Citations

Abstract Some studies show that childbearing at older age is associated with lower risk of endometrial cancer, but whether the association is independent of number of children or other factors still requires clarification. We pooled individual-level data from epidemiologic studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Data on age at last birth and/or last pregnancy were available from 14 studies: 11 case-control studies and 3 cohort studies; the latter were analyzed using a nested case-control design. A total of 9,613 endometrial cancer cases and 17,112 controls were included in the analysis. The majority of women were White (82%) and older than 55 years (69%). We estimated the effects of age at last birth using data from 12 studies and age at last pregnancy using data from 10 studies on the risk of endometrial cancer by calculating odds ratios (OR) and 95% confidence intervals (95% CI) using logistic regression models. Potential confounders included in the analysis were race, body mass index, parity, age at menarche, age at first birth, oral contraceptive use, postmenopausal hormone use, smoking status, and report of diabetes. After adjusting for potential confounders, a reduction in endometrial cancer risk was observed in women with increasing age at last birth (P trend <0.0001) and age at last pregnancy (P trend <0.0001). The OR per five-year increase in age at last birth and age at last pregnancy was 0.90 (95%CI: 0.86, 0.94) and 0.91 (95% CI: 0.87, 0.95), respectively. Women who had their last child at an age >40 years were at a 34% decreased risk compared with women who had their last child at an age <25 years (95% CI: 0.52, 0.82). Compared to women with age at last pregnancy <25 years, those with age at last pregnancy >40 years had a 30% decreased risk of endometrial cancer (95%CI: 0.57, 0.86). Inverse associations were observed for Whites and Asians in race-specific analysis and also in analysis restricted to women with at least 2 births. In this large pooled analysis, we show that late age at last birth or last pregnancy is a strong and independent protective factor for endometrial 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 1900. doi:10.1158/1538-7445.AM2011-1900

Abstract Development of efficacious strategies for eradication of glioblastoma multiforme (GBM) remains a significant challenge. While treatment of GBM with radiation and temozolomide (TMZ) has improved clinical outcome, lack of long-term efficacy can be due to the ability of GBM to acquire resistance to therapy by modulation of signaling pathways that control DNA repair and cell survival. The HDM2 antagonist, Nutlin3, blocks interactions of HDM2 with key signaling molecules such as p53, p73α, and HIF1α, and modulates their downstream effector function. A panel of human GBM cell lines is currently being used to monitor the extent to which Nutlin3 can sensitize cells to TMZ. In vitro survival assays indicate that Nutlin3 potentiates TMZ-mediated cell death; analysis of cell survival data using Dose Effect CalcuSyn software indicates that the combination index value was < 1 and indicative of a synergistic effect between Nutlin3 and TMZ. Western analyses of p53 wild-type GBM indicated increased p53 stabilization and activation of down-stream targets in cells treated with the combination of Nutlin3/TMZ compared to vehicle, TMZ, or Nutlin3. In addition, time-course studies indicated that U87-MG cells treated with Nutlin3/TMZ in comparison to single agent resulted in increased γ-H2AX and DNA-strand breaks. Efficacy studies using ectopic U87-MG xenografts indicated that 2 cycles of 5-consecutive days of Nutlin3/TMZ led to a significant decrease in tumor growth compared to vehicle or single agent (p < 0.001) with no signs of off-target toxicity. Regulation of DNA repair was further analyzed using the primary GBM.10 line that when grown as an ectopic xenograft, expresses the direct-reversal repair protein, O6-methylguanine DNA methyltransferase (MGMT) and proteins involved in base-excision repair (BER). In vivo target-validation studies using GBM.10 xenografts confirmed that repair of TMZ-mediated DNA damage is modulated in the presence of Nutlin3. GBM.10 xenografts were treated with vehicle, TMZ, nutlin3, or TMZ/Nutlin3 and modulation of critical targets determined by Western analyses. Increases in total p53, p53 phosphorylated at residue serine16, p73α, and substantial decreases in MGMT and the BER protein, APE-1, were observed following treatment with Nutlin3/TMZ compared to vehicle or single-agent exposure. Busso et al (Oncogene 2009) recently reported that HDM2 can monoubiquitinate APE-1 leading to proteosomal-mediated degradation. In addition, recombinant activity assays in our laboratory indicate that HDM2 directly monoubiquitinates recombinant MGMT and may play a role in its degradation. These data suggest that DNA repair proteins required for repair of TMZ-mediated DNA damage can be downregulated by altering HDM2-mediated signaling. Combination therapy that targets the p53-HDM2 E3 ligase network and DNA repair represents a novel approach towards improving treatment of GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5373.

Abstract Obesity and black race have been associated with excess risk of multiple myeloma. The association of obesity with monoclonal gammopathy of undetermined significance (MGUS) is unknown. Further, it is not known whether the increased risk of multiple myeloma and MGUS in blacks is related to socioeconomic status, genetic susceptibility, or both. We screened 1000 black and 996 white women (range, 40-79 years) of similar socioeconomic status for MGUS; the aim of the study was to assess MGUS risk in relation to obesity and race. A total of 39 (3.9%) blacks and 21 (2.1%) whites had MGUS. On multivariate analysis, obesity (odds ratio [OR] = 1.8; P = .04), black race (OR = 1.8; P = .04), and increasing age (> 55 vs < 43 years; OR = 2.5; P = .03) were independently associated with an excess risk of MGUS. Our findings support the hypothesis that obesity is etiologically linked to myelomagenesis. The 2-fold excess of MGUS among blacks compared with whites of similar socioeconomic status supports a role for susceptibility genes in MGUS.

Abstract Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.

Purpose To evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study. Patients and Methods Patients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m2 monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF). Results A total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD ≥ 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received ≥ eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks. Conclusion Ixabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.

Three cDNA with D region gene features have been identified from the H-2v haplotype. Provisionally, the sequences have been designated as D/Lv1, D/Lv2, and D/Lv3. The coding segments for the antigen binding domain (ABD) of all three D/Lv genes were engineered into a class I genomic expression vector and expressed in L cells. FACS analysis of the three D/Lv-Ld gene transfectants revealed that the D/Lv1 molecules were recognized by both monoclonal antibodies (mAbs) 141 and 142, and the D/Lv2 molecules were recognized by mAb 143. In addition to the D/Lv1 molecules, the mAb 141 also recognized the D/Lv3 molecules. Both the D/Lv1-Ld and D/Lv2-Ld transfectants were killed efficiently by H-2Dv region-specific alloreactive CTL. The D/Lv3 gene is the first identified D region gene other than D and L that is transcribed abundantly in spleen and the D/Lv3 RNA is present as two alternatively spliced forms. Structural analysis of the D/Lv3 hybrid molecules showed that it was susceptible to proteolysis and thermolabile at 37 degrees C, suggesting D/Lv3 is a transcribed pseudogene. A parsimony tree analysis of three D/Lv sequences with a set of class I gene sequences revealed that the H-2v sequences clustered with D region genes. The presence of a third gene with D/L-like features in H-2v, yet structurally different from the known D/L alleles, raises the possibility that the current D/L genes evolved from a family of D/L-like genes, some of which are no longer represented among many of the mouse major histocompatibility complex haplotypes. The observation that D region alleles cluster into subgroups suggests that the alleles are not all related to each other by linear descent through a single locus. We propose that current alleles are derived from more than one ancestral locus in a manner similar to the origin of the gamma 2 a immunoglobulin constant region alleles.

ABSTRACT Polycystin‐2 (PC2), encoded by the PKD2 gene, mutated in 10‐15% of autosomal‐dominant polycystic kidney disease (ADPKD) patients, is a Ca 2+ ‐permeable cation channel present in kidney epithelia and other tissues. As PC2 was found expressed in B‐lymphoblastoid cells (LCLs) and Ca 2+ signaling pathways are important regulators of B cell function activities, we investigated whether PC2 plays some role in B‐LCLs. In LCLs, PC2 was found mainly in ER membranes but ~8 times less than in kidney HEK293 cells. The same reductions were found in PKD2 and PKD1 RNA; thus, PKD genes maintained, in LCLs, the same reciprocal proportion as they do in kidney cells. In LCLs obtained from subjects carrying PKD2 mutations (PKD2‐LCLs) and showing reduced PC2 levels, intracellular Ca 2+ concentrations evoked by platelet‐activating factor (PAF), were significantly lower than in non‐PKD‐LCLs. This reduction was also found in PKD1‐ LCLs but without PC2 reductions. Likewise, cell proliferation, which is controlled by Ca 2+ , was reduced in PKD2‐ and PKD1‐LCLs. Moreover, in LCLs with PKD2 nonsense mutations, aminoglycoside antibiotics reduced the PC2 defect by promoting readthrough of stop codons. Therefore, PC2 and PC1 are functionally expressed in LCLs, which provide a model, easily obtainable from ADPKD patients, to study PKD gene expression and function.