The heat shock protein Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention. The natural rotenoid deguelin was identified as an Hsp90 inhibitor, but concerns about neurotoxicity have limited prospects for clinical development. In this study, we report progress on deguelin analogs that address this limitation, focusing on the novel analog SH-1242 as a candidate to broadly target human lung cancer cells, including those that are chemoresistant or harboring KRAS mutations. In a KRAS-driven Sadie Buckallewmouse model of lung cancer, SH-1242 administration reduced tumor multiplicity, volume and load. Similarly, in human cell line-based or patient-derived tumor xenograft models, SH-1242 induced apoptosis and reduced tumor vasculature in the absence of detectable toxicity. In contrast to deguelin, SH-1242 toxicity was greatly reduced in normal cells and when administered to rats did not produce obvious histopathological features in the brain. Mechanistic studies revealed that SH-1242 bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the ability to interact with its co-chaperones and clients and triggering a degradation of client proteins without affecting Hsp70 expression. Taken together, our findings illustrate the superior properties of SH-1242 as an Hsp90 inhibitor as an effective antitumor and minimally toxic agent, providing a foundation for advancing further preclinical and clinical studies.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 14 Δεκεμβρίου 2015
Deguelin analog SH-1242 inhibits Hsp90 activity and exerts potent anticancer efficacy with limited neurotoxicity
Peptide-drug conjugate GnRH-sunitinib targets angiogenesis selectively at the site of action to inhibit tumor growth
The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogs of a clinically established antiangiogenic compound (sunitinib) from which a lead candidate (SAN1) was conjugated to the targeting peptide [D-Lys6]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared to equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (~4-fold) following dosing of SAN1GSC compared to equimolar amounts of non-conjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof of concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation.
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Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis
MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers including frequently in colorectal cancer, where their function and pathobiological importance has been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain the tumorigenic phenotype, we reconstituted its signaling axis in colon cancer cells harboring MLK4 inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3 and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer.
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Control of PD-L1 expression by oncogenic activation of the AKT/mTOR pathway in non-small cell lung cancer
Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT/mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFN-gamma-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest oncogenic activation of the AKT/mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.
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Bereavement is associated with an increased risk of HPV infection and cervical cancer: an epidemiological study in Sweden
Grief over the loss of a family member may cause physical and mental illness, but an association between bereavement and cancer risk has not been established. Based on the Swedish National Cervical Screening Register (1969-2011) including 14,011,269 smears from 2,466,107 women, we conducted two nested case-control studies to examine the associations of bereavement (i.e., loss of a family member due to death) with abnormal cytology (390,310 first abnormal and 1,951,319 normal smears) and in situ/invasive cervical cancer (75,128 case and 375,640 control women), both individually matched on year of birth and screening adherence. Among 1,696 of the control women, we further investigated bereavement in association with HPV infection, both HPV16 and other HPV types. Bereavement was consistently associated with a 4-9% increased risk for first abnormal cytology, in situ and invasive cervical cancer (all P<0.02). The associations became stronger when multiple losses, loss of child, sibling or spouse, and loss due to unnatural cause were analyzed separately (P for trend or difference<0.0001), and for women with high screening adherence (P for difference<0.05). Among 1,696 women who had not developed cervical cancer, we further investigated the link between bereavement and HPV infection. Bereavement was associated with a 62% increased risk of HPV16 infection, high viral load, and recurrent infection, and was also more strongly associated with HPV infections designated as high-risk compared to low-risk determinants of cervical carcinogenesis. Collectively, our findings demonstrate that bereavement is associated with an increased risk of developing cervical cancer. Further, they suggest that this association may be attributed to stress-induced oncogenic HPV infections.
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An anti-EGFR IgA that displays improved pharmacokinetics and myeloid effector cell engagement in vivo
Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe pre-clinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared to wild type IgA2m(1), the engineered molecule lacked two N-glycosylation sites (N166, N337), two free cysteines (C311, C472) and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared to wild type IgA. In vitro, Fab- and Fc-mediated effector functions such as inhibition of ligand binding, receptor modulation and engagement of myeloid effector cells for antibody-dependent cell-mediated cytotoxicity were similar between wild type and engineered IgA2. The engineered antibody displayed lower levels of terminal galactosylation leading to reduced asialoglycoprotein-receptor binding and to improved pharmacokinetic properties. In a long-term in vivo model against EGFR-positive cancer cells, improved serum half-life translated into higher efficacy of the engineered molecule, which required myeloid cells expressing human FcαRI for its full efficacy. However, Fab-mediated effector functions contributed to the in vivo efficacy since the novel IgA antibody demonstrated therapeutic activity also in non-FcalphaRI transgenic mice. Together, these results demonstrate that engineering of an IgA antibody can significantly improve its pharmacokinetics and its therapeutic efficacy to inhibit tumor growth in vivo.
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Myeloid CCL9 and Tumor Cell Survival in Premetastatic Organ
Tumor cell survival in the hostile distant organ is a rate-limiting step in cancer metastasis. Bone marrow–derived myeloid cells can form a premetastatic niche and provide a tumor-promoting microenvironment. However, it is unclear whether these myeloid cells in the premetastatic site have any direct effect on tumor cell survival. Here, we report that chemokine CCL9 was highly induced in Gr-1+CD11b+ immature myeloid cells and in premetastatic lung in tumor-bearing mice. Knockdown of CCL9 in myeloid cells decreased tumor cell survival and metastasis. Importantly, CCL9 overexpression in myeloid cells lacking TGFβ signaling rescued the tumor metastasis defect observed in mice with myeloid-specific Tgfbr2 deletion. The expression level of CCL23, the human orthologue for CCL9, in peripheral blood mononuclear cells correlated with progression and survival of cancer patients. Our study demonstrates that CCL9 could serve as a good candidate for anti-metastasis treatment by targeting the rate-limiting step of cancer cell survival. In addition, targeting CCL9 may avoid the adverse effects of TGFβ-targeted therapy. Cancer Res; 75(24); 5283–98. ©2015 AACR.
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Cooperation of Oncogenic KRAS and PIK3CA in Lung Cancer
KRAS-activating mutations drive human non–small cell lung cancer and initiate lung tumorigenesis in genetically engineered mouse (GEM) models. However, in a GEM model of KRASG12D-induced lung cancer, tumors arise stochastically following a latency period, suggesting that additional events are required to promote early-stage tumorigenic expansion of KRASG12D-mutated cells. PI3Kα (PIK3CA) is a direct effector of KRAS, but additional activation of PI3′-lipid signaling may be required to potentiate KRAS-driven lung tumorigenesis. Using GEM models, we tested whether PI3′-lipid signaling was limiting for the promotion of KRASG12D-driven lung tumors by inducing the expression of KRASG12D in the absence and presence of the activating PIK3CAH1047R mutation. PIK3CAH1047R expression alone failed to promote tumor formation, but dramatically enhanced tumorigenesis initiated by KRASG12D. We further observed that oncogenic cooperation between KRASG12D and PIK3CAH1047R was accompanied by PI3Kα-mediated regulation of c-MYC, GSK3β, p27KIP1, survivin, and components of the RB pathway, resulting in accelerated cell division of human or mouse lung cancer–derived cell lines. These data suggest that, although KRASG12D may activate PI3Kα by direct biochemical mechanisms, PI3′-lipid signaling remains rate-limiting for the cell-cycle progression and expansion of early-stage KRASG12D-initiated lung cells. Therefore, we provide a potential mechanistic rationale for the selection of KRAS and PIK3CA coactivating mutations in a number of human malignancies, with implications for the clinical deployment of PI3′ kinase–targeted therapies. Cancer Res; 75(24); 5378–91. ©2015 AACR.
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Dependence Receptor and Cancer
Data accumulating over the last 20 years support the notion that some transmembrane receptors are activated not only by their respective ligands but also, differentially, by the withdrawal or absence of these same ligands. In this latter setting, these receptors actively trigger apoptosis. They have been dubbed dependence receptors because their expression confers a state of ligand dependence for survival on the expressing cells. Twenty of these receptors have been identified to date, and several have been shown to inhibit tumor progression by inducing apoptosis. As a corollary, these receptors, or their transduced death signals, are frequently silenced in cancer cells as a selective mechanism to prevent cell death, allowing invasion and metastasis. Drugs aimed at inducing programmed cell death in neoplastic cells by re-engaging the proapoptotic activity induced by unliganded dependence receptors are in late-stage preclinical tests, poised for clinical evaluation. This approach may offer novel opportunities for patient treatments. In this review, we discuss the implications of dependence receptors in limiting cancer progression and address the therapeutic perspectives brought to light by this paradigm. Cancer Res; 75(24); 5171–5. ©2015 AACR.
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Lysosomal Transport of Noncleavable Maytansine ADC Warhead
Antibody–drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino acid-linker-warheads within the lysosome, which then enter the cytoplasm by an unknown mechanism. We hypothesized that a lysosomal transporter was responsible for delivering noncleavable ADC catabolites into the cytoplasm. To identify candidate transporters, we performed a phenotypic shRNA screen with an anti-CD70 maytansine-based ADC. This screen revealed the lysosomal membrane protein SLC46A3, the genetic attenuation of which inhibited the potency of multiple noncleavable antibody–maytansine ADCs, including ado-trastuzumab emtansine. In contrast, the potencies of noncleavable ADCs carrying the structurally distinct monomethyl auristatin F were unaffected by SLC46A3 attenuation. Structure–activity experiments suggested that maytansine is a substrate for SLC46A3. Notably, SLC46A3 silencing led to relative increases in catabolite concentrations in the lysosome. Taken together, our results establish SLC46A3 as a direct transporter of maytansine-based catabolites from the lysosome to the cytoplasm, prompting further investigation of SLC46A3 as a predictive response marker in breast cancer specimens. Cancer Res; 75(24); 5329–40. ©2015 AACR.
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Druggable Mutations in Childhood Cancer
Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular-targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies. Cancer Res; 75(24); 5176–86. ©2015 AACR.
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IL15 in T-cell Therapy of Cancer
Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long-lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8+ memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T-cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell–based immunotherapy of cancer. Cancer Res; 75(24); 5187–93. ©2015 AACR.
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miR-124 Represses Prostate Cancer Cell Growth
miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment. Cancer Res; 75(24); 5309–17. ©2015 AACR.
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Federated Cancer Research Network for Data and Biospecimens
Advances in cancer research and personalized medicine will require significant new bridging infrastructures, including more robust biorepositories that link human tissue to clinical phenotypes and outcomes. In order to meet that challenge, four cancer centers formed the Text Information Extraction System (TIES) Cancer Research Network, a federated network that facilitates data and biospecimen sharing among member institutions. Member sites can access pathology data that are de-identified and processed with the TIES natural language processing system, which creates a repository of rich phenotype data linked to clinical biospecimens. TIES incorporates multiple security and privacy best practices that, combined with legal agreements, network policies, and procedures, enable regulatory compliance. The TIES Cancer Research Network now provides integrated access to investigators at all member institutions, where multiple investigator-driven pilot projects are underway. Examples of federated search across the network illustrate the potential impact on translational research, particularly for studies involving rare cancers, rare phenotypes, and specific biologic behaviors. The network satisfies several key desiderata including local control of data and credentialing, inclusion of rich phenotype information, and applicability to diverse research objectives. The TIES Cancer Research Network presents a model for a national data and biospecimen network. Cancer Res; 75(24); 5194–201. ©2015 AACR.
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Polarity Checkpoint Provides Drug Sensitivity
The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133+ tumor-propagating cells isolated from primary GBM cell lines. We show that CD133+ cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133− cells. Furthermore, CD133+ cells exhibited an extended G2–M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133+ cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P < 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133+ cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment. Cancer Res; 75(24); 5355–66. ©2015 AACR.
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Cancer Education
Modern cancer therapy/care involves the integration of basic, clinical, and population-based research professionals using state-of-the-art science to achieve the best possible patient outcomes. A well-integrated team of basic, clinical, and population science professionals and educators working with a fully engaged group of creative junior investigators and trainees provides a structure to achieve these common goals. To this end, the structure provided by cancer-focused educational programs can create the integrated culture of academic medicine needed to reduce the burden of cancer on society. This summary outlines fundamental principles and potential best practice strategies for the development of integrated educational programs directed at achieving a work force of professionals that broadly appreciate the principals of academic medicine spanning the breadth of knowledge necessary to advance the goal of improving the current practice of cancer care medicine. Cancer Res; 75(24); 5202–5. ©2015 AACR.
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The Inescapable Influence of Noncoding RNAs in Cancer
This report summarizes information presented at the 2015 Keystone Symposium on "MicroRNAs and Noncoding RNAs in Cancer." Nearly two decades after the discovery of the first miRNA, the role of noncoding RNAs in developmental processes and the mechanisms behind their dysregulation in cancer has been steadily elucidated. Excitingly, miRNAs have begun making their way into the clinic to combat diseases such as hepatitis C and various forms of cancer. Therefore, at this Keystone meeting, novel findings were presented that enhance our view on how small and long noncoding RNAs control developmental timing and oncogenic processes. Recurring themes included (i) how miRNAs can be differentially processed, degraded, and regulated by ribonucleoprotein complexes, (ii) how particular miRNA genetic networks that control developmental process, when disrupted, can result in cancer disease, (iii) the technologies available to therapeutically deliver RNA to combat diseases such as cancer, and (iv) the elucidation of the mechanism of actions for long noncoding RNAs, currently a poorly understood class of noncoding RNA. During the meeting, there was an emphasis on presenting unpublished findings, and the breadth of topics covered reflected how inescapable the influence of noncoding RNAs is in development and cancer. Cancer Res; 75(24); 5206–10. ©2015 AACR.
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eIF4G1 Targeting in BRAF-Resistant and BRAF WT Melanoma
Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF, and NF1-mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Furthermore, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAF-independent and BRAFi-resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers. Cancer Res; 75(24); 5211–8. ©2015 AACR.
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Nitric Oxide Is an Epigenetic Regulator of Gene Expression
Altered nitric oxide (•NO) metabolism underlies cancer pathology, but mechanisms explaining many •NO-associated phenotypes remain unclear. We have found that cellular exposure to •NO changes histone posttranslational modifications (PTM) by directly inhibiting the catalytic activity of JmjC-domain containing histone demethylases. Herein, we describe how •NO exposure links modulation of histone PTMs to gene expression changes that promote oncogenesis. Through high-resolution mass spectrometry, we generated an extensive map of •NO-mediated histone PTM changes at 15 critical lysine residues on the core histones H3 and H4. Concomitant microarray analysis demonstrated that exposure to physiologic •NO resulted in the differential expression of over 6,500 genes in breast cancer cells. Measurements of the association of H3K9me2 and H3K9ac across genomic loci revealed that differential distribution of these particular PTMs correlated with changes in the level of expression of numerous oncogenes, consistent with epigenetic code. Our results establish that •NO functions as an epigenetic regulator of gene expression mediated by changes in histone PTMs. Cancer Res; 75(24); 5299–308. ©2015 AACR.
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Next-Generation Sequencing of Penile Carcinoma
Penile squamous cell carcinoma (PeSCCA) is a rare malignancy for which there are limited treatment options due to a poor understanding of the molecular alterations underlying disease development and progression. Therefore, we performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations in a retrospective cohort of 60 fixed tumor samples from 43 PeSCCA cases (including 14 matched primary/metastasis pairs). We identified a median of two relevant somatic mutations and one high-level copy-number alteration per sample (range, 0–5 and 0–6, respectively). Expression of HPV and p16 was detectable in 12% and 28% of patients, respectively. Furthermore, advanced clinical stage, lack of p16 expression, and MYC and CCND1 amplifications were significantly associated with shorter time to progression or PeSCCA-specific survival. Notably, four cases harbored EGFR amplifications and one demonstrated CDK4 amplification, genes for which approved and investigational targeted therapies are available. Importantly, although paired primary tumors and lymph node metastases were largely homogeneous for relevant somatic mutations, we identified heterogeneous EGFR amplification in primary tumor/lymph node metastases in 4 of 14 cases, despite uniform EGFR protein overexpression. Likewise, activating HRAS mutations occurred in 8 of 43 cases. Taken together, we provide the first comprehensive molecular PeSCCA analysis, which offers new insight into potential precision medicine approaches for this disease, including strategies targeting EGFR. Cancer Res; 75(24); 5219–27. ©2015 AACR.
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Pim Kinases Mediate Resistance to MET Inhibitors
Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non–small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of antiapoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer. Cancer Res; 75(24); 5318–28. ©2015 AACR.
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Genomic Profiling of Merkel Cell Carcinomas
Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res; 75(24); 5228–34. ©2015 AACR.
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Comprehensive Phenotyping of Rare PIK3CA Variants
Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. Although PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07% to 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of mitogen-activated protein kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. Cancer Res; 75(24); 5341–54. ©2015 AACR.
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Years of potential life lost for brain and CNS tumors relative to other cancers in adults in the United States, 2010
Background
Years of potential life lost (YPLL) complement incidence and survival rates by measuring how much a patient's life is likely to be shortened by his or her cancer. In this study, we examine the impact of death due to brain and other central nervous system (CNS) tumors compared to other common cancers in adults by investigating the YPLL of adults in the United States.
MethodsMortality and life table data were obtained from the Centers for Disease Control and Prevention's National Center for Health Statistics Vital Statistics Data for 2010. The study population included individuals aged 20 years or older at death who died from one of the selected cancers. YPLL was calculated by taking an individual's age at death and finding the corresponding expected remaining years of life using life table data.
ResultsThe cancers with the greatest mean YPLL were other malignant CNS tumors (20.65), malignant brain tumors (19.93), and pancreatic cancer (15.13) for males and malignant brain tumors (20.31), breast cancer (18.78), and other malignant CNS tumors (18.36) for females. For both sexes, non-Hispanic whites had the lowest YPLL, followed by non-Hispanic blacks, and Hispanics.
ConclusionMalignant brain and other CNS tumors have the greatest mean YPLL, thereby reflecting their short survival time post diagnosis. These findings will hopefully motivate more research into mitigating the impact of these debilitating tumors.
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Molecular subgroups of medulloblastoma identification using noninvasive magnetic resonance spectroscopy
Background
Medulloblastomas in children can be categorized into 4 molecular subgroups with differing clinical characteristics, such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, noninvasive tool that is used to determine the metabolic characteristics of tumors and provide diagnostic information without the need for tumor tissue. In this study, we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma and allow accurate subgroup determination.
MethodsMRS was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of 14 metabolites were analyzed to determine those that were the most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier for distinguishing between combined Group 3/4 and SHH tumors.
ResultsMedulloblastomas across molecular subgroups revealed distinct spectral features. Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids, and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. A 5-metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate, and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated area under the curve [AUC] = 0.88).
ConclusionsThe data show that medulloblastomas of Group 3/4 differ metabolically as measured using MRS when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups.
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Hope and mood changes throughout the primary brain tumor illness trajectory
Background
The ambiguity of defining hope impacts the level of readiness faced by health care professionals treating patients with glioma, a disease with unpredictable outcomes. This study describes the report of hope and the relationship between hope and mood in adult brain tumor patients at various points in the illness trajectory.
MethodsThis was a cross-sectional study with data collection including use of the Herth Hope Index (HHI), the Profile of Mood States-Short Form (POMS-SF), and clinical information. Descriptive statistics were used to report sample characteristics. Spearman's rho and Mann-Whitney tests were used to compare and differentiate scores.
ResultsEighty-two patients ranging in age from 22 to 78 years (median, 44.5 y) participated in the study. Patients were primarily male (57.3%), married (76.8%), and had a high-grade glioma (35.4%). Nearly half had recurrence, and more than 20% were on active treatment. The overall HHI total score for the sample was 41.32 (range: 13–48). Patients with recurrence had a lower HHI interconnectedness (median = 14.00) score and higher total mood disturbance (median = 14.00) compared with patients without recurrence (median = 15.00 and median = 0.00, respectively; P < .05). All negative mood states on the POMS-SF were negatively correlated with HHI subscales.
ConclusionsOverall, patients reporting more hope also reported less overall mood disturbance As expected, patients with tumor recurrence reported lower hope and higher mood disturbance than those who were newly diagnosed or without recurrence. Targeting interventions specifically tailored to an individual's needs for improvement in quality of life throughout the disease course may include measures to address hope in order to facilitate positive coping strategies.
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Differentiation of high-grade and low-grade diffuse gliomas by intravoxel incoherent motion MR imaging
Background
Our aim was to assess the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs).
MethodsForty-five patients with diffuse glioma (age 50.9 ± 20.4 y; 26 males, 19 females) were assessed with IVIM imaging using 13 b-values (0–1000 s/mm2) at 3T. The perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were calculated by fitting the bi-exponential model. The apparent diffusion coefficient (ADC) was obtained with 2 b-values (0 and 1000 s/mm2). Relative cerebral blood volume was measured by the dynamic susceptibility contrast method. Two observers independently measured D, ADC, D*, and f, and these measurements were compared between the LGG group (n = 16) and the HGG group (n = 29).
ResultsBoth D (1.26 ± 0.37 mm2/s in LGG, 0.94 ± 0.19 mm2/s in HGG; P < .001) and ADC (1.28 ± 0.35 mm2/s in LGG, 1.03 ± 0.19 mm2/s in HGG; P < .01) were lower in the HGG group. D was lower than ADC in the LGG (P < .05) and HGG groups (P < .0001). D* was not different between the groups. The f-values were significantly larger in HGG (17.5 ± 6.3%) than in LGG (5.8 ± 3.8%; P < .0001) and correlated with relative cerebral blood volume (r = 0.85; P < .0001). Receiver operating characteristic analyses showed areas under curve of 0.95 with f, 0.78 with D, 0.73 with ADC, and 0.60 with D*.
ConclusionIVIM imaging is useful in differentiating HGGs from LGGs.
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Smoking and adult glioma: a population-based case-control study in China
Background
Smoking increases the risk of numerous cancers; however, an association of smoking with adult gliomas has not been found in a population.
MethodsThis case-control study included 4556 glioma cases (ICD-9 code 191.0–191.9) aged ≥30 years and 9112 controls from a national survey of smoking and mortality in China in 1989–1991. Controls from 325 255 surviving spouses of all-cause deaths were randomly assigned to cases in each of 103 areas according to sex and age groups at a ratio of 2:1. Smoking information was ascertained retrospectively by interviewing surviving spouses.
ResultsAfter adjustment for confounders, smoking increased the risk of glioma deaths by 11% (odds ratio [OR] = 1.11; 95% confidence interval [CI]: 1.03–1.21). Compared with non-smokers; the increased risk was 9% (OR = 1.09; 95% CI: 0.99–1.20) in men and 16% (OR = 1.16; 95% CI: 1.00–1.36) in women. The risk increased with age and doses. For individuals aged ≥50 years, smoking was associated with higher risk of glioma death by 25% (OR = 1.25; 95% CI: 1.15–1.38); this increased risk for smokers who smoked ≥20 cigarettes daily for ≥30 years was 53% (OR = 1.53; 95% CI: 1.34–1.74). There were similar findings in both men and women and with either pathology-based or non–pathology-based comparisons.
ConclusionsThis study indicates that smoking is associated with glioma deaths in the Chinese population. Long-term heavy smoking could be a factor for risk stratification in individuals attending brain tumor clinics.
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Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection
Background
While standards for the treatment of newly diagnosed glioblastomas exist, therapeutic regimens for tumor recurrence remain mostly individualized. The role of a surgical resection of recurrent glioblastomas remains largely unclear at present. This study aimed to assess the effect of repeated resection of recurrent glioblastomas on patient survival.
MethodsIn a multicenter retrospective-design study, patients with primary glioblastomas undergoing repeat resections for recurrent tumors were evaluated for factors affecting survival. Age, Karnofsky performance status (KPS), extent of resection (EOR), tumor location, and complications were assessed.
ResultsFive hundred and three patients (initially diagnosed between 2006 and 2010) undergoing resections for recurrent glioblastoma at 20 institutions were included in the study. The patients' median overall survival after initial diagnosis was 25.0 months and 11.9 months after first re-resection. The following parameters were found to influence survival significantly after first re-resection: preoperative and postoperative KPS, EOR of first re-resection, and chemotherapy after first re-resection. The rate of permanent new deficits after first re-resection was 8%.
ConclusionThe present study supports the view that surgical resections of recurrent glioblastomas may help to prolong patient survival at an acceptable complication rate.
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Prediction of life expectancy in patients with spinal epidural metastasis
Background
The treatment of spinal epidural metastasis is multidisciplinary and usually involves a team of medical oncologists, radiologists, radiotherapists, and spinal surgeons. Life expectancy is one of the factors considered when deciding whether surgery is warranted. Because expert estimates of life expectancy are generally not reliable, a prediction model is needed. Here, we temporally validated a model that was previously validated geographically.
MethodsThe records of 110 consecutive patients who were referred with a spinal epidural metastasis were collected prospectively from 2009 to 2013 in order to validate the model, which was published in 2011. The actual and estimated life expectancies were represented graphically, and calibration and discrimination were determined. The calibration slope, Harrell's c-index, D, and RD2 were calculated. Hazard ratios in the derivation set of 2011 were compared with the validation set. Misspecification was determined using the joint test for β*.
ResultsThe calibration slope was 0.64 ± 0.15 (95% CI: 0.34–0.94), Harrell's c-index was 0.72, D was 1.08, and RD2 was 0.22, indicating slightly worse discrimination in the derivation set. The joint test for β* = 0 was statistically significant and indicated misspecification; however, this misspecification was attributed entirely to the surgical group.
ConclusionsWe validated a prediction model for surgical decision making, showing that the model's overall performance is good. Based on these results, this model will help clinicians to decide whether to offer surgery to patients with spinal epidural metastasis.
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Rates and risks for late referral to hospice in patients with primary malignant brain tumors
Background
Primary malignant brain tumors (PMBTs) are devastating malignancies with poor prognosis. Optimizing psychosocial and supportive care is critical, especially in the later stages of disease.
MethodsThis retrospective cohort study compared early versus late hospice enrollment of PMBT patients admitted to the home hospice program of a large urban, not-for-profit home health care agency between 2009 and 2013.
ResultsOf 160 patients with PMBT followed to death in hospice care, 32 (22.5%) were enrolled within 7 days of death. When compared with patients referred to hospice more than 7 days before death, a greater proportion of those with late referral were bedbound at admission (97.2% vs 61.3%; OR=21.85; 95% CI, 3.42–919.20; P < .001), aphasic (61.1% vs 20.2%; OR = 6.13; 95% CI, 2.59–15.02; P < .001), unresponsive (38.9% vs 4%; OR = 14.76,;95% CI, 4.47–57.98; P < .001), or dyspneic (27.8% vs 9.7%; OR = 21.85; 95% CI, 3.42–10.12; P = .011). In multivariable analysis, male patients who were receiving Medicaid or charitable care and were without a health care proxy were more likely to enroll in hospice within 1 week of death.
ConclusionsLate hospice referral in PMBT is common. PMBT patients enrolled late in hospice are severely neurologically debilitated at the time hospice is initiated and therefore may not derive optimal benefit from multidisciplinary hospice care. Men, patients with lower socioeconomic status, and those without a health care proxy may be at risk for late hospice care and may benefit from proactive discussion about end-of-life care in PMBT, but prospective studies are needed.
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The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma
Background
Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process.
MethodsSerial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed.
ResultsThe number of microbleeds increased with time for all patients, with initial onset occurring at 8–22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01).
ConclusionsWe have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT.
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USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance
Background
Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed.
MethodsWe determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells.
ResultsUSP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice.
ConclusionUSP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.
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Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation
Background
Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells.
MethodsIn the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo.
ResultsWe showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth.
ConclusionsTaken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.
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Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma
Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood–brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM.
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Isocitrate dehydrogenase mutations in gliomas
Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg132 of IDH1 and Arg172 of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2 mutations on molecular classification and glioma therapy.
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Cloning, expression, and antiviral activity of interferon β from the Chinese microbat, Myotis davidii
Abstract
Bats are natural reservoir hosts for many viruses that produce no clinical symptoms in bats. Therefore, bats may have evolved effective mechanisms to control viral replication. However, little information is available on bat immune responses to viral infection. Type I interferon (IFN) plays a key role in controlling viral infections. In this study, we report the cloning, expression, and biological activity of interferon β (IFNβ) from the Chinese microbat species, Myotis davidii. We demonstrated the upregulation of IFNB and IFN-stimulated genes in a kidney cell line derived from M. davidii after treatment with polyI:C or infection with Sendai virus. Furthermore, the recombinant IFNβ inhibited vesicular stomatitis virus and bat adenovirus replication in cell lines from two bat species, M. davidii and Rhinolophus sinicus. We provide the first in vitro evidence of IFNβ antiviral activity in microbats, which has important implications for virus interactions with these hosts.
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Cancers, Vol. 7, Pages 2459-2465: Acute Myeloid Leukemia with Isolated Trisomy 19 Associated with Diffuse Myelofibrosis and Osteosclerosis
Primary myelofibrosis (PMF), per WHO criteria, is a clonal myeloproliferative neoplasm that usually presents with a proliferation of granulocytic and megakaryocytic lineages with an associated fibrous deposition and extramedullary hematopoiesis. The bone marrow histologic findings of this disorder are typically characterized by the presence of myeloid metaplasia with an associated reactive fibrosis, angiogenesis, and osteosclerosis. However, marked myelofibrosis is not solely confined to PMF and may also be associated with other conditions including but not limited to acute megakaryoblastic leukemias (FAB AML-M7). Here, we describe a rare case of a non-megakaryoblastic acute myeloid leukemia with marked myelofibrosis with osteosclerosis and an isolated trisomy 19. A 19-year-old male presented with severe bone pain of one week duration with a complete blood cell count and peripheral smear showing a mild anemia and occasional circulating blasts. A follow up computed tomography (CT) scan showed diffuse osteosclerosis with no evidence of hepatosplenomegaly or lymphadenopathy. Subsequently, the bone marrow biopsy showed markedly sclerotic bony trabeculae and a hypercellular marrow with marked fibrosis and intervening sheets of immature myeloid cells consistent with myeloblasts with monocytic differentiation. Importantly, these myeloblasts were negative for megakaryocytic markers (CD61 and vWF), erythroid markers (hemoglobin and E-cadherin), and lymphoid markers (CD3, CD19, and TdT). Metaphase cytogenetics showed an isolated triosomy 19 with no JAK2 V617F mutation. The patient was treated with induction chemotherapy followed by allogenic hematopoietic stem cell transplantation which subsequently resulted in a rapid resolution of bone marrow fibrosis, suggesting graft-anti-fibrosis effect. This is a rare case of a non-megakaryoblastic acute myeloid leukemia with myelofibrosis and osteosclerosis with trisomy 19 that may provide insights into the prognosis and therapeutic options of future cases.
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Changing trends in the clinicopathological features and clinical outcomes of medullary thyroid carcinoma
Background
The early detection of papillary thyroid cancer has contributed to the increase in the incidence and improved clinical outcomes. However, recent changes of medullary thyroid carcinoma (MTC) over time remain unclear. We evaluated changes of the clinicopathological characteristics and clinical outcomes in patients with MTC in recent years.
Methods
A total of 109 MTC patients were classified based on the year of initial surgery: 1996–2000 (n = 14), 2001–2006 (n = 39), and 2007–2011 (n = 56).
Results
The primary tumor size significantly decreased and the proportion of microMTCs (size ≤1 cm) increased over time (P = 0.002 and P < 0.001, respectively). The proportion of patients with cervical lymph node (LN) metastasis significantly decreased (P = 0.037), and the ratio of metastatic LNs significantly decreased (P = 0.011). Disease-free survival (DFS) rate of patients was significantly improved over time (P = 0.007). There was no significant difference in DFS between microMTC and macroMTC patients. However, more advanced LN stage patients demonstrated more recurrences (P < 0.001). Especially, there were significantly more recurrences in patients with N1b diseases in comparison with patients without cervical LN metastases (P < 0.001).
Conclusions
The prognosis of MTC patients has significantly improved in recent years. These changes could be associated with the early diagnosis before development of lateral and extensive cervical LN metastases. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.
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Stereotactic body radiation therapy for small primary or recurrent hepatocellular carcinoma in 132 Chinese patients
Aim
To evaluate the efficacy of stereotactic body radiation therapy (SBRT) in small hepatocellular carcinoma (HCC) patients.
Methods
From March 2009 to April 2015, we treated 132 small HCC patients with SBRT. Eligibility criteria included longest tumor diameter ≤5.0 cm; Child-Turcotte-Pugh (CTP) Class A or B; unfeasible, difficult or refusal to undergo other surgery or percutaneous ablative therapies; and tumor recurrence after other local treatment. The dose of 42–46 Gy in 3–5 fractions and 28–30 Gy in 1 fraction was prescribed.
Results
Of the treated patients, 114 were classified as CTP A and 18 as CTP B. Median tumor size was range 1.1–5.0 cm. The local control rate at 1 years was 90.9%. OS at 1, 3, and 5 years was 94.1%, 73.5%, and 64.3%, respectively. PFS at 1, 3, and 5 years was 82.7%, 58.3%, and 36.4%, respectively. Hepatic toxicity grade ≥3 was observed in 11 patients. Multivariate analysis revealed that CTP B was associated with worse OS (P < 0.001) and multiple nodules were associated with worse PFS (P = 0.001).
Conclusions
SBRT is a promising alternative treatment for patients with primary or recurrent small HCC who are unsuitable for surgical resection or local ablative therapy. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.
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Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)
Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Sook Ryun Park, Young Soo Park, Min-Hee Ryu, Baek-Yeol Ryoo, Chang Gok Woo, Hwoon-Yong Jung, Jeong Hoon Lee, Gin Hyug Lee, Yoon-Koo Kang
PurposeThe intratumoural heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is a major challenge when identifying patients who might benefit from HER2-targeting therapy. We investigated the significance of re-evaluation of HER2 status in primary sites and metastatic or recurrent sites in advanced gastric cancer patients whose primary tumours were initially HER2-negative.Patients and methodsIn part I of this study, we evaluated the significance of repeat endoscopic biopsy in unresectable or metastatic gastric cancer patients whose tumours were initially HER2-negative. In part II, we examined the HER2 positivity rate in metastatic or recurrent sites in patients whose primary tumours were HER2-negative in biopsy or surgical specimens.ResultsIn part I (n = 183), we identified patients with HER2-positive tumours for a rescued HER2 positivity rate of 8.7% (95% confidence interval [CI], 4.6–12.8%) that was associated with tumour location (diffuse stomach versus other = 0% versus 11.7%, P = 0.013), Bormann type (IV versus others = 0% versus 11.7%, P = 0.013), and initial biopsy HER2 immunohistochemistry score (0 versus 1 versus 2=6.7% versus 15.4% versus 25.0%, P = 0.028). Part II (n = 175) resulted in HER2 positivity of 5.7% (95% CI 2.3–9.1%) that was significantly associated with metastatic site (liver versus others = 17.2% versus 3.4%, P = 0.012). When compared with a historical control that showed HER2 positivity on initial assessment, patients who had rescued HER2 positivity had similar treatment benefits from trastuzumab-containing first-line chemotherapy.ConclusionRepeat HER2 assessment in primary and metastatic or recurrent sites is recommended in patients with advanced gastric cancer whose primary tumour is initially HER2-negative.
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Genetic heterogeneity after first-line chemotherapy in high-grade serous ovarian cancer
Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Sandrina Lambrechts, Dominiek Smeets, Matthieu Moisse, Elena Ioana Braicu, Adriaan Vanderstichele, Hui Zhao, Els Van Nieuwenhuysen, Els Berns, Jalid Sehouli, Robert Zeillinger, Silvia Darb-Esfahani, Dan Cacsire Castillo-Tong, Diether Lambrechts, Ignace Vergote
BackgroundMost high-grade serous ovarian carcinoma (HGSOC) patients benefit from first-line platinum-based chemotherapy, but progressively develop resistance during subsequent lines. Re-activating BRCA1 or MDR1 mutations can underlie platinum resistance in end-stage patients. However, little is known about resistance mechanisms occurring after a single line of platinum, when patients still qualify for other treatments.MethodsIn 31 patients with primary platinum-sensitive HGSOC, we profiled tumours collected during debulking surgery before and after first-line chemotherapy using whole-exome sequencing and single nucleotide polymorphism profiling.ResultsBesides germline BRCA1/2 mutations, we observed frequent loss-of-heterozygosity in homologous recombination (HR) genes and mutation spectra characteristic of HR-deficiency in all tumours. At relapse, tumours differed considerably from their primary counterparts. There was, however, no evidence of events reactivating the HR pathway, also not in tumours resistant to second-line platinum. Instead, a platinum score of 13 copy number regions, among other genes including MECOM, CCNE1 and ERBB2, correlated with platinum-free interval (PFI) after first-line therapy, whereas an increase of this score in recurrent tumours predicted the change in PFI during subsequent therapy.ConclusionsAlready after a single line of platinum, there is huge variability between primary and recurrent tumours, advocating that in HGSOC biopsies need to be collected at relapse to tailor treatment options to the underlying genetic profile. Nevertheless, all primary platinum-sensitive HGSOCs remained HR-deficient, irrespective of whether they became resistant to second-line platinum, further suggesting these tumours qualify for second-line Poly APD ribose polymerase (PARP) inhibitor treatment. Finally, chromosomal instability contributes to acquired resistance after a single line of platinum therapy.
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Melanoma burden by melanoma stage: Assessment through a disease transition model
Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Isabelle Tromme, Catherine Legrand, Brecht Devleesschauwer, Ulrike Leiter, Stefan Suciu, Alexander Eggermont, Julie Francart, Frederic Calay, Juanita A. Haagsma, Jean-François Baurain, Luc Thomas, Philippe Beutels, Niko Speybroeck
BackgroundThe total burden of melanoma has already been studied but little is known about the distribution of this burden amongst localised, node metastatic and distant metastatic stages.MethodsDisability-adjusted life years (DALY) assesses disease burden, being the sum of years of life with disability (YLD) and years of life lost (YLL). A melanoma disease model was developed in order to predict the evolution of patients from diagnosis until death. The model was applied to a large cohort of 8016 melanoma patients recorded by the Belgian Cancer Registry for incidence years 2009–2011. DALYs were calculated for each American Joint Committee on Cancer stage, considering stage at diagnosis on the one hand and time spent in localised, node metastatic and visceral metastatic stages on the other. Probabilistic sensitivity analyses and scenario analyses were performed to explore uncertainty.FindingsOur analyses resulted in 3.67 DALYs per melanoma, 90.81 per 100,000 inhabitants, or 32.67 per death due to melanoma. The total YLL accounted for 80.4% of the total DALY. Stages I, II, III and IV patients at diagnosis generated, respectively, 27.8%, 32.7%, 26.2% and 13.3% of the total YLL. For the time spent in each stage, localised melanomas, node metastatic melanomas, and distant metastatic accounted, respectively, for 34.8%, 52.6% and 12.6% of the total YLD. Parametric uncertainty was very limited, but the influence of using pre-2010 Global Burden of Disease approaches was substantial.InterpretationThe total DALY for melanoma was consistent with the previous studies. Our results in terms of proportions of DALY/YLL/YLD per stage could be extrapolated to other high-income countries. YLDs generated by localised melanoma which will never metastasize were inferior to YLLs resulting from stage IA melanomas. This result supports the hypothesis that efforts for an earlier diagnosis of melanoma are important.FundingNone.
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Risk-adapted approach for fever and neutropenia in paediatric cancer patients – A national multicentre study
Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Karin G.E. Miedema, Wim J.E. Tissing, Floor C.H. Abbink, Lynne M. Ball, Erna M.C. Michiels, Michel J. van Vliet, Wilma Y. de Vries, Willem A. Kamps, Obbe F. Norbruis, Marta Fiocco, Hester A. de Groot-Kruseman, Marianne D. van de Wetering, Eveline S.J.M. de Bont
BackgroundIn this national multicentre study, we examined the safety of reducing antibiotics in selected paediatric cancer patients with febrile neutropenia.MethodsPatients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk and received antibiotic therapy. Remaining patients were allocated to low- or medium risk, depending on their interleukin-8 level. Low-risk patients did not receive any antibiotics and were discharged from the hospital after having been afebrile for 12 h. Medium-risk patients were re-evaluated after 72 h of antibiotic treatment and, in selected patients, antibiotics were stopped.ResultsTwo hundred thirty-three febrile neutropenic episodes in 141 paediatric cancer patients were included in the study. Sixty-four episodes were classified high risk (28%), 122 medium risk (52%), and 47 (20%) low risk. In the medium-risk group, antibiotics were stopped after 72 h in 50 in 122 episodes (41%). Median duration of antibiotic treatment and hospital admission was significantly lower in low- and medium-risk episodes with early discharge. No failures were observed in the medium-risk group with early discharge. In the low-risk group, six failures were observed (12.8%), due to coagulase-negative staphylococci-positive blood cultures and recurrent fever.ConclusionWe showed that it is safe to shorten antibiotic treatment to 72 h in selected medium-risk patients with febrile neutropenia, regardless of the neutrophil count. The safety of withholding antibiotics in selected low-risk paediatric cancer patients with febrile neutropenia requires further investigation, using more suitable definitions for safety. Reduction in hospital admissions allows children with cancer more time at home and consequently improves their quality of life.
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Utility of the CPS+EG staging system in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated with neoadjuvant chemotherapy
Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Frederik Marmé, Bianca Lederer, Jens-Uwe Blohmer, Serban Dan Costa, Carsten Denkert, Holger Eidtmann, Bernd Gerber, Claus Hanusch, Jörn Hilfrich, Jens Huober, Christian Jackisch, Sherko Kümmel, Sibylle Loibl, Stefan Paepke, Michael Untch, Gunter von Minckwitz, Andreas Schneeweiss
BackgroundPathologic complete response after neoadjuvant chemotherapy (NACT) correlates with overall survival (OS) in primary breast cancer. A recently described staging system based on pre-treatment clinical stage (CS), final pathological stage (PS), estrogen receptor (ER) status and nuclear grade (NG) leads to a refined estimation of prognosis in unselected patients. Its performance in luminal type breast cancers has not been determined. This study investigates the clinical utility of this CPS+EG score when restricted to hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) patients and compares the results to a cohort of unselected patients.MethodsThe CPS+EG score was calculated for 6637 unselected patients and 2454 patients with HR+/HER2− tumours who received anthracycline/taxane-based NACT within 8 prospective German trials.ResultsFive-year disease-free survival (DFS) and OS were 75.6% and 84.1% for the unselected cohort and 80.6% and 87.8% for the HR+/HER2− subgroup, respectively. The CPS+EG system distinguished different prognostic groups with 5-year DFS ranging from 0% to 91%. The CPS+EG system leads to an improved categorisation of patients by outcome compared to CS, PS, ER or NG alone. When applying the CPS+EG score to the HR+/HER2− subgroup, a shift to lower scores was observed compared to the overall population, but 5-year DFS and OS for the individual scores were identical to that observed in the overall population.ConclusionsIn HR+/HER2− patients, the CPS+EG staging system retains its ability to facilitate a refined stratification of patients according to outcome. It can help to select candidates for post-neoadjuvant clinical trials in luminal breast cancer.
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Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics
Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): A. Lipton, K. Fizazi, A.T. Stopeck, D.H. Henry, M.R. Smith, N. Shore, M. Martin, S. Vadhan-Raj, J.E. Brown, G.E. Richardson, F. Saad, D.A. Yardley, K. Zhou, A. Balakumaran, A. Braun
BackgroundAnalyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics.Patients and MethodsPatients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson–Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type.ResultsCompared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79–0.84; bone metastasis location, 0.78–0.83; bone metastasis number, 0.78–0.84; visceral metastasis presence/absence, 0.80–0.82; uNTx level, 0.73–0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76–0.83; bone metastasis location, 0.78–0.84; bone metastasis number, 0.79–0.81; visceral metastasis presence/absence, 0.79–0.81; uNTx level, 0.74–0.83). Similar results were observed in subgroups across tumour types.ConclusionDenosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.
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MicroRNAs as potential diagnostic and prognostic biomarkers in melanoma
Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Hamed Mirzaei, Sharareh Gholamin, Soodabeh Shahidsales, Amirhossein Sahebkar, Mahmoud Reza Jafaari, Hamid Reza Mirzaei, Seyed Mahdi Hassanian, Amir Avan
Melanoma is a life-threatening malignancy with poor prognosis and a relatively high burden of mortality in advanced stages. The efficacy of current available therapeutic strategies is limited, with a survival rate of less than 10%. Despite rapid advances in biomarker-guided drug development in different tumour types, including melanoma, only a very small number of biomarkers have been identified. Recently, microRNAs (miRNAs) have emerged as a molecular regulator in the development and progression of melanoma. Aberrant activation of some known miRNAs, e.g. let-7a and b, miR-148, miR-155, miR-182, miR-200c, miR-211, miR-214, miR-221 and 222, has been recognised to be linked with melanoma-associated genes such as NRAS, microphthalmia-associated transcription factor, receptor tyrosine kinase c-KIT, AP-2 transcription factor, etc. There is accumulating evidence suggesting the potential impact of circulating miRNAs as diagnostic and therapeutic markers in diseases. In addition, miRNAs have turned out to play important roles in drug-resistance mechanisms; suggesting their modulation as a potential approach to overcome chemoresistance. This review highlights recent preclinical and clinical studies on circulating miRNAs and their potential role as diagnosis, and therapeutic targets in melanoma.
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