Citations

Abstract Bladder cancer is the 5th most commonly diagnosed cancer in the United States. Because superficial bladder cancer (SBC) recurs in about 60% of cases, standard treatment involves tumor resection followed by intravesical therapies to prevent recurrence, as well as lifelong periodic cystoscopy. There is an urgent need for better intravesical therapies to prevent both the recurrence and progression of SBC. Recent evidence has demonstrated that glycogen synthase kinase – 3 beta (GSK3β) plays an important role in pancreatic, ovarian and colon cancers; however, to date the possible role of this important kinase has not been examined in bladder cancer. We propose that GSK3β plays a cancer promoting role in bladder cancer and that inhibition of GSK3β will reduce bladder cancer growth. The GSK3β inhibitor, AR-A014418, has been demonstrated to reduce tumor growth in the previously cited cancers. AR-A014418 reduced cell proliferation of three bladder cancer cell lines (HT1376, T24 and UM-UC-3) with EC50 values of 17.5μM for HT1376, 8μM for T24, and 10μM for UM-UC-3 cells. The effect of AR-A014418 on downstream targets in these cell lines was evaluated by Western blots which indicated an increase in apoptosis in these cells in response to drug treatment as demonstrated by the presence by both PARP and caspase 3 cleavage. The NFkB downstream target XIAP also exhibited reduced protein levels after drug treatment. The HT1376 cell line was transduced with luciferase containing lentivirus particles to generate a luciferase expressing cell line, HT1376-LUC to use for both ectopic and orthotopic models of bladder cancer growth. The efficacy of AR-A014418 in reducing bladder cancer tumor growth was tested in an ectopic mouse model. HT1376-LUC cells mixed with matrigel were transplanted into the right flank of 50 female nude mice. After one week, mice containing tumors with an average volume of 52 mm3 were randomized into four treatment groups of 10 mice each. Mice were treated twice weekly via IP injection with placebo, 1, 5 or 7mg/kg AR-A014418. Tumor sizes were measured and imaged for luciferase activity once weekly. Tumor growth was inhibited by both 5mg/kg and 7mg/kg doses by 19 days of treatment (p < 0.05, Student's T test). Together, the in vitro and in vivo data suggest that GSK3β is a novel target for bladder cancer treatment. Future studies using an orthotopic model of bladder cancer are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1671. doi:10.1158/1538-7445.AM2011-1671

Abstract Breast cancer is the most common form of cancer diagnosed and the second leading cause of cancer death among women in the United States. Cancer metastases are the major cause of morbidity and mortality among breast cancer patients. The central importance of the HER2/RAS signaling pathway has been well established in promoting tumor growth, invasion and metastasis of human breast cancer. Even though oncogenic K-RAS mutations are rare in breast cancer, activation of the growth-promoting ERBB/RAS pathway has been consistently documented in high-grade breast tumors. As such, novel approaches to inhibit activated HER2/RAS signals constitute important measures to block tumor growth and metastasis in mammary tumors. In this study, instead of targeting an upstream signaling component such as HER2/EGFR/RAS, we targeted the most downstream signaling module identified in the ERBB/RAS pathway – the SIAH proteolytic machinery. SIAH is an evolutionarily conserved RING E3 ligase that is a critical “gatekeeper” required for RAS signal transduction in human cancer cells. SIAH is specifically expressed in tumor cells in 120 human breast cancer patients examined so far. The increased SIAH expression is correlated with increased grades and aggressiveness of human breast cancer. We asked whether inhibiting the gatekeeper function of SIAH would be effective in blocking mammary tumorigenesis and metastasis in human breast cancer. Our results indicated that SIAH2-deficiency successfully abolished tumor growth of three breast cancer cell lines (MDA-MB-231, MDA-MB-435 and MDA-MB-468) in soft agar assays as well as in athymic nude mice. Importantly, by inhibiting SIAH2 function in highly aggressive human breast cancer cells, we are able to completely block tumorigenesis and metastasis of two highly invasive and metastatic human breast cancer cell lines (MDA-MB-231 and MDA-MB-435). These results suggest that SIAH2 may be an attractive and new drug target for novel breast cancer therapy. Developing anti-SIAH molecules will aid in expanding our arsenal of effective anticancer therapies. By attacking the growth-promoting HER2/EGFR/RAS pathway at multiple signaling modules simultaneously – a multi-pronged synergistic inhibition at upstream (HER2/EGFR membrane receptors), midstream (RAS/RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules in the HER2/EGFR/RAS pathway in parallel, we may be in a position to halt the genesis, progression and metastasis of human breast cancer. Thus, SIAH-dependent proteolysis may be an Achilles heel for breast cancer. SIAH inhibition may represent an innovative and logical way to inhibit HER2/EGFR/K-RAS activation, alleviate tumor burdens, halt cancer metastasis, and improve the efficacy for the future treatment of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1659. doi:10.1158/1538-7445.AM2011-1659

Abstract Ovarian carcinoma is a significant cause of cancer mortality in women in the United States. Increasing evidence has demonstrated that differential methylation status in lymphocyte DNA may be linked to risk of carcinogenesis. We are investigating the differential DNA methylation in germline DNA obtained from pre-treatment ovarian cancer cases (n=256) and individually-age matched controls (n=274) using the Illumina Infinium Human Methylation 27K BeadChip. We are first studying methylation and the common moderate-risk alleles for ovarian cancer on chromosomes 2q31, 3q25, 8q24, 9p22, 17q21, and 19p13. Within each locus, we correlated single nucleotide polymorphism (SNP) genotypes with methylation values at relevant nearby CpG sites. Preliminary results are available on the first set of 84 cases and 90 controls. At 2q31, cases with TG or TT genotype at rs2072590 were hypomethylated at HOXD1 (a homeobox transcription factor) compared to cases with GG genotype (mean beta TG/TT=0.08, GG=0.09, p=0.034); and at 17q21, cases with AG or GG genotype at rs9303542 were hypomethylated at SKAP1 (a T-cell adaptor protein) compared to cases with AA genotype (mean beta AG/GG=0.14, AA=0.16, p=0.045). At these two loci, similar trends were seen among controls. Logistic regression adjusted for age and methylation chip was then used to assess the association between SNP genotype and ovarian cancer risk, with and without inclusion of the relevant methylation value. At HOXD1 rs2072590, the per-allele ovarian cancer risk of 1.34 attenuated to 1.25 with inclusion of the HOXD1 methylation value as a covariate, suggesting that the disease association may be mediated in part through methylation. Though based on preliminary data, results are consistent with a role for inherited variation on germline methylation at HOXD1 and SKAP1. Analysis of methylation on additional genotyped cases and controls is underway. Finally, because, trans effects may also exist, we are assessing relationships between genotype and methylation at other loci throughout the genome. Such correlative molecular studies have the potential to help elucidate mechanisms underlying associations from genome-wide association studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5616. doi:10.1158/1538-7445.AM2011-5616

Abstract Germline mutations in BRCA2 predispose to breast, ovarian and other cancers. Although most mutations in the gene are known to be pathogenic, there is an increasing number of missense variants for which the contribution to cancer risk is unclear. These missense substitutions are referred to as VUS (variants of uncertain significance). Because loss of BRCA2 HR function leads to defective DNA double-strand break repair and an increased risk of cancer, we evaluated the utility of a cell-based Homologous Recombination (HR) assay for determination of the cancer relevance of BRCA2 VUS. Specifically, we studied VUS localized in the BRCA2 DNA binding domain (DBD) for effects on HR. We transfected full length wild-type and mutant BRCA2 constructs into V-C8 BRCA2 deficient cells along with an I-Sce1-expressing plasmid which induces an unique double strand break in an integrated DR-GFP reporter plasmid. We evaluated the ability of each BRCA2 mutant to repair the induced break by quantifying the GFP positive cells, generated by HR repair of the DNA break, with fluorescent activated cell sorting (FACS). To establish the sensitivity and specificity of the HR assay we evaluated a series of known deleterious and known neutral with the HR assay. These mutations of known effect were identified using a multifactorial likelihood approach, based on available family data, with a prior probability approach based on sequence conservation (A-GVGD) algorithm (http://agvgd.iarc.fr/agvgd_input.php). We calculated the total odds of pathogenicity for co-segregation of variants with the disease in affected carrier families, co-occurrence of VUS (in trans) with deleterious mutations and for family history of cancer of VUS and combined this odds with the A-GVGD based prior probabilities to generate the posterior probability of pathogenicity for each variant. Using this approach we successfully classified 31 VUS as either neutral or deleterious. By comparing these data with results from the HR assay we established that the assay is 100% sensitive (95% CI: 75.3% – 100%) and 100% specific (95% CI: 82.4% – 100%) for deleterious mutations in the BRCA2 DBD domain. In summary we evaluated the sensitivity and specificity of the HR assay for VUS in the DBD relative to a probability model based on family data and A-GVGD algorithm and we showed that the assay was highly sensitive and specific. Based on these results we propose that the HR assay can be used as a classifier of the clinical relevance of the VUS in the absence of direct genetic and family data. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5591. doi:10.1158/1538-7445.AM2011-5591

Abstract INTRODUCTION: Mammographic breast density is a strong risk factor for breast cancer (BC). We established the Mayo Mammography Health Study (MMHS) cohort study at the Mayo Clinic in Rochester, Minnesota (MN) to examine the association of breast density with BC. We evaluated the influence of the image acquisition technique on the density and BC association. METHODS: From October 2003 to September 2006, all women scheduled for screening mammography at the Mayo Clinic were invited to participate. Eligible women were residents of MN, Iowa (IA) or Wisconsin (WI); age 35+; and had no personal history of BC. A risk factor questionnaire, consent form and permission to link to tumor registries were obtained. Incident BC was identified through 2009 by linkage to the Mayo and state cancer registries. A case-cohort of all incident BCs and 2300 randomly selected women (the subcohort) were used to examine the association of breast density and BC using digitized film mammograms at the time of enrollment while controlling for the influence of the acquisition parameters (peak kilovoltage, milliampere-second, and compressed breast thickness). Two density measures were considered: a quantitative percent density (PD) measure estimated using the computer-assisted thresholding program, Cumulus (University of Toronto), and the 4-category clinical BI-RADS measure. Proportional hazards regression was used to calculate hazards ratios (HR) and 95% confidence intervals (CI) for BC associated with quartiles of PD (0-6.2%,6.3-14.9%, 15.0-25.7% and 25.8%+) and BI-RADS categories 1-4 (almost entirely fatty to extremely dense). All models included age, postmenopausal hormone use (PMH), BMI, and menopausal status. The influence of acquisition parameters was evaluated by examining models with and without their inclusion. RESULTS: A total of 20,982 (50%) women participated in MMHS; 1058 (5%) with a prior history of BC were excluded, for a total cohort of 19,924. Compared to nonresponders, responders were younger (57.5 vs. 58.4 yrs), more likely to have ever used PMH (45% vs. 33%), and more likely to have a BC family history (19% vs 16%). The case-cohort consisted of 317 incident cases and 2300 women in the subcohort. Women were excluded from the current analysis if PD could not be estimated or if acquisition parameters were not available, leaving 249 cases and 1937 in the subcohort. As expected, PD was associated with BC [HR (95% CI): 1.0 (REF), 2.1 (1.4-3.1), 3.0 (2.0-4.5), and 4.6 (3.0-7.0) for quartiles; p-trend<0.001]. Controlling for acquisition parameters attenuated the association [HR (95% CI): 1.0 (REF), 2.3 (1.5-3.4), 2.4 (1.6-3.7), and 3.0 (1.8-5.0) for quartiles; p-trend<0.001]. Results for BI-RADS density were similar to those for PD. CONCLUSION: This study confirms that breast density is a significant risk factor for BC and demonstrates that the acquisition technique confounds the density and BC risk association. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3716. doi:10.1158/1538-7445.AM2011-3716

Abstract Background: Endometrial carcinoma is the most common gynecological malignancy in the western world. Activating mutations of the fibroblast growth factor receptor 2 (FGFR2) have been described in 12-16% of endometrial cancers. Moreover, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their receptors are involved in the neovascularization, invasiveness, and metastatic potential of endometrial cancer. Therefore, suppression of FGFR/VEGFR/PDGFR signaling by TKI258 may represent a novel approach for treatment of endometrial cancer. Experimental Design: The aims of this study were 1.) to assess the effect of TKI258 on tumor cell growth in two-dimensional (2D) and three-dimensional (3D) culture assays using a panel of 20 human endometrial cancer cell lines, 2.) to identify candidate molecular markers predicting sensitivity using baseline gene expression profiling and mutational analyses, and 3.) to determine the in vivo antineoplastic activity of TKI258 in endometrial cancer xenograft models. In addition, we screened 200 fresh frozen endometrial cancer specimens to comprehensively assess the distribution pattern of PI3K, PTEN, and FGFR mutations in endometrial cancer. Results: Concentration-dependent anti-proliferative effects of TKI285 using 2D assays were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC50 range: 0.42µM – 3.06 µM). The three most sensitive endometrial cancer cell lines demonstrated activating FGFR2 mutations (MFE296: N549K, IC50 0.42µM; AN3CA: N549K and K310R, IC50 0.50µM; MFE280: S252W, IC50 0.66µM). Assessment of TKI258 responses in 3D assays demonstrated similar results to those observed in 2D culture assays in that the 3 cell lines harboring FGFR2 mutations were the most sensitive to TKI258 achieving 100% growth inhibition at a concentration of 1µM. AN3CA and MFE296 endometrial cancer cells formed xenografts in nude mice and antitumor activity was studied in both models. Inhibition of p-FGFR, p-PDGFR, p-VEGFR-2, pAKT and p-ERK1/2 were observed. Comprehensive data on the pattern of PI3K, PTEN and FGFR mutations in endometrial cancer will be provided. Conclusion: TKI258 demonstrates significant antitumor activity in endometrial cancer cells with FGFR2 mutations. This study provides a strong rationale for the clinical evaluation of TKI258 in patients with endometrial cancer, specifically in those harboring FGFR2 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3589. doi:10.1158/1538-7445.AM2011-3589

Abstract We have previously identified serine protease HtrA1 as a down-regulated gene in ovarian cancer and loss of HtrA1 may contribute to cell resistance to cisplatin treatment. However, the exact mechanism by which HtrA1 regulates chemosensitivity in ovarian cancer is currently unknown. Here, we used mixture-based oriented peptide library approach and identified XIAP, an important member of the inhibitor of apoptosis (IAP) protein family, as one possible substrate of HtrA1. Recombinant wild type (WT) HtrA1 but not protease-inactive SA mutant HtrA1 can cleave XIAP protein in vitro. Over-expression of HtrA1 led to decreased level of XIAP in OV167 and OV202 ovarian cancer cells, while down-regulation of HtrA1 resulted in increased level of XIAP in SKOV3 ovarian cancer cells. CDDP treatment enhanced the cleavage of XIAP by HtrA1. Immuno-precipitation assay revealed that HtrA1 binds to XIAP directly both in vitro and in vivo. Increased cell resistance to cisplatin treatment was observed in SKOV3 and TOV-21G cells after stable knockdown of HtrA1 with shRNA. In contrast, over-expression of HtrA1 in OV202 cells promotes cell sensitivity to cisplatin treatment which can be reversed by increased expression of XIAP. In conclusion, our experiments reveal XIAP as a novel substrate of HtrA1 and the mechanism by which HtrA1 confers cell sensitivity to cisplatin treatment may be partially through its degradation of XIAP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1531. doi:10.1158/1538-7445.AM2011-1531

Abstract Most breast cancer deaths are the consequence of metastasis from the primary site. In order to metastasize, tumor cells must escape the physical barriers that contain the growing primary tumor, enter the vascular system, exit the vascular system at a distant point, and colonize a distant organ. An important mediator of metastasis is matrix metalloproteinase-9, a member of the MMP family that has been found to be upregulated both in breast cancer cells and in the surrounding tumor stroma. Studies using animal models have sometimes produced apparently contradictory findings, due in part to methodology in which MMP-9 expression is suppressed throughout the host organism and throughout the course of tumor initiation and progression. To define the specific role of tumor cell-produced MMP-9 in metastasis of human breast cancer, we implemented a bioluminescent imaging animal model of metastasis in which luciferase-expressing MDA-MB-231 cells, infected either with control nontarget lentivirus (MDA-MB-231-NT) or with shRNA lentivirus targeting MMP-9 (MDA-MB-231-MMP9-KD), were orthotopically implanted into the mammary fat pads of immunocompromised mice. Tumor growth and development of lung metastases were assessed over 10 weeks using an IVIS imager. At 11 weeks mice were sacrificed, and tumor progression was assessed by ex vivo lung imaging and by immunohistochemical processing of the tumors and the lungs. Imaging studies revealed that primary tumors developing from MMP-9 knockdown cells grew more slowly throughout the course of the study (ranging from 25% to 50%), and that while the majority of the control group developed lung metastases, none of the mice injected with MDA-MB-231-MMP9-KD cells showed metastatic progression. After sacrifice, the measured tumor weight showed a median of 99 mg for the MDA-MB-231-MMP9-KD and 158 mg for the MDA-MB-231-NT tumors, showing that knockdown of MMP-9 inhibited tumor growth. Ex vivo imaging of the lungs confirmed the in vivo studies: no metastases were detected from MDA-MB-231-MMP9-KD cells, while all lungs of the MDA-MB-231-NT injected mice had detectable metastases (p=0.0079). Similarly, a single level immunohistochemical correlate found no metastases in the MDA-MB-231-MMP9-KD mice, while 3 of 4 mice with the non-target control cells showed large metastases (median 7×103 μm2). Our results demonstrate that expression of MMP-9 by human breast cancer cells plays a significant role in the progression of tumor growth and metastasis and provide insight into the potential of MMP-9 as a target for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1497. doi:10.1158/1538-7445.AM2011-1497

Abstract Batracylin (NSC 320846, BAT) is a heterocyclic arylamine and topoisomerase II inhibitor that was shown to be active in several murine tumor models. Pharmacology and toxicology studies demonstrated marked species differences in sensitivity to the toxic effects of BAT attributed to metabolism to N-acetylbatracylin (NacBAT) by N-acetyltransferase (NAT). It was subsequently shown that BAT is a preferential substrate for human NAT2; thus production of NacBAT is likely subject to population variability as a function of known NAT2 polymorphisms. A phase I clinical trial of BAT in patients with advanced cancer and slow acetylator NAT2 genotypes to reduce the risk of toxicity due to NacBAT is ongoing and a potentially dose-limiting toxicity of cystitis/hemorrhagic cystitis was observed in several patients. In order to determine if this toxicity is due to BAT, NacBAT, and/or other metabolites, we investigated the in vitro metabolism of BAT and NacBAT in human (h) and rat (r) liver microsomes (LM) and hepatocytes, and the in vivo metabolism of BAT and NacBAT in rats. 14C-BAT and differentially deuterated (d3- and d4-) BAT were provided to facilitate metabolic profiling. d3- and d4- NacBAT were generated in situ. BAT, NacBAT and their metabolites were detected and quantified by HPLC with diode array, fluorescence, radiochemical and mass spectrometry as appropriate. The goals of these investigations were to obtain a detailed metabolic profile for BAT in rats and humans and to elucidate pathways that might contribute to BAT toxicity. In NADPH-fortified microsomal preparations, loss of BAT was accompanied by formation of one hydroxylated metabolite in hLM and three hydroxylated metabolites in rLM. The single hydroxylated metabolite found in incubations of NacBAT with hLM was attributed to deacetylation by microsomal carboxlesterase. Six mono- and di- hydroxy NacBAT metabolites were found in incubations of NacBAT with rLM. Hydroxylation sites were identified with deuterated BAT and NacBAT. Incubation with recombinant cytochomes P450 (CYPs) identified rCYP1A1, rCYP1A2, hCYP1A1 and hCYP1B1 as the major CYP isoforms that metabolize BAT and NacBAT. Glucuronide conjugates of BAT and NacBAT were identified in rat and human hepatocyte incubations. NacBAT, hydroxylated BAT and NacBAT, and glucuronide conjugates were detected in in vivo metabolism and pharmacokinetic studies with BAT and NacBAT in rats. Finally, thiol-containing adducts, consistent with metabolic activation of BAT, were identified in kidney and urine samples from in vivo metabolism and pharmacokinetic studies with rats. In conclusion, we characterized the in vitro and in vivo metabolism of BAT and identified a pathway for metabolic activation of BAT to potential toxic metabolites. Supported by NCI Contract N01-CM-52206. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1303. doi:10.1158/1538-7445.AM2011-1303

Abstract Background: ABT-888 is an inhibitor of poly(ADP-ribose) polymerase1 (PARP1) and PARP2, two highly conserved enzymes implicated in DNA repair, maintenance of genomic stability, and regulation of transcription. Topotecan (TPT) is a water soluble camptothecin derivative with antitumor activity against ovarian tumors. The combination of ABT-888 with TPT is under investigation in phase I trials because PARP inhibition sensitizes tumors cells to TPT in vitro and in vivo. In those trials, the pharmacokinetics of TPT and ABT-888 are being studied to determine if ABT-888 levels are sufficient to modulate PARP activity and to investigate the potential interaction between TPT and ABT-888. Methods: Advanced cancer patients with ECOG performance scores 0-2, adequate hematological, renal and hepatic function were treated with ABT-888 on days 1-3, 8-10, and 15-17 every 28 days. Topotecan was administered on days 2, 9 and 16 every 28 days. DLTs were defined as grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 anemia or ≥ grade 3 non-hematologic toxicities despite maximal supportive care. ABT-888 and Toptoecan pharmacokinetics were characterized in all patients. Analysis of urinary recovery is ongoing. Results: In this ongoing Phase I trial, 13 female patients with ovarian (n=12) or breast (n=1) cancer have been enrolled to date and pharmacokinetic data is available for 12 of those patients. ABT-888/TPT dose levels are: Level 1- 10 mg/ 2 mg/m2, Level 2- 20 mg/2 mg/m2, Level 3- 10 mg/3 mg/m2, and Level 4- 20 mg/3 mg/m2. The combination of ABT-888 with topotecan has been tolerable, with no dose limiting toxicity, and dose escalation continues at dose level 5. Topotecan t1/2 and clearance values were 3.0 ± 0.5 hrs and 9.50 ± 1.51 L/hr/m2 when administered alone, and were not affected by administration with ABT-888. When administered alone, ABT-888 t1/2, Cmax, AUC0-∞ values after the 10 mg dose were 8.2 ± 2.4 hrs, 432 ± 217 nM, and 2568 ± 1300 nM*hr, respectively. ABT-888 t1/2, Cmax, AUC values after the 20 mg dose were 5.7 ± 3.1 hrs, 600 ± 165 nM, and 3870± 934 respectively. When administered with TPT, ABT-888 t1/2, Cmax, AUC values after the 10 mg dose were 7.2 ± 2.1 hrs, 412 ± 283 nM, and 2705± 1089 nM*hr are: nM*hr respectively. ABT-888 t1/2, Cmax and AUC values after the 20 mg dose combined with TPT were 5.8 ± 2.2 hrs, 664 ± 97.6 nM, and 4283± 936 nM*hr respectively. Conclusions: Plasma clearance of TPT and ABT-888 does not appear to be altered when they are administered together. The effect of co-administration of these agents on renal clearance is presently under investigation and those results will be presented. This work was supported by NIH grants R25 GM75148-04, U01CA069912-16S and MM01-RR00585. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1301. doi:10.1158/1538-7445.AM2011-1301