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, Ana Ferrer, , , , Eugènia Abella, Santiago Gardella, Lourdes Escoda, Antoni Asensi, Llorenç Font, et al.
Clinical Cancer Research, Volume 14, pp 155-161; https://doi.org/10.1158/1078-0432.ccr-07-1371

Abstract:
Purpose: Fludarabine, cyclophosphamide, and mitoxantrone (FCM) results in a high response rate in previously treated patients with chronic lymphocytic leukemia (CLL). The aim of this study was to investigate FCM as frontline therapy in CLL.
, Charity Scripture, Edwin Posadas, Lokesh Jain, , , John J. Wright, Yunkai Yu, Liang Cao, Seth M. Steinberg, et al.
Clinical Cancer Research, Volume 14, pp 209-214; https://doi.org/10.1158/1078-0432.ccr-07-1355

Abstract:
Purpose: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC). Experimental Design: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles. Results: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimenn. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0-12) and maximum concentration (Cmax) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (tmax) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively. Conclusions: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.
Lorenzo M Leoni, Brandi Bailey, Jack Reifert, Heather H Bendall, Robert W Zeller, , Gary Elliott, Christina C Niemeyer
Clinical Cancer Research, Volume 14, pp 309-317; https://doi.org/10.1158/1078-0432.ccr-07-1061

Abstract:
Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds. Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
Xiong Li, Thomas A. Gardner, Chinghai Kao, You-Hong Liu, Sang-Jin Lee, Meei-Huey Jeng
Clinical Cancer Research, Volume 14, pp 291-299; https://doi.org/10.1158/1078-0432.ccr-07-0867

Abstract:
Purpose: Our previous studies coadministering a replication-deficient adenovirus expressing endostatin and angiostatin fusion gene (EndoAngio) and a prostate-restricted, replication-competent adenovirus (PRRA) showed dramatic antitumor efficacy. This study integrated EndoAngio with an improved PRRA vector to make a single antiangiogenic PRRA, thereby exerting a similarly dramatic antitumor effect with feasibility for future clinical trials.
, Y. Zhao, R. M. Simon
Clinical Cancer Research, Volume 14, pp 108-114; https://doi.org/10.1158/1078-0432.ccr-07-0443

Abstract:
A common goal of gene expression microarray studies is the development of a classifier that can be used to divide patients into groups with different prognoses, or with different expected responses to a therapy. These types of classifiers are developed on a training set, which is the set of samples used to train a classifier. The question of how many samples are needed in the training set to produce a good classifier from high-dimensional microarray data is challenging. We present a model-based approach to determining the sample size required to adequately train a classifier. It is shown that sample size can be determined from three quantities: standardized fold change, class prevalence, and number of genes or features on the arrays. Numerous examples and important experimental design issues are discussed. The method is adapted to address ex post facto determination of whether the size of a training set used to develop a classifier was adequate. An interactive web site for performing the sample size calculations is provided. We showed that sample size calculations for classifier development from high-dimensional microarray data are feasible, discussed numerous important considerations, and presented examples.
, Lilian Lee, Kevin Graham, Thevagi Satkunendran, Koichi Yoshikawa, Erick Ling, Lauren Harper, , Erica Nieuwenhuis, Ian D. Clarke, et al.
Cancer Research, Volume 69, pp 4682-4690; https://doi.org/10.1158/0008-5472.can-09-0342

Abstract:
Subpopulations of tumorigenic cells have been identified in many human tumors, although these cells may not be very rare in some types of cancer. Here, we report that medulloblastomas arising from Patched-1–deficient mice contain a subpopulation of cells that show a neural precursor phenotype, clonogenic and multilineage differentiation capacity, activated Hedgehog signaling, wild-type Patched-1 expression, and the ability to initiate tumors following allogeneic orthotopic transplantation. The normal neural stem cell surface antigen CD15 enriches for the in vitro proliferative and in vivo tumorigenic potential from uncultured medulloblastomas, supporting the existence of a cancer stem cell hierarchy in this clinically relevant mouse model of cancer. [Cancer Res 2009;69(11):4682–90]
Lanlan Wei, , Hebin Song, Anastacia M. Maldonado,
Cancer Research, Volume 69, pp 4878-4884; https://doi.org/10.1158/0008-5472.can-08-4695

Abstract:
High-risk human papillomavirus (HPV) infections are necessary but insufficient causes of cervical cancers. Other risk factors for cervical cancer (e.g., pregnancy, smoking, infections causing inflammation) can lead to high and sustained nitric oxide (NO) concentrations in the cervix, and high NO levels are related to carcinogenesis through DNA damage and mutation. However, the effects of NO exposure in HPV-infected cells have not been investigated. In this study, we used the NO donor DETA-NO to model NO exposure to cervical epithelium. In cell culture media, 24-hour exposure to 0.25 to 0.5 mmol/L DETA-NO yielded a pathologically relevant NO concentration. Exposure of cells maintaining episomal high-risk HPV genomes to NO increased HPV early transcript levels 2- to 4-fold but did not increase viral DNA replication. Accompanying increased E6 and E7 mRNA levels were significant decreases in p53 and pRb protein levels, lower apoptotic indices, increased DNA double-strand breaks, and higher mutation frequencies when compared with HPV-negative cells. We propose that NO is a molecular cofactor with HPV infection in cervical carcinogenesis, and that modifying local NO cervical concentrations may constitute a strategy whereby HPV-related cancer can be reduced.[Cancer Res 2009;69(11):4878–84]
, , Jesper B. Bramsen, , , Ramshanker Ramanathan, Niels Fristrup, , , , et al.
Cancer Research, Volume 69, pp 4851-4860; https://doi.org/10.1158/0008-5472.can-08-4043

Abstract:
MicroRNAs (miRNA) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Here, we profiled the expression of 290 unique human miRNAs in 11 normal and 106 bladder tumor samples using spotted locked nucleic acid–based oligonucleotide microarrays. We identified several differentially expressed miRNAs between normal urothelium and cancer and between the different disease stages. miR-145 was found to be the most down-regulated in cancer compared with normal, and miR-21 was the most up-regulated in cancer. Furthermore, we identified miRNAs that significantly correlated to the presence of concomitant carcinoma in situ. We identified several miRNAs with prognostic potential for predicting disease progression (e.g., miR-129, miR-133b, and miR-518c*). We localized the expression of miR-145, miR-21, and miR-129 to urothelium by in situ hybridization. We then focused on miR-129 that exerted significant growth inhibition and induced cell death upon transfection with a miR-129 precursor in bladder carcinoma cell lines T24 and SW780 cells. Microarray analysis of T24 cells after transfection showed significant miR-129 target down-regulation (P = 0.0002) and pathway analysis indicated that targets were involved in cell death processes. By analyzing gene expression data from clinical tumor samples, we identified significant expression changes of target mRNA molecules related to the miRNA expression. Using luciferase assays, we documented a direct link between miR-129 and the two putative targets GALNT1 and SOX4. The findings reported here indicate that several miRNAs are differentially regulated in bladder cancer and may form a basis for clinical development of new biomarkers for bladder cancer. [Cancer Res 2009;69(11):4851–60]
Hyunju Lee, F. Stephen Hodi, Anita Giobbie-Hurder, Patrick A. Ott, Elizabeth I. Buchbinder, Rizwan Haq, Sara Tolaney, , Kevin Zhang, Hilary Donahue, et al.
Cancer Immunology Research, Volume 5, pp 1133-1140; https://doi.org/10.1158/2326-6066.cir-17-0208

Abstract:
Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti–PD-1 monotherapy or combination anti–PD-1 and anti–CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti–PD-1 monotherapy or anti–PD-1 and anti–CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder. Thyrotoxicosis as the initial presentation occurred in the majority of patients (93% and 56% of the patients receiving combination therapy and monotherapy, respectively). The onset pattern of the thyroid disorder was significantly different between the two groups (P = 0.01). Subsequently, 76% and 90% of the patients with thyrotoxicosis evolved to develop hypothyroidism in the combination and monotherapy groups, respectively. In the combination therapy and monotherapy groups, the median times to onset of thyrotoxicosis and hypothyroidism after first treatment were 21 and 63 days, and 31 and 68 days, respectively. The median time for transition from thyrotoxicosis to hypothyroidism was 42 days in both groups. Our study demonstrates that most thyroid disorders induced by either anti–PD-1 or combination anti–PD-1 and anti–CTLA-4 therapy are thyroiditis. The time to onset of thyrotoxicosis after treatment initiation and evolution of thyrotoxicosis to hypothyroidism was short, emphasizing the importance of close monitoring of thyroid function in these patients. Cancer Immunol Res; 5(12); 1133–40. ©2017 AACR.
, Malini Mukherjee, Madhuwanti Srinivasan, Sandhya Sharma, , Feiyan Mo, , Jordan S. Orange, Malcolm K. Brenner
Cancer Immunology Research, Volume 6, pp 47-58; https://doi.org/10.1158/2326-6066.cir-17-0126

Abstract:
T cells expressing second-generation chimeric antigen receptors (CARs) specific for CD5, a T-cell surface marker present on normal and malignant T cells, can selectively kill tumor cells. We aimed to improve this killing by substituting the CD28 costimulatory endodomain (28.z) with 4-1BB (BB.z), as 28.z CD5 CAR T cells rapidly differentiated into short-lived effector cells. In contrast, 4-1BB costimulation is known to promote development of the central memory subpopulation. Here, we found BB.z CD5 CAR T cells had impaired growth compared with 28.z CD5.CAR T cells, due to increased T-cell–T-cell fratricide. We demonstrate that TRAF signaling from the 4-1BB endodomain upregulated the intercellular adhesion molecule 1, which stabilized the fratricidal immunologic synapse between CD5 CAR T cells. As the surviving BB.z CD5 CAR T cells retained the desired central memory phenotype, we aimed to circumvent the 4-1BB–mediated toxicity using a regulated expression system that reversibly inhibits CAR expression. This system minimized CAR signaling and T-cell fratricide during in vitro expansion in the presence of a small-molecule inhibitor, and restored CAR expression and antitumor function of transduced T cells in vivo. These studies reveal a mechanism by which 4-1BB costimulation impairs expansion of CD5 CAR T cells and offer a solution to mitigate this toxicity. Cancer Immunol Res; 6(1); 47–58. ©2017 AACR.
, Victoria Shang Wu, Noriko Kanaya, Karineh Petrossian, , Duc Nguyen, , Hsu Hang-Kai, , Hannah Lu, et al.
Clinical Cancer Research, Volume 24, pp 395-406; https://doi.org/10.1158/1078-0432.ccr-17-1983

Abstract:
Purpose: Therapeutic strategies against hormonal receptor-positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth-driver of trastuzumab-resistant COH-SC31 tumors, but an accelerator in trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied with increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with anti-estrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusion:Compared to the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupling with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice.
Cancer Discovery, Volume 7, pp 1358.1-1358; https://doi.org/10.1158/2159-8290.cd-nb2017-149

Abstract:
Long ignored, the importance of circadian rhythms—the focus of this year's Nobel Prize in Physiology or Medicine—is beginning to gain attention from researchers interested in cancer prevention, drug discovery, and therapeutic optimization.
Cancer Discovery, Volume 7, pp 1365.2-1365; https://doi.org/10.1158/2159-8290.cd-rw2017-205

Abstract:
Specific USP7 inhibitors stabilized p53 and exhibited toxicity in tumor cells in vitro and in vivo.
Abstract:
Expression of synthetic RNA-based gene circuits in tumors induces an antitumor T-cell response.
Abstract:
Deleting Adrb2, encoding the β2-adrenergic receptor, in tumor endothelial cells suppresses angiogenesis.
Abstract:
Trastuzumab deruxtecan achieved responses in patients with breast, gastric, and gastroesophageal tumors.
Abstract:
SLC38A9 acts as a lysosomal arginine sensor to activate mTORC1 signaling and support tumor growth.
Xuewei Zhang, , Masafumi Toyoshima, Masumi Ishibashi, Toshinori Usui, Junko Minato, Mahy Egiz, Shogo Shigeta, Todd Fox, Tye Deering, et al.
Molecular Cancer Therapeutics, Volume 17, pp 50-59; https://doi.org/10.1158/1535-7163.mct-17-0173

Abstract:
Ceramides are bioactive lipids that mediate cell death in cancer cells, and ceramide-based therapy is now being tested in dose-escalating phase I clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics, and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL), we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knockdown of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pronecroptotic target for ceramide in ovarian cancer models. Mol Cancer Ther; 17(1); 50–59. ©2017 AACR.
Yuanzheng Yang, , Zhichao Zhou, Jason G. Fewell,
Molecular Cancer Therapeutics, Volume 17, pp 130-139; https://doi.org/10.1158/1535-7163.mct-17-0042

Abstract:
The metastatic potential of osteosarcoma cells is inversely correlated to cell surface FAS expression. Downregulation of FAS allows osteosarcoma cells to escape FAS ligand–mediated apoptosis when they enter a FAS ligand–positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates FAS expression in osteosarcoma. We further demonstrated an inverse correlation between FAS expression and miR-20a expression. However, the mechanism of FAS regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of FAS regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo. We investigated whether miR-20a's downregulation of FAS was mediated by binding to the 3′-untranslated region (3′-UTR) of FAS mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the FAS mRNA 3′-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated FAS 3′-UTR. In contrast, overexpression of miR-20a resulted in downregulation of FAS promoter activity. Similarly, the inhibition of miR-20a increased FAS promoter activity. The critical region identified on the FAS promoter was between −240 bp and −150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of FAS and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates FAS expression through the modulation of the FAS promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential. Mol Cancer Ther; 17(1); 130–9. ©2017 AACR.
, Weijun Cheng, Holly Hamilton, Anthony L. Nicholas, Darren H. Wakefield, Aaron Almeida, Andrei V. Blokhin, Jeffrey Carlson, Zane C. Neal, Vladimir Subbotin, et al.
Molecular Cancer Therapeutics, Volume 17, pp 140-149; https://doi.org/10.1158/1535-7163.mct-17-0471

Abstract:
Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an over-abundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently over-expressed in ccRCC. We demonstrate that functional delivery of a HIF2α specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.
Molecular Cancer Therapeutics, Volume 17, pp 196-203; https://doi.org/10.1158/1535-7163.mct-17-0442

Abstract:
Labetuzumab govitecan (IMMU-130), an antibody–drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ∼500 or ∼16 μg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1% to 2% injected dose/mL after 5 minutes; overall, approximately 20% was converted to SN-38 and SN-38G. At 1 hour with IMMU-130, 45% to 63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. AUC analysis found that SN-38 levels were approximately 11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130–treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. On the basis of the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared with irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety. Mol Cancer Ther; 17(1); 196–203. ©2017 AACR.
Tadaaki Yamada, Joseph M. Amann, Azusa Tanimoto, , Takehito Shukuya, Cynthia Timmers, Seiji Yano, Konstantin Shilo,
Molecular Cancer Therapeutics, Volume 17, pp 17-25; https://doi.org/10.1158/1535-7163.mct-17-0146

Abstract:
Non–small cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS–ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell-cycle regulators p21Cip1 and p27Kip1. We now show that an HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine whether the combination of a MEK inhibitor with an HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and an HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS-mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell-cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell-cycle inhibitors p21Cip1 and p27Kip1. These results demonstrate that control of FOXOs localization and expression is critical in RAS-driven lung cancer cells, suggesting that the dual molecular-targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations. Mol Cancer Ther; 17(1); 17–25. ©2017 AACR.
Bas D. Koster, Mari F.C.M. Van Den Hout, Berbel J.R. Sluijter, Barbara G. Molenkamp, Ronald J.C.L.M. Vuylsteke, Arnold Baars, Paul A.M. Van Leeuwen, Rik J. Scheper, M. Petrousjka Van Den Tol, , et al.
Clinical Cancer Research, Volume 23, pp 5679-5686; https://doi.org/10.1158/1078-0432.ccr-17-0944

Abstract:
Purpose: Although risk of recurrence after surgical removal of clinical stage I–II melanoma is considerable, there is no adjuvant therapy with proven efficacy. Here, we provide clinical evidence that a local conditioning regimen, aimed at immunologic arming of the tumor-draining lymph nodes, may provide durable protection against disease recurrence (median follow-up, 88.8 months). Experimental Design: In two randomized phase II trials, patients, diagnosed with stage I–II melanoma after excision of the primary tumor, received local injections at the primary tumor excision site within 7 days preceding re-excision and sentinel lymph node (SLN) biopsy of either a saline placebo (n = 22) or low-dose CpG type B (CpG-B) with (n = 9) or without (n = 21) low-dose GM-CSF. Results: CpG-B treatment was shown to be safe, to boost locoregional and systemic immunity, to be associated with lower rates of tumor-involved SLN (10% vs. 36% in controls, P = 0.04), and, at a median follow-up of 88.8 months, to profoundly improve recurrence-free survival (P = 0.008), even for patients with histologically confirmed (i.e., pathologic) stage I–II disease (P = 0.02). Conclusions: Potentially offering durable protection, local low-dose CpG-B administration in early-stage melanoma provides an adjuvant treatment option for a large group of patients currently going untreated despite being at considerable risk for disease recurrence. Once validated in a larger randomized phase III trial, this nontoxic immunopotentiating regimen may prove clinically transformative. Clin Cancer Res; 23(19); 5679–86. ©2017 AACR.
Cancer Prevention Research, Volume 10, pp 704-709; https://doi.org/10.1158/1940-6207.CAPR-17-0084

Abstract:
Introduction: Use of non-cigarette tobacco products such as cigars and pipe has been increasing, even though these products entail exposure to similar carcinogens to those in cigarettes. More research is needed to explore the risk of these products to guide cancer prevention efforts. Methods: To measure the association between cigars and/or pipe smoking, and cancer incidence in men, we performed meta-analyses of data from five prospective cohorts. Cox regression was used to evaluate the association between different aspects of cigars and pipe smoking and risk of each smoking-related cancer (head and neck, esophagus, lung, stomach, liver, pancreas, kidney, and bladder) for each study. Adjusted HRs were combined using random-effects models. Results: Cigars and/or pipe smokers were at increased risk for head and neck [HR, 1.51; 95% confidence interval (CI), 1.22–1.87], lung (HR, 2.04; 95% CI, 1.68–2.47), and liver cancers (HR, 1.56; 95% CI, 1.08–2.26). Ever-smokers of cigars and/or pipe had an increased risk of developing a smoking-related cancer when compared with never smokers of any tobacco product (overall HR, 1.07; 95% CI, 1.03–1.12). The risk for smoking-related cancers was also increased in mixed smokers who smoked cigars or pipe as well as cigarettes, even when they were smoking predominantly pipe or cigars. Discussion: This pooled analysis highlights the increased risk for smoking-related cancers, particularly for lung and head and neck cancers in exclusive and predominant smokers (former and current) of cigars and pipe. Tobacco prevention efforts should include these products in addition to cigarettes. Cancer Prev Res; 10(12); 704–9. ©2017 AACR.
Soumyasri Das Gupta, Misaal Patel, Joseph Wahler, Min Ji Bak, Brian Wall, Mao-Jung Lee, Yong Lin, Weichung Joe Shih, Li Cai, Chung S. Yang, et al.
Cancer Prevention Research, Volume 10, pp 694-703; https://doi.org/10.1158/1940-6207.CAPR-17-0190

Abstract:
Despite experimental evidence elucidating the antitumor activities of tocopherols, clinical trials with α-tocopherol (α-T) have failed to demonstrate its beneficial effects in cancer prevention. This study compared the chemopreventive efficacy of individual tocopherols (α-, δ-, and γ-T) and a γ-T–rich tocopherol mixture (γ-TmT) in the August-Copenhagen Irish (ACI) rat model of estrogen-mediated mammary cancer. Female ACI rats receiving 17β-estradiol (E2) implants were administered with 0.2% α-T, δ-T, γ-T, or γ-TmT for 30 weeks. Although α-T had no significant effects on mammary tumor growth in ACI rats, δ-T, γ-T, and γ-TmT reduced mammary tumor volume by 51% (P< 0.05), 60% (P< 0.01), and 59% (P< 0.01), respectively. Immunohistochemical analysis revealed that δ-T, γ-T, and γ-TmT reduced levels of the cell proliferation marker, proliferating cell nuclear antigen, in the rat mammary tumors. To gain further insight into the biological functions of different forms of tocopherols, RNA-seq analysis of the tumors was performed. Treatment with γ-T induced robust gene expression changes in the mammary tumors of ACI rats. Ingenuity Pathway Analysis identified “Cancer” as a top disease pathway and “Tumor growth” and “Metastasis” as the top signaling pathways modulated by γ-T. Although the results need further functional validation, this study presents an unbiased attempt to understand the differences between biological activities of individual forms of tocopherols at the whole transcriptome level. In conclusion, δ-T and γ-T have superior cancer preventive properties compared to α-T in the prevention of estrogen-mediated mammary carcinogenesis. Cancer Prev Res; 10(12); 694–703. ©2017 AACR.
, , Jinsil Kim, Kishore Nannapaneni, , Pentao Liu, David A. Largaespada, , Nancy A. Jenkins, Neal G. Copeland
Cancer Research, Volume 69, pp 8150-8156; https://doi.org/10.1158/0008-5472.can-09-1135

Abstract:
Recent advances in cancer therapeutics stress the need for a better understanding of the molecular mechanisms driving tumor formation. This can be accomplished by obtaining a more complete description of the genes that contribute to cancer. We previously described an approach using the Sleeping Beauty (SB) transposon system to model hematopoietic malignancies in mice. Here, we describe modifications of the SB system that provide additional flexibility in generating mouse models of cancer. First, we describe a Cre-inducible SBase allele, RosaSBaseLsL, that allows the restriction of transposon mutagenesis to a specific tissue of interest. This allele was used to generate a model of germinal center B-cell lymphoma by activating SBase expression with an Aid-Cre allele. In a second approach, a novel transposon was generated, T2/Onc3, in which the CMV enhancer/chicken β-actin promoter drives oncogene expression. When combined with ubiquitous SBase expression, the T2/Onc3 transposon produced nearly 200 independent tumors of more than 20 different types in a cohort of 62 mice. Analysis of transposon insertion sites identified novel candidate genes, including Zmiz1 and Rian, involved in squamous cell carcinoma and hepatocellular carcinoma, respectively. These novel alleles provide additional tools for the SB system and provide some insight into how this mutagenesis system can be manipulated to model cancer in mice. [Cancer Res 2009;69(20):8150–6]
, Sabine Hagemann, Katharina Hanna,
Cancer Research, Volume 69, pp 8127-8132; https://doi.org/10.1158/0008-5472.can-09-0458

Abstract:
The cytosine analogues azacytidine and decitabine are currently being developed as drugs for epigenetic cancer therapy. Although various studies have shown that both drugs are effective in inhibiting DNA methylation, it has also become clear that their mode of action is not limited to DNA demethylation. Because azacytidine is a ribonucleoside, the primary target of this drug may be cellular RNA rather than DNA. We have now analyzed the possibility that azacytidine inhibits the RNA methyltransferase DNMT2. We found that DNMT2 is variably expressed in human cancer cell lines. RNA bisulfite sequencing showed that azacytidine, but not decitabine, inhibits cytosine 38 methylation of tRNAAsp, a major substrate of DNMT2. Azacytidine caused a substantially stronger effect than decitabine on the metabolic rate of all the cancer cell lines tested, consistent with an effect of this drug on RNA metabolism. Of note, drug-induced loss of RNA methylation seemed specific for DNMT2 target sites because we did not observe any significant demethylation at sites known to be methylated by other RNA methyltransferases. Our results uncover a novel and quantifiable drug activity of azacytidine and raise the possibility that tRNA hypomethylation might contribute to patient responses. [Cancer Res 2009;69(20):8127–32]
, Philippe Frit, , , Patrick Calsou
Cancer Research, Volume 69, pp 8120-8126; https://doi.org/10.1158/0008-5472.can-08-4400

Abstract:
One hallmark of apoptosis is DNA degradation that first appears as high molecular weight fragments followed by extensive internucleosomal fragmentation. During apoptosis, the DNA-dependent protein kinase (DNA-PK) is activated. DNA-PK is involved in the repair of DNA double-strand breaks (DSB) and its catalytic subunit is associated with the nuclease ARTEMIS. Here, we report that, on initiation of apoptosis in human cells by agents causing DNA DSB or by staurosporine or other agents, ARTEMIS binds to apoptotic chromatin together with DNA-PK and other DSB repair proteins. ARTEMIS recruitment to chromatin showed a time and dose dependency. It required DNA-PK protein kinase activity and was blocked by antagonizing the onset of apoptosis with a pan-caspase inhibitor or on overexpression of the antiapoptotic BCL2 protein. In the absence of ARTEMIS, no defect in caspase-3, poly(ADP-ribose) polymerase-1, and XRCC4 cleavage or in H2AX phosphorylation was observed and DNA-PK catalytic subunit was still phosphorylated on S2056 in response to staurosporine. However, DNA fragmentation including high molecular weight fragmentation was delayed in ARTEMIS-deficient cells compared with cells expressing ARTEMIS. In addition, ARTEMIS enhanced the kinetics of MLL gene cleavage at a breakage cluster breakpoint that is frequently translocated in acute or therapy-related leukemias. These results show a facilitating role for ARTEMIS at least in early, site-specific chromosome breakage during apoptosis. [Cancer Res 2009;69(20):8120–6]
, Mototsugu Oya, , , Masaru Ishida, , , Motowo Nakajima,
Clinical Cancer Research, Volume 14, pp 6055-6061; https://doi.org/10.1158/1078-0432.ccr-08-0750

Abstract:
Purpose: Heparanase activity has been detected in many malignant tumors, showing a correlation with the metastatic potential. The present study was undertaken to investigate the expression of heparanase and its prognostic significance in renal cell carcinomas (RCC). Experimental Design: Nineteen RCCs and 6 nonneoplastic renal tissues were analyzed for heparanase mRNA expression by real-time PCR. Heparanase protein expression was semiquantitatively investigated by immunohistochemistry in 70 RCCs. Involvement of heparanase in the invasiveness of RCC cell lines, 786-O and Caki-2 cells, was examined by down-regulating the gene expression with small interfering RNA (siRNA) using the Matrigel invasion assay. Results: The expression level of heparanase mRNA was significantly higher in clear cell RCCs than in papillary RCCs, chromophobe RCCs, and nonneoplastic renal tissues. Heparanase was predominantly immunolocalized to cell surface and cytoplasm of clear cell RCCs and mean expression levels of heparanase were significantly higher in clear cell RCCs than in papillary and chromophobe RCCs. The protein expression levels were positively correlated with primary tumor stage, distant metastasis, and histologic grade. Targeting of heparanase mRNA expression in 786-O and Caki-2 cells with siRNA down-regulated the mRNA expression and inhibited the Matrigel invasion by these cells, whereas nonsilencing siRNA showed no effect. Multivariate Cox analysis revealed that elevated heparanase expression was a significant and an independent predictor of disease-specific survival (odds ratio, 8.814; P = 0.019). Conclusions: These data suggest that heparanase plays an important role in invasion and metastasis and silencing of the gene might be a potential therapeutic target in clear cell RCCs.
, David J. Baer, Laura L. Johnson, Terry J. Hartman, Joanne F. Dorgan, William S. Campbell, Beverly A. Clevidence, Philip R. Taylor
Cancer Epidemiology Biomarkers & Prevention, Volume 15, pp 2502-2507; https://doi.org/10.1158/1055-9965.epi-06-0499

Abstract:
Background: Both obesity and sex hormones are known risk factors for postmenopausal breast cancer. Although adiposity and sex hormones have been studied in the past, previous reports in postmenopausal women have not been conducted under carefully controlled dietary conditions. In this study, we investigated the usefulness of body mass index (BMI) as a sufficient adiposity measurement to assess associations with sex hormone levels.
, Bendix Carstensen, , , Maja Primic Žakelj, Gill Lawrence, Matti Hakama,
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 2191-2199; https://doi.org/10.1158/1055-9965.epi-05-0231

Abstract:
Rapid increases in cervical adenocarcinoma incidence have been observed in Western countries in recent decades. Postulated explanations include an increasing specificity of subtype—the capability to diagnose the disease, an inability of cytologic screening to reduce adenocarcinoma, and heterogeneity in cofactors related to persistent human papillomavirus infection. This study examines the possible contribution of these factors in relation with trends observed in Europe. Age-period-cohort models were fitted to cervical adenocarcinoma incidence trends in women ages 30. Whereas increasing specificity of subtype with time may be responsible for some of the increases in several countries, the changing distribution and prevalence of persistent infection with high-risk human papillomavirus types, alongside an inability to detect cervical adenocarcinoma within screening programs, would accord with the temporal profile observed in Europe. The homogeneity of trends in adenocarcinoma and squamous cell carcinoma in birth cohort is consistent with the notion that they share a similar etiology irrespective of the differential capability of screen detection. Screening may have had at least some impact in reducing cervical adenocarcinoma incidence in several countries during the 1990s.
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1738-1740; https://doi.org/10.1158/1055-9965.epi-05-0201

Abstract:
Background: Tobacco smoking is the principal cause of lung cancer. The risk of lung cancer in the offspring of lung cancer patients is about twice higher than the risk in the general population. The present study investigated the contribution of shared smoking habits to the familial clustering of lung cancer. Methods: We estimated the relative risk of lung cancer attributable to smoking according to the extent to which smokers transmit their smoking habits to the offspring (heritability of smoking), the prevalence of smoking in the general population, and the risk of lung cancer for smokers compared with nonsmokers. Findings: The relative risk of lung cancer for the offspring of lung cancer patients attributable to smoking was 1.19 when published data on smoking practice were modeled (i.e., assuming that the heritability of smoking was 0.5, the smoking prevalence 40%, and the odds ratio of lung cancer for smokers versus nonsmokers was 20). Interpretation: Most familial cases of lung cancer cannot be attributed to shared smoking habits. The example of smoking can be used for other familial cancers, for which no strong environmental risk factors are usually known, to infer the primary role for heritable genes.
, Shibao Feng, Janet Cañar, Maureen McGlinchey Ford, Kenneth P. Tercyak
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1976-1980; https://doi.org/10.1158/1055-9965.epi-05-0141

Abstract:
Tobacco use is the leading preventable cause of death for the U.S. Hispanic population. The goal of this study was to identify social and behavioral correlates of smoking behavior among urban, multiethnic Latino primary care patients seen in community clinics. Spanish-language interviews were completed with 141 current smokers and 158 former and nonsmokers. Twenty countries of origin were represented. Eighty-three percent of participants were from Central or South America and 71% spoke primarily Spanish. Current smokers were more likely than nonsmokers or former smokers to originate from South America (38% versus 26%) and to be single (63% versus 42%). Current smokers also were more likely to use alcohol on a regular basis (59% versus 31%) and to experience daily symptoms of depression (29% versus 19%). Logistic regression analysis suggested a moderating effect of depression on the relationship between alcohol use and smoking, such that current users of alcohol who reported depression were more likely to smoke (82%) than were current users of alcohol who did not report depression (56%). As both social and behavioral factors were uniquely associated with smoking, country of origin, marital status, and comorbid alcohol use and depression should be considered in designing and implementing tobacco control interventions targeted to this community.
, , Marc J. Gunter, Paul Strickland, Nathaniel Rothman
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 2030-2034; https://doi.org/10.1158/1055-9965.epi-04-0854

Abstract:
We carried out a clinic-based case-control study specifically designed to address the hypothesis that dietary intake of polycyclic aromatic hydrocarbons (PAH) is associated with colorectal adenoma risk. We developed a food frequency questionnaire with detailed questions on meat-cooking methods and doneness levels and a benzo[a]pyrene (BaP) database (as a surrogate for total carcinogenic PAHs) based on the collection and analysis of a wide range of food samples. We estimated BaP intake derived from meat and from all foods to test its relationship with risk of colorectal adenomas. The median (10th and 90th percentiles) BaP intake in controls was 5 ng/d (0.2 and 66 ng/d) estimated from meat and 73 ng/d (35 and 140 ng/d) from all foods. In cases, median BaP intake was 17 ng/d (0.5 and 101 ng/d) from meat and 76 ng/d (44 and 163 ng/d) from all foods. Multivariate analysis was carried out on 146 cases and 228 controls. The odds ratios (95% confidence interval) for dietary BaP from meat with the first quintile as the reference group were 1.19 (0.51-2.80) for the second quintile, 1.71 (0.76-3.83) for the third quintile, 2.16 (0.96-4.86) for the fourth quintile, and 2.82 (1.24-6.43) for the fifth quintile (Ptrend = 0.01). Increased risk of colorectal adenomas was more strongly associated with BaP intake estimated from all foods: 2.61 (1.08-6.29) for the second quintile, 4.21 (1.79-9.91) for the third quintile, 2.45 (0.98-6.12) for the fourth quintile, and 5.60 (2.20-14.20) for the fifth quintile (Ptrend = 0.002). This study provides evidence that dietary BaP plays a role in colorectal adenoma etiology.
, Rashida K. Rana, , , Gerald Gough, Jeanne M. Pimenta
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1157-1164; https://doi.org/10.1158/1055-9965.epi-04-0812

Abstract:
Low-grade squamous intraepithelial lesions (LSIL) associated with certain human papillomavirus (HPV) genotypes may preferentially progress to cervical cancer. HPV genotyping may thus have the potential to improve the effectiveness of screening programs and to reduce overtreatment. LSIL cases (n = 8,308) from 55 published studies were included in a meta-analysis. HPV genotype distribution was assessed by geographic region and in comparison with published data on cervical squamous cell carcinoma (SCC). HPV detection in LSIL was 80% in North America but less than 70% in other regions, most likely reflecting regional differences in LSIL diagnosis. Among 5,910 HPV-positive LSILs, HPV16 was the most common genotype (26.3%) followed by HPV31 (11.5%), HPV51 (10.6%), and HPV53 (10.2%). HPV-positive LSILs from Africa were 2-fold less likely to be infected with HPV16 than those in Europe, and HPV-positive LSILs from North America were more likely to be infected with HPV18 than those from Europe or South/Central America. Interpretation for rarer genotypes was hampered by variation in HPV testing methodology. SCC/LSIL prevalence ratios indicated that HPV16 was 2-fold and HPV18 was 1.5-fold more common in SCC than in HPV-positive LSIL, thus appearing more likely to progress than other high-risk genotypes (SCC/LSIL prevalence ratios between 0.05 and 0.85). HPV53 and HPV66 showed SCC/LSIL ratios of 0.02 and 0.01, respectively. HPV genotype distribution in LSIL differs from that in cervical cancer, highlighting the importance of HPV genotype in the risk of progression from LSIL to malignancy. Some regional differences in the relative importance of HPV genotypes in LSIL were noted.
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1810-1818; https://doi.org/10.1158/1055-9965.epi-04-0793

Abstract:
Several potential functional polymorphisms (Arg194Trp, Arg280His, Arg399Gln) in the DNA base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been implicated in cancer risk. Our meta-analysis on total of 11,957 cancer cases and 14,174 control subjects from 38 published case-control studies showed that the odds ratio (OR) for the variant genotypes (Trp/Trp + Arg/Trp) of the Arg194Trp polymorphism, compared with the wild-type homozygote (Arg/Arg), was 0.89 [95% confidence interval (95% CI), 0.81-0.98] for all tumor types without between-study heterogeneity. Similarly, the overall risk for the combined variant genotypes (His/His + Arg/His) of the Arg280His, compared with the wild homozygote (Arg/Arg), was 1.19 (95% CI, 1.00-1.42). However, there was no main effect in either recessive or dominant modeling for the Arg399Gln, and the variant Gln/Gln homozygote was not associated with overall cancer risk (OR, 1.01; 95% CI, 0.90-1.14). The analyses suggest that XRCC1 Arg194Trp, Arg280His polymorphisms may be biomarkers of cancer susceptibility and a single larger study with thousands of subjects and tissue-specific biochemical and biological characterization is warranted to further evaluate potential gene-to-gene and gene-to-environment interactions on XRCC1 polymorphisms and cancer risk.
, Jeremy Holtzman, Kerry S. Courneya, , , Robert Kane
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1588-1595; https://doi.org/10.1158/1055-9965.epi-04-0703

Abstract:
Background: Approximately 9.8 million cancer survivors are alive in the United States today. Enthusiasm for prescribing physical activity for cancer survivors depends on evidence regarding whether physical activity during or after completion of treatment results in improved outcomes such as cardiorespiratory fitness, fatigue, symptoms, quality of life, mental health, or change in body size. Methods: A systematic qualitative and quantitative review of the English language scientific literature identified controlled trials of physical activity interventions in cancer survivors during and after treatment. Data from 32 studies were abstracted, weighted mean effect sizes (WMES) were calculated from the 22 high-quality studies, and a systematic level of evidence criteria was applied to evaluate 25 outcomes. Results: There was qualitative and quantitative evidence of a small to moderate effect of physical activity interventions on cardiorespiratory fitness (WMES = 0.51 and 0.65 during and after treatment respectively, P< 0.01), physiologic outcomes and symptoms during treatment (WMES = 0.28, P< 0.01 and 0.39, P< 0.01, respectively), and vigor posttreatment (WMES = 0.83, P = 0.04). Physical activity was well tolerated in cancer survivors during and after treatment, but the available literature does not allow conclusions to be drawn regarding adverse events from participation. Conclusions: Physical activity improves cardiorespiratory fitness during and after cancer treatment, symptoms and physiologic effects during treatment, and vigor posttreatment. Additional physical activity intervention studies are needed to more firmly establish the range and magnitude of positive effects of physical activity among cancer survivors.
, , , , Elizabeth Clipp, Karen Kuntz, , Melissa Napolitano, Jane Onken, , et al.
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1453-1459; https://doi.org/10.1158/1055-9965.epi-04-0620

Abstract:
Background: This report examines the outcome data for Project PREVENT, a two-site randomized control trial designed to reduce behavioral risk factors for colorectal cancer among individuals who have been diagnosed with adenomatous colon polyps.
Ozlem E. Tulunay, , Steven G. Carmella, Yan Zhang, Charlotte Lemmonds, Sharon Murphy, Dorothy K. Hatsukami
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1283-1286; https://doi.org/10.1158/1055-9965.epi-04-0570

Abstract:
Exposure of nonsmokers to environmental tobacco smoke results in increased risk for cancer and other diseases. In spite of this finding, some restaurants and bars continue to permit smoking. This study examined the uptake of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent lung carcinogen, in nonsmokers who work in restaurants and bars that permitted smoking. Urine samples were collected for 24 hours on working and nonworking days and were analysed for total NNAL [the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Glucs)], metabolites of NNK. In addition, urine samples were analysed for total nicotine (nicotine plus nicotine glucuronide), and total cotinine (cotinine plus cotinine-N-glucuronide). The results showed significant increases in urinary levels of total NNAL, total nicotine, and total cotinine on working days compared with nonworking days. The results of this study show that smoke exposure in bars and restaurants may have important health effects on nonsmoking employees, elicited by the increase in carcinogen levels.
Christina A. Clarke, Sally L. Glaser, Theresa H.M. Keegan, Antoinette Stroup
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1441-1447; https://doi.org/10.1158/1055-9965.epi-04-0567

Abstract:
Hodgkin's lymphoma occurrence has long been noted to associate with higher socioeconomic status (SES). However, the Hodgkin's lymphoma-SES association has not been examined recently or across important, possibly etiologically distinct, patient subgroups. In ∼150 million person-years of observation in the multiethnic population of California, we examined the association of Hodgkin's lymphoma incidence with a composite measure of neighborhood-level SES in patient subgroups defined by age, sex, race/ethnicity, and Hodgkin's lymphoma histologic subtype. Using population-based cancer registry data on 3,794 Hodgkin's lymphoma patients diagnosed 1988 to 1992 and 1990 census data, we assigned a previously validated, multidimensional SES index to census block groups of patient residence. We then calculated neighborhood SES-specific incidence rates and estimated rate ratios using Poisson regression. Positive neighborhood SES gradients in Hodgkin's lymphoma incidence were observed only in young adults (ages 15-44 years at diagnosis) with nodular sclerosis Hodgkin's lymphoma and older adult (ages ≥45 years) White and Hispanic males with mixed cellularity Hodgkin's lymphoma. For young adults, associations were marked in Hispanic and Asian women, weaker in Hispanic and White men and White women, and subtle to nonexistent in Blacks and Asian men. Neighborhood SES gradients in Hodgkin's lymphoma incidence varied by age, sex, race/ethnicity, and histologic subtype, underscoring etiologic complexity in Hodgkin's lymphoma. Racial/ethnic gradients were not entirely explained by neighborhood SES. In California, etiologically relevant exposures for young adult Hodgkin's lymphoma, the most common form, could associate more with race/ethnicity or foreign birthplace than neighborhood SES and may be modified by reproductive or other sex-specific factors.
, , Manuela A. Orjuela, Xinhua Liu, Dorothy P. Warburton, Frederica P. Perera
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 506-511; https://doi.org/10.1158/1055-9965.epi-04-0566

Abstract:
Molecular and traditional epidemiology studies have indicated a possible relationship between in utero environmental exposures and increased risk for childhood cancers, especially acute leukemias. Chromosomal aberrations have been associated with environmental exposures and cancer risk in adults. In order to more clearly define the association between prenatal exposures to carcinogenic polycyclic aromatic hydrocarbons (PAH) and chromosomal aberrations, chromosomal aberration frequencies were measured in a subset of 60 newborns from the Columbia Center for Children's Environmental Health (CCCEH) Prospective Cohort Study. The subset was composed of African American and Dominican, nonsmoking mother-newborn pairs residing in low-income neighborhoods of New York City, who were exposed to varying levels of airborne PAHs. Prenatal exposure was assessed by questionnaire, personal air monitoring during the third trimester, and PAH-DNA adducts in umbilical cord blood. Chromosomal aberrations were measured in cord blood lymphocytes by fluorescence in situ hybridization. PAH-DNA adducts were not associated with chromosomal aberrations. However, airborne PAHs were significantly associated with stable aberration frequencies in cord blood (P< 0.01). Moreover, stable aberration frequencies were significantly higher among African American newborns compared with Dominican, despite no significant differences in PAH exposure. These results show for the first time an association between prenatal exposure to airborne carcinogenic PAHs and chromosomal aberrations in cord blood, suggesting that such prenatal exposures have the potential to cause cytogenetic damage that has been related to increased cancer risk in other populations. If confirmed, this finding may open new avenues for prevention.
, Erica S. Breslau, Trevor Thompson, Vicki B. Benard
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1143-1148; https://doi.org/10.1158/1055-9965.epi-04-0559

Abstract:
Objective: Many women in the U.S. undergo routine cervical cancer screening, but some women have rarely or never had a Papanicolaou (Pap) test. Studies of other cancer screening tests (for example, mammograms) have shown that physician recommendation to get a screening test is one of the strongest predictors of cancer screening.
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 467-475; https://doi.org/10.1158/1055-9965.epi-04-0551

Abstract:
Mucosal human papillomaviruses (HPV) are the cause of cervical cancer and likely a subset of head and neck squamous cell carcinomas (HNSCC), yet the global prevalence and type distribution of HPV in HNSCC remains unclear. We systematically reviewed published studies of HNSCC biopsies that employed PCR-based methods to detect and genotype HPV to describe the prevalence and type distribution of HPV by anatomic cancer site. Geographic location and study size were investigated as possible sources of variability. In the 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9% [95% confidence interval (95% CI), 24.7-27.2]. HPV prevalence was significantly higher in oropharyngeal SCCs (35.6% of 969; 95% CI, 32.6-38.7) than oral SCCs (23.5% of 2,642; 95% CI, 21.9-25.1) or laryngeal SCCs (24.0% of 1,435; 95% CI, 21.8-26.3). HPV16 accounted for a larger majority of HPV-positive oropharyngeal SCCs (86.7%; 95% CI, 82.6-90.1) compared with HPV-positive oral SCCs (68.2%; 95% CI, 64.4-71.9) and laryngeal SCCs (69.2%; 95% CI, 64.0-74.0). Conversely, HPV18 was rare in HPV-positive oropharyngeal SCCs (2.8%; 95% CI, 1.3-5.3) compared with other head and neck sites [34.1% (95% CI, 30.4-38.0) of oral SCCs and 17.0% (95% CI, 13.0-21.6) of laryngeal SCCs]. Aside from HPV16 and HPV18, other oncogenic HPVs were rarely detected in HNSCC. Tumor site–specific HPV prevalence was higher among studies from North America compared with Europe and Asia. The high HPV16 prevalence and the lack of HPV18 in oropharyngeal compared with other HNSCCs may point to specific virus-tissue interactions. Small sample size and publication bias complicate the assessment of the prevalence of HPV in head and neck sites beyond the oropharynx.
, Walter C. Willett, , Edward Giovannucci
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 835-841; https://doi.org/10.1158/1055-9965.epi-04-0545

Abstract:
Epidemiologic studies of dietary marine n-3 fatty acids and risk of colorectal cancer have been inconsistent, and their relation to risk of colorectal adenoma has not been evaluated in detail. We examined dietary marine n-3 fatty acids and the ratio of marine n-3 to total n-6 fatty acids (n-3/n-6 ratio) in relation to risk of adenoma of the distal colon or rectum among 34,451 U.S. women who were initially free of colorectal cancer or polyps, who completed a semiquantitative food frequency questionnaire in 1980, and who underwent endoscopy from 1980 to 1998. We documented 1,719 distal colorectal adenoma cases (705 large adenomas, 897 small adenomas, 1,280 distal colon adenomas, and 505 rectal adenomas) during 18 years of follow-up. Neither dietary marine n-3 fatty acids nor n-3/n-6 ratio were associated with risk of total distal colorectal adenoma after adjustment for age and established risk factors [multivariable relative risk (RR) for extreme quintiles of dietary marine n-3 fatty acids = 1.04; 95% confidence interval (95% CI), 0.84-1.27, Ptrend = 0.66; RR for extreme quintiles of n-3/n-6 ratio = 1.02; 95% CI, 0.83-1.25; Ptrend = 0.86]. Similarly, no significant associations were observed separately for distal colon or rectal adenoma. However, higher intake of dietary marine n-3 fatty acids was nonsignificantly but suggestively inversely associated with large adenoma (RR, 0.74; 95% CI, 0.54-1.01; Ptrend = 0.16) but directly associated with small adenoma (RR, 1.36; 95% CI, 1.02-1.81; Ptrend = 0.09). Our findings do not support the hypothesis that a higher intake of marine n-3 fatty acids or a higher n-3/n-6 ratio reduces the risk of distal colorectal adenoma but are suggestive that higher intake may reduce the progression of small adenomas to large adenomas.
, Elizabeth Ward, Howard J. Martin, Colleen C. McLaughlin, ,
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 590-595; https://doi.org/10.1158/1055-9965.epi-04-0522

Abstract:
Background: Striking geographic variation in prostate cancer death rates have been observed in the United States since at least the 1950s; reasons for these variations are unknown. Here we examine the association between geographic variations in prostate cancer mortality and regional variations in access to medical care, as reflected by the incidence of late-stage disease, prostate-specific antigen (PSA) utilization, and residence in rural counties.
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 1370-1375; https://doi.org/10.1158/1055-9965.epi-04-0498

Abstract:
Objective: Exposure to toxins in tobacco smoke is influenced by how a cigarette is smoked. Cigarettes have been designed to allow for a range of puffing behavior and to provide different, nonlinear tar and nicotine yields in response to different puffing profiles. However, puffing behavior and its influence upon risk-exposure has yet to be assessed outside the laboratory, in smokers' natural environment. Method: Fifty-nine adult smokers used a portable device to measure smoking topography over the course of three 1-week trials. Participants were asked to smoke their usual “regular yield” brand through the device for trial 1 and again, 6 weeks later, at trial 2. Half the subjects were then randomly assigned to switch to a “low-yield” brand for trial 3. Results: The findings show a high degree of stability in puffing behavior within the same subject over time but considerable variability between smokers. Smokers who were switched to a “low-yield” cigarette increased their total smoke intake per cigarette by 40% (P = 0.007), with no significant change in their salivary cotinine levels. Cigarettes smoked per day and nicotine yield were only weakly associated with salivary cotinine levels; however, salivary cotinine was strongly associated with a composite measure that included cigarettes per day, brand elasticity, and puffing behavior (sr = 0.61, P< 0.001). Conclusions: These findings provide strong evidence of behavioral compensation to low-yield cigarettes from in vivo measures of smoking behavior. The findings also show the importance of brand elasticity and smoking topography in predicting nicotine uptake and smoke exposure.
Shuang-Yuan Kuang, Suree Lekawanvijit, Niwat Maneekarn, Satawat Thongsawat, Kimberly Brodovicz, Kenrad Nelson, John D. Groopman
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 380-384; https://doi.org/10.1158/1055-9965.epi-04-0380

Abstract:
Hepatocellular carcinoma is one of the leading causes of cancer death worldwide. The etiology of liver cancer is multifactorial, and infection with hepatitis B virus (HBV), whose pathogenesis is exacerbated by the acquisition of mutations that accelerate carcinogenesis, or hepatitis C virus (HCV) and dietary exposure to aflatoxin B1 all contribute to elevating one's risk for this disease. In this study, we sought to determine the contributions of these agents by measuring the occurrence of an HBV 1762T/1764A double mutation, an aflatoxin-specific 249G→T mutation of the p53 gene, and HCV in plasma of 34 HCC cases and 68 age- and gender-matched controls, and in 25 liver tumors from northern Thailand. In total, 14 cases, 5 controls, and 19 tumors had detectable levels of HBV DNA. All 14 cases, 2 controls (2.9%), and 17 tumors (89.5%) were positive for the HBV double mutation. Nine cases (26.5%), 10 controls (14.7%), and 6 tumors (24%) were positive for the p53 mutation. Five cases (14.7%), no controls, and 4 tumors (16%) had both mutations. The median age of HCC diagnosis in these 5 cases was 34 years versus 51 years for other cases. Five cases (14.7%) and 1 control (1.5%) were HCV enzyme immunoassay positive. Thus, specific HBV, HCV, and aflatoxin biomarkers reveal the complexity of risks contributing to HCC in northern Thailand and suggest further application of these biomarkers as intermediate end points in prevention, intervention trials, and etiologic investigations.
, , , , Pingping Qu, Shuying S. Li, Mary P. Bronner,
Cancer Epidemiology Biomarkers & Prevention, Volume 14, pp 605-608; https://doi.org/10.1158/1055-9965.epi-04-0058

Abstract:
Several characteristics of aberrant crypt foci (ACF) suggest that they are precursors of colorectal cancer, but the factors that promote or inhibit their growth are largely unknown. We conducted a pilot study to explore whether factors associated with risk of colorectal cancer are also associated with number or size of rectal ACF. Thirty-two U.S. veterans, ages 50 to 80 years, were recruited to undergo magnifying chromoendoscopy for imaging of rectal ACF and colonoscopy for identification of polyps or cancer. Participants completed a questionnaire on cigarette smoking, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and family history of colorectal cancer. Fisher's exact test was used to assess the statistical significance of associations between colorectal cancer risk factors and characteristics of ACF. Cochran-Mantel-Haenszel statistics and polytomous regression were used to test the significance of associations adjusted for age. Participants with a history of adenoma had more ACF than those without (age-adjusted P = 0.02), but the numbers in the two groups overlapped markedly. Older participants had more (P = 0.06) and larger (P = 0.009) ACF than younger participants. No associations were identified between either ACF number or size and cigarette smoking, use of NSAIDs, or family history of colorectal cancer. These findings suggest that persons with adenomas have somewhat more rectal ACF than persons without, and that older age is a risk factor for ACF growth. Future research should be directed toward developing techniques to identify ACF that are likely to progress to cancer and the modifiable factors that promote or inhibit such progression.
Monica Ropolo, , Fabrizio Griffero, Mara Foresta, Gianluigi Casartelli, Annalisa Zunino, , Enrico Cappelli, Gianluigi Zona, Renato Spaziante, et al.
Molecular Cancer Research, Volume 7, pp 383-392; https://doi.org/10.1158/1541-7786.mcr-08-0409

Abstract:
It has been reported that cancer stem cells may contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. We have examined DNA repair in five stem and nonstem glioma cell lines. The population doubling time was significantly increased in stem compared with nonstem cells, and enhanced activation of Chk1 and Chk2 kinases was observed in untreated CD133+ compared with CD133 cells. Neither DNA base excision or single-strand break repair nor resolution of pH2AX nuclear foci were increased in CD133+ compared with CD133 cells. We conclude that glioma stem cells display elongated cell cycle and enhanced basal activation of checkpoint proteins that might contribute to their radioresistance, whereas enhanced DNA repair is not a common feature of these cells. (Mol Cancer Res 2009;7(3):383–92)
Ursula B. McGovern, Richard E. Francis, , Stephanie K. Guest, Jun Wang, Stephen S. Myatt, Janna Krol, Jimmy M-M. Kwok, Andreas Polychronis, R. Charles Coombes, et al.
Molecular Cancer Therapeutics, Volume 8, pp 582-591; https://doi.org/10.1158/1535-7163.mct-08-0805

Abstract:
Gefitinib (Iressa) is a specific and effective epidermal growth factor receptor inhibitor. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-epidermal growth factor receptor therapies and provide information for overcoming gefitinib resistance. In this study, we investigated the role and regulation of FOXM1 in response to gefitinib treatment in breast cancer. Using the gefitinib-sensitive breast carcinoma cell lines BT474 and SKBR3 as well as the resistant lines MCF-7, MDA-MB-231, and MDA-MB-453, we showed that gefitinib represses the expression of the transcription factor FOXM1 in sensitive, but not resistant, cells. FOXM1 repression by gefitinib is associated with FOXO3a activation and is mediated at the transcriptional level and gene promoter level. These results were verified by immunohistochemical staining of biopsy samples from primary breast cancer patients obtained from a gefitinib neoadjuvant study. We also showed that ectopic expression of an active FOXO3a represses FOXM1 expression, whereas knockdown of FOXO3a expression using small interfering RNA can up-regulate FOXM1 and its downstream targets polo-like kinase, cyclin B1, and CDC25B and rescue sensitive BT474 cells from gefitinib-induced cell proliferative arrest. These results suggest that gefitinib represses FOXM1 expression via FOXO3a in breast cancer. We further showed that overexpression of a wild-type FOXM1 or a constitutively active FOXM1, ΔN-FOXM1, abrogates the cell death induced by gefitinib, indicating that FOXM1 has a functional role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib. In summary, our study defined FOXM1 as a cellular target and marker of gefitinib activity in breast cancer. [Mol Cancer Ther 2009;8(3):582–91]
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