingly being integrated into the fields of biology, molecular biology, and pharmacology. However, a difficult problem has been the rapid and fluid access to and integration of the data, which tends to reside in huge unwieldy databases. One set of cell lines with substantial potential for benefit from this type of access and integration is the NCI-60 cancerous cell lines. We present here a set of tools within our CellMiner web-application designed to address this need for the areas of transcript expression, microRNA expression, gene DNA copy number, variant status, and drug activity. CellMiner allows the user to rapidly access data for relative levels of transcript expression for 26,065 genes, 360 microRNAs, and 20,602 compounds including 102 Food and Drug Administration (FDA)-approved drugs. These levels in turn create patterns across the NCI-60 that can be compared to one another using our “pattern match” tool. Together, these tools allow one to query the data for potential relationships between these parameters, in a manner specific to a users area of expertise and interest, in a rapid and flexible manner without the need for expertise in computer science or bioinformatics. Comparisons of transcript/drug will be demonstrated with SLFN11/topotecan; variant/drug with BRAF V600E/vemurafinib; colon tissue-of origin specific genes with TRIM15, RNF43, and VIL1; and DNA copy number change with CDKN2A (p16). The data are publicly available at http://discover.nci.nih.gov/cellminer. Citation Format: William C. Reinhold, Margot Sunshine, Sudir Varma, Hongfang Liu, Ogan Abaan, Paul Meltzer, Joel Morris, Kurt Kohn, James Doroshow, Yves Pommier. Web-based access using CellMiner for gene expression, DNA copy number, microRNA transcript levels, variant status, drug activity, and their pattern comparisons for the NCI-60. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3177. doi:10.1158/1538-7445.AM2013-3177

Abstract EGFR and EGFR ligand upregulation has been widely seen in both human chronic pancreatitis and pancreatic ductal adenocarcinoma (PDA) for many years; however the role of EGFR in PDA was poorly understood. Recently we and others have shown that genetic ablation of EGFR effectively prevents both spontaneous and cerulein induced tumorigenesis in the pancreas of the LSL-KrasG12D/+;Ptf1aCre/+ (KC) mouse model of pancreatic tumorigenesis. Pockets of EGFR upregulation localized in single acini of KC mice appear to precede pancreatic intraepithelial neoplasia (PanIN) formation in spontaneous tumorigenesis, coupled with a distinct spatially localized immune response. Ubiquitous EGFR upregulation is observed throughout the pancreas upon induction of pancreatitis in wild-type (WT) and KC mice, returning to normal levels in WT mice but continuing to increase along with the widespread tumorigenesis in cerulein treated KC mice. Comparison of cerulein treated KC mice with the EGFRf/f;LSL-KrasG12D/+;Ptf1aCre/+ mice (EKC), which are largely resistant to cerulein induced pancreatitis, offers an opportunity to identify signals in the KC mouse which could be responsible for the upregulation of EGFR and subsequent tumorigenesis. Citation Format: Christopher J. Halbrook, Kenneth K. Takeuchi, Howard C. Crawford. Regulation of EGFR in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3030. doi:10.1158/1538-7445.AM2013-3030

Abstract Glioblastoma multiforme (GBM) is the most common primary central nervous system tumor accounting for approximately 40% of all primary malignant brain tumors. The mechanism driving the development and recurrence of GBM is still largely unknown which greatly limits the successful treatment of this disease. The tumor necrosis factor receptor superfamily member TNFRSF19 (TROY) is a type I cell surface receptor protein containing the highly conserved TNFR cysteine-rich motifs in the extracellular domain and a tumor necrosis factor-receptor-associated factor (TRAF) - binding sequence in the cytoplasmic domain. We recently demonstrated that increased expression of TROY stimulated glioma cell migration in vitro and increased cell invasion in an organotypic brain slice model. Conversely, siRNA mediated knockdown of TROY expression inhibited glioma cell migration. In addition, profiling of TROY in brain tumor samples indicated that TROY mRNA expression was significantly increased in GBM samples, directly correlated with increasing glial tumor grade, and inversely correlated with patient outcome suggesting that TROY expression may play a role in GBM invasion and is a good indicator of survival outcome. In the current study, we investigated the role of TROY in therapeutic resistance and survival signaling. We report that TROY protein expression was significantly increased in patient GBM tumor samples with TROY mRNA exhibiting increased expression in the invasive cell population. Aberrant expression of TROY in mouse astrocytes in situ using glial-specific gene transfer in transgenic mice induced astrocyte migration within the brain supporting an important role for TROY in glioma cell migration. Notably, increased TROY expression did not increase cell proliferation but increased resistance of glioma cells to both radiation and temozolomide induced apoptosis while knockdown of TROY increased temozolomide sensitivity. TROY induced resistance to TMZ was dependent upon Akt and NF-κB activation. We also report that TROY induced NF-κB phosphorylation and stimulation of migration required the membrane proximal region of the TROY cytoplasmic domain and that knockdown of TROY expression increased survival in a xenograft model. The current results further support a role for TROY in GBM and suggest that targeting TROY and its signaling pathway represents a potential approach to increase tumor vulnerability and improve the therapeutic response of glioblastoma. Citation Format: Harshil D. Dhruv, Serdar Tuncali, Jean Kloss, Zhongbo Yang, Cassie Schumacher, Bart Williams, Julianna Ross, Nhan Tran, Joseph Loftus. TNFRSF19 (TROY) promotes glioma cell survival signaling and therapeutic resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2621. doi:10.1158/1538-7445.AM2013-2621

Abstract Colorectal cancer (CRC) is estimated to be the third most common cancer in both men and women in the US in 2012, accounting for over 50,000 deaths. Familial CRC accounts for approximately 30% of all CRC, yet only 5% of familial CRCs can be attributed to mutations in known hereditary colon cancer (HCC) genes. Many families with a strong family history of CRC do not have mutations in known CRC genes. Finding the genes underpinning CRC in these families may improve screening for disease and allow the development of more targeted therapeutics. We completed targeted sequencing of over 2,000 genes and miRNAs in 1,500 cases of CRC from the Colon Cancer Family Registry (CCFR) in an effort to identify rare variants associated with CRC risk and to identify mutations in known CRC genes missed by conventional sequencing. Several categories of genes were included: 18 known HCC genes; 18 candidate HCC genes; 185 genes in previously reported CRC linkage peaks; 1,423 miRNAs; and 363 genes identified through whole exome sequencing of 40 affected cases in 16 families with hereditary CRC (n=2,007 total genes sequenced). Genomic DNA samples were indexed, then libraries were made using Agilent's SureSelect Targeted Enrichment kit. Samples were pooled (96 samples/pool), then each pool of samples was run on five lanes on an Illumina HiSeq2000 (average of 19.2 samples/lane). GenomeGPS, an in-house developed workflow, was used for read alignment, variant calling, and annotation. In early analyses of the first 161 cases, the mean number of mapped reads exceeded 20 million per sample and over 90% of the target region exceeded 40x coverage. A total of 26,484 SNPs were identified and passed quality filtering. Sequencing identified known mutations in MMR genes in positive control cases as well as mutations in HCC genes in previously untested cases. Analysis is currently on-going on the remaining samples and we will report results on the full set of 1500 cases at the meeting. Citation Format: Melissa S. DeRycke, Shanaka R. Gunawardena, Sumit Middha, Shannon K. McDonnell, Shaun M. Riska, Zachary C. Fogarty, Bruce W. Eckloff, Daniel J. Schaid, Ellen L. Goode, Stephen N. Thibodeau. Targeted sequencing to identify rare variants in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2548. doi:10.1158/1538-7445.AM2013-2548

Abstract Background: Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) are collectively classified as myeloproliferative neoplasms (MPN). Given that little is known about their etiology, we investigated the role of anthropometric, medical and lifestyle factors in the development of MPNs and the common subtypes (ET & PV) in a population-based cohort of women. Methods: The IWHS is a prospective cohort of Iowa women aged 55-69 years at enrollment in 1986. Participants completed 6 self-administered questionnaires between 1986-2004. This analysis includes 27370 women who completed the 1993 questionnaire, had no history of cancer, and were enrolled in Medicare at least 1 year. MPN cases through 2004 were identified by linkage to Medicare. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression, with age as the underlying time variable. Results: After >250,000 person-years of follow-up, 257 cases of MPNs were identified (172 ET, 64 PV and 21 MF). Height, body mass index (BMI) and waist-to-hip ratio were not associated with risk of MPN. In subtype analysis, BMI was positively associated with risk of ET (RR=1.52 for >29.3 vs <23.5 kg/m2; p-trend=0.042) but not PV. Physical activity (PA) showed a suggestive association with MPN (RR=0.74 for high vs low activity; p-trend=0.063), specific only to ET (RR=0.66; p-trend=0.04). Diabetes (DM) was positively associated with risk of MPN (RR=1.51; 95% CI 1.02-2.24), also specific only to ET (RR=1.82; 95% CI 1.16-2.84). Regular use of aspirin, but not other non-steroidal anti-inflammatory agents, was associated with a lower risk of MPN (RR=0.71; 95% CI 0.55-0.92); slightly stronger for ET (RR=0.68; 95% CI 0.50-0.93) than for PV (RR=0.84; 95% CI 0.50-1.43). There was no dose-response with frequency of use. Cigarette smoking was associated with risk of MPN, which was stronger for PV (RR=0.94 for former and RR=2.83 for current; p-trend=0.016) than for ET (RR=1.28 for former and RR=1.32 for current; p-trend=0.15). There were no associations with alcohol use. In a multivariate model for ET, the associations for BMI (RR=1.28; p-trend=0.21) and DM (RR=1.51; 95% CI 0.92-2.46) attenuated, while there was little change for PA (RR=0.66; p-trend=0.062) or aspirin use (RR=0.70; 95% CI 0.51-0.96). In PV, there was little impact on the association with smoking (RR=0.92 for former and RR=2.67 for current; p-trend=0.028) after adjustment for BMI, PA, DM and aspirin use. Conclusions: Risk factors were unique to the 2 most common types of MPN. ET was associated with obesity-related factors (PV was not), and PV was associated with current smoking (ET was not). Aspirin use had a stronger inverse association for ET. Our results suggest distinct etiologies of these PMN subtypes, and raises mechanistic hypotheses related to inflammation for ET and smoking-related carcinogenic pathways for PV. Citation Format: Alexis D. Leal, Carrie A. Thompson, Alice Wang, Robert A. Vierkant, Thomas M. Habermann, Julie A. Ross, Beth A. Virnig, James R. Cerhan. Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in the Iowa Women's Health Study (IWHS) cohort. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2536. doi:10.1158/1538-7445.AM2013-2536

Abstract BACKGROUND: Biobanks collect and store biological samples and data from participants for use in research by multiple investigators. The Mayo Clinic Biobank was established by the Mayo Clinic Center for Individualized Medicine with a goal to support a wide array of health-related research studies at Mayo Clinic, including cancer studies. The Biobank is not focused on any particular disease, however, through annotation by questionnaires, the Mayo electronic medical record (EMR), and the Mayo Cancer Registry, it is a useful clinical research resource for cancer related studies. METHODS: Recruitment started in April 2009. Our goal is 50,000 enrollees. Eligible subjects are adult Mayo Clinic patients, U.S residents, and able to consent. Mailed invitations were sent to patients with appointments in certain Mayo Clinic departments. Each participant completed a health history questionnaire including a wide variety of health information as well as whether they or their 1st-degree relatives had ever been diagnosed with specific cancers. For self-reported cancers, subjects were asked to provide the age they were first diagnosed. Subjects also provided a blood sample and granted research access to clinically collected specimens and data from their Mayo Clinic record, at enrollment and into the future. All research projects utilizing samples from this resource are required to return to the Biobank the data generated from their projects. RESULTS: In the first three years, 21736 subjects consented to participate (30% response rate). Participants are 58% female, 95% White, and range in age from 18 to 97 with a median age of 62. At enrollment, 74% were residents in Minnesota, 6% in Iowa, 4% in Wisconsin, and 15% in the other states. Twelve percent reported being a current smoker, while 59% were never smokers. The most common self-reported cancers at baseline were non-melanoma skin cancer (n=2950), prostate cancer (n=1107), breast cancer (n=941), melanoma (n=692), colorectal cancer (n=296), cervical cancer (n=240), sarcoma (n=233), urinary/bladder (n=211), lymphoma (n=187), thyroid cancer (n=186), endometrial cancer (n=170), kidney cancer (n=163), lung cancer (n=145). Excluding non-melanoma skin cancer, 16188 (74%) (6516 male, 9672 female) self-reported being cancer free at baseline. Data will be presented on the frequency of incident cancers diagnosed since enrollment in the Biobank. To date, the Biobank has served as a source of controls for 17 cancer related studies on genetic susceptibility, including studies of the breast, colon, myeloma, brain, lung, pancreas, endometrium, and kidneys. CONCLUSIONS: The Mayo Clinic Biobank has quickly been established as a valuable resource for cancer researchers at Mayo Clinic - primarily as a source of controls for genetic studies. As the Biobank continues to grow in sample size and length of follow-up, it will also serve as a cohort study of cancer incidence embedded within an EMR of a large health organization. Citation Format: Janet E. Olson, Euijung Ryu, Kiley J. Johnson, Karen Maschke, Jody A. Morrisette, Mark Liebow, Paul Y. Takahashi, Ruchi G. Sharma, Kari S. Anderson, Matthew A. Hathcock, Jyotishman Pathak, Noralane M. Lindor, Timothy J. Beebe, Stephen N. Thibodeau, James R. Cerhan. The Mayo Clinic Biobank - A growing resource for cancer related studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2515. doi:10.1158/1538-7445.AM2013-2515

Abstract NSC 373981 is 1-ethanol, 2-nitro-naphtho[2,1-b]furan that has demonstrated activity in the NCI60 anticancer screen and in the mouse hollow-fiber assay. Growth inhibitory activity was also observed in several xenograft models. There is some evidence that antitumor activity is greater in vivo than would be predicted by the in vitro results, suggesting the possibility of activating metabolism. While the mechanism of anticancer activity is unknown, naphthofurans have been reported to modulate certain nuclear receptors. The purpose of this study was to characterize the plasma pharmacokinetics of NSC 373981 following i.v. and i.p. administration to athymic nude mice and to characterize potential metabolites of this compound in plasma, urine, and bile. We developed and validated suitable positive ionization LC/MS/MS methodology for measuring NSC 373981 that utilized liquid extraction with 1-chlorobutane and MS/MS detection with the 258>212 and 244>169 transitions, respectively, for NSC 373981 and NSC 329226, an analog that was used as the internal standard. Baseline separations were achieved on a Polaris C18 column under a mobile phase consisting of 70:30 methanol:water containing 0.1% formic acid. Standard curves were linear over the concentration range 2.5-1000 ng/mL with a lower limit of detection of 2.5 ng/mL. NSC 373981 was stable under acidic, neutral and basic conditions, as well as human and mouse plasma during 24-hr incubation at 37°C. NSC 373981 pharmacokinetics were characterized in male nu/nu mice after a 37.5 mg/kg i.v. dose or a 150 mg/kg i.p. dose. Plasma, bile, urine and feces were collected for 24-hr after drug administration. Following i.v. administration, the peak concentration was > 5.9 μg/mL and the terminal elimination half-life was 1.2 hours. Volume of distribution and plasma clearance values were 694 ml and 390 mL/hr, respectively. Following i.p. administration, NSC373981 reached a peak concentration of 2.1 μg/mL at 15 minutes and the terminal elimination half-life was 36.8 hours. The i.p. bioavailability of NSC373981 was 58%. In vivo metabolite profiles were characterized in plasma, urine, feces, and bile. We detected several Phase I metabolites in these samples including those produced by reduction of the aromatic nitro group, oxidation of the primary alcohol moiety on the reduced metabolite, oxidation of the primary alcohol moiety, benzylic hydroxylation, hydroxylation and dihydrodiol formation on the naphthalene moiety, and Phase II metabolites including glucuronidation of the carboxylic acids and a glutathione metabolite of hydroxylated NSC 373981. Supported by NCI contract N01-CM-2011-00014. Citation Format: Joel M. Reid, Sarah A. Buhrow, Renee M. McGovern, Joseph M. Covey, Matthew M. Ames. Pharmacokinetics and in vivo metabolism of the naphthofuran NSC373981 in male nu/nu mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2462. doi:10.1158/1538-7445.AM2013-2462