Cancer-Initiating Cell Targeting Immunotherapy

Purpose: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence, and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy.

Experimental Design: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CICs was analyzed by cDNA microarray and RT-PCR. Protein expression of olfactory receptor family 7 subfamily C member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene overexpression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by a flow cytometer and analyzed. CTLs specific for OR7C1 peptide were generated, and the antitumor effect was addressed by mice adoptive transfer model.

Results: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicity than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific CTLs showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater antitumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model.

Conclusions: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy. Clin Cancer Res; 22(13); 3298–309. ©2016 AACR.

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Individualized Tamoxifen Dose Escalation

Tamoxifen may require metabolic activation to endoxifen for efficacy in treating hormone receptor–positive breast cancer. Dose escalation in patients with low endoxifen concentrations could enhance treatment efficacy. This approach is clinically feasible, and successfully increases endoxifen concentrations; however, it is unknown whether patients benefit from individualized tamoxifen dose escalation. Clin Cancer Res; 22(13); 3121–3. ©2016 AACR.

See related article by Fox et al., p. 3164

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Sym004 Overcomes EGFR-Mediated Cetuximab Resistance

Purpose: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations.

Experimental Design: Functional studies were performed to assess drug–receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample.

Results: Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy.

Conclusions: Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials. Clin Cancer Res; 22(13); 3260–7. ©2016 AACR.

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Testosterone in Androgen Receptor Signaling and DNA Repair

Androgen suppression mediates transcriptional downregulation of DNA repair genes. Stimulation with supraphysiologic levels of dihydrotestosterone induces formation of lethal DNA breaks through recruitment of topoisomerase II enzymes to fragile DNA sites. Bipolar castration and stimulation that contributes to increasing DNA damage represents a novel strategy of sensitizing prostate cancer to cytotoxic therapies, including radiotherapy. Clin Cancer Res; 22(13); 3124–6. ©2016 AACR.

See related article by Hedayati et al., p. 3310

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TRIM24 Activates Androgen Receptor Signaling in Prostate Cancer [Prostate Cancer]

TRIM24 promotes cell proliferation in SPOP-mutant and castration-resistant prostate cancer (CRPC).

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Surveying Breast Cancer's Genomic Landscape [News in Brief]

An in-depth analysis has produced the most comprehensive portrait to date of the myriad genomic alterations involved in breast cancer. In sequencing the whole genomes of 560 breast cancers and combining this information with published data from another 772 breast tumors, the research team uncovered several new genes and mutational signatures that potentially influence this disease.

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Ovarian Cancer Disseminates via Distinct Modes of Intraperitoneal Spread [Ovarian Cancer]

High-grade serous ovarian cancer intraperitoneal spread arises primarily from monoclonal seeding.

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Nivolumab Doubles Survival for Patients with HNSCC [News in Brief]

In patients with head and neck squamous cell carcinoma refractory to platinum-based chemotherapy, those treated with nivolumab had a 30% reduction in the risk of death compared with those assigned to receive one of three single-agent chemotherapies, according to a recent phase III trial. In addition, 1-year survival among nivolumab recipients was double that of those who received a chemotherapeutic, the current standard of care.

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ATXN7L3 and ENY2 Direct H2B Deubiquitination Implicated in Tumor Growth [Ubiquitination]

H2Bub1 DUBs compete for binding to the adaptor proteins ATXN7L3 and ENY2 that facilitate DUB activity.

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Dabrafenib Active in Rare NSCLC Subtype [News in Brief]

Results from a phase II trial show that the BRAF inhibitor dabrafenib has significant single-agent activity in patients with advanced non–small cell lung cancer harboring the BRAF V600E mutation. However, data from another arm of the study suggest that combining dabrafenib with a MEK inhibitor may be a more effective treatment strategy for these patients.

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A LincRNA Risk Variant Promotes Pancreatic Tumorigenesis [Pancreatic Cancer]

The PDAC risk variant of LINC00673 is targeted by miR-1231 to promote PDAC growth.

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Colorectal Cancer Yields to Dual HER2 Blockade [News in Brief]

According to data from a phase II study, the anti-HER2 combination of trastuzumab and lapatinib is active in patients with KRAS–wild-type, HER2-positive metastatic colorectal cancer. None of the study participants responded to previous, standard treatment with the EGFR inhibitors cetuximab or panitumumab, but 30% achieved an objective response to dual HER2 blockade.

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Splicing May Be Therapeutically Targetable in Acute Myeloid Leukemia [Splicing]

Cells with mutations in spliceosomal genes may be preferentially sensitive to splicing disruption.

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FOXP3+ T-cell Subsets Are Associated with Distinct Colon Cancer Prognoses [Colon Cancer]

Elevated FOXP3, in the absence of FOXP3^lo T cells, is associated with poor colon cancer prognosis.

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ERCC2 Mutations Are Associated with a Specific Mutational Signature [Mutations]

A distinct mutational signature is linked to NER pathway mutations and smoking in urothelial tumors.

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Third-Generation mTOR Inhibitors Overcome Resistance Mutations [Drug Design]

Bivalent mTOR inhibitors overcome resistance to 1st and 2nd generation mTOR inhibitors.

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Effector T Cells Reduce Fibroblast-Mediated Chemoresistance [Ovarian Cancer]

T cell–derived IFN signaling shapes cancer chemosensitivity.

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The Landscape of Arm-Level Copy-Number Alterations Reveals Survival Loci [Genomics]

Analysis of TCGA copy number and clinical data identified candidate drivers within prognostic SCNAs.

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SIRT6 Loss Promotes PDAC Progression by Epigenetic Induction of LIN28B [Pancreatic Cancer]

SIRT6 loss cooperates with oncogenic KRAS to accelerate PDAC progression and metastasis.

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OLIG2 Mediates a Phenotypic Switch between Two Glioma Subtypes [Glioma]

Levels of the proneural-associated gene OLIG2 determine glioma phenotype and regulate cell growth.

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Oncogenic Splicing Factor U2AF35 Mutations Disrupt ATG7 mRNA Processing [Splicing]

U2AF35(S34F) transforms cells via altered ATG7 pre-mRNA processing, inducing an autophagy defect.

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Cancer Cell-Astrocyte Gap Junctions Promote Brain Metastasis Formation [Metastasis]

Carcinoma–astrocyte gap junctions drive growth and chemoresistance of brain metastases.

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An Analog-Sensitive Approach Reveals Specific Functions of PARP1 [Transcriptional Regulation]

PARP1 ADP ribosylates and inhibits NELF, enhancing Pol II pause release and transcription elongation.

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BGB-283 Deemed Effective in Phase I Study [News in Brief]

In a phase I trial, BGB-283, which targets the RAF family of proteins, was found to be safe and tolerable—and effective—in treating patients with a variety of solid tumors harboring mutations in BRAF, KRAS, and NRAS.

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Sdc1-coupled IGF1R promotes myeloma survival

Syndecan-1 (Sdc1/CD138) expression is linked to disease severity in multiple myeloma (MM), although the causal basis for this link remains unclear. Here we report that capture of the IGF1 receptor (IGF1R) by Sdc1 suppresses ASK1-dependent apoptosis in MM cells. Sdc1 binds two different fractions of IGF1R, one that is constitutively active and a second that is activated by IGF1 ligand. Notably, IGF1R kinase activity in both fractions is blocked by synstatinIGF1R (SSTN¬IGF1R), a peptide that inhibits IGF1R capture by Sdc1, as well as by a truncated peptide (SSTNIGF1R-T) that appears to be specific for MM cells. Mechanistically, we show that ASK1 is bound to active IGF1R and inhibited by Tyr and Ser83/Ser966 phosphorylation. When IGF1R engagement with Sdc1 is blocked by SSTN¬IGF1R, ASK1 becomes activated, and initiates JNK- and caspase-3-mediated apoptosis. In pharmacological tests, we find SSTN¬IGF1R is highly stable in human plasma and displays a half-life of 27 hr in mice, wherein it significantly reduces both the size and neovascularization of CAG myeloma tumor xenografts. Taken together, our results offer a preclinical proof of concept and mechanistic rationale for the exploration of SSTNIGF1R as an experimental therapeutic to dually attack MM tumor cell survival and tumor angiogenesis.

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MEF2D integrates environment signals to ZEB1 to promote EMT

Epithelial-mesenchymal transition (EMT) is an essential mechanism of metastasis including in colorectal cancer (CRC). While EMT processes are often triggered in cancer cells by their surrounding microenvironment, how EMT-relevant genes controlling these processes is not well understood. In multiple types of cancers, the transcription factor MEF2D has been implicated in cell proliferation, but its contributions to metastasis have not been addressed. Here we show MEF2D is overexpressed in clinical CRC tissues where its high expression correlates with metastatic process. Functional investigations showed that MEF2D promoted cancer cell invasion and EMT and that it was essential for certain microenvironment signals to induce EMT and metastasis in vivo. Mechanistically, MEF2D directly regulated transcription of the EMT driver gene ZEB1 and facilitated histone acetylation at the ZEB1 promoter. More importantly, MEF2D responded to various tumor microenvironment signals and acted as a central integrator transducing multiple signals to activate ZEB1 transcription. Overall, our results define a critical function for MEF2D in upregulating EMT and the metastatic capacity of CRC cells. Further, they offer new insights into how microenvironment signals activate EMT-relevant genes and deepen the pathophysiological significance of MEF2D, with potential implications for the prevention and treatment of metastatic CRC.

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Wnt/beta-catenin signaling in Ewing sarcoma

Ewing sarcomas are characterized by the presence of EWS/ETS fusion genes in the absence of other recurrent genetic alterations and mechanisms of tumor heterogeneity that contribute to disease progression remain unclear. Mutations in the Wnt/beta-catenin pathway are rare in Ewing sarcoma but the Wnt pathway modulator LGR5 is often highly expressed, suggesting a potential role for the axis in tumor pathogenesis. We evaluated beta-catenin and LGR5 expression in Ewing sarcoma cell lines and tumors and noted marked intra- and inter-tumor heterogeneity. Tumors with evidence of active Wnt/beta-catenin signaling were associated with increased incidence of tumor relapse and worse overall survival. Paradoxically, RNA sequencing revealed a marked antagonism of EWS/ETS transcriptional activity in Wnt/beta-catenin activated tumor cells. Consistent with this, Wnt/beta-catenin activated cells displayed a phenotype that was reminiscent of Ewing sarcoma cells with partial EWS/ETS loss of function. Specifically, activation of Wnt/beta-catenin induced alterations to the actin cytoskeleton, acquisition of a migratory phenotype and up regulation of EWS/ETS-repressed genes. Notably, activation of Wnt/beta-catenin signaling led to marked induction of tenascin C (TNC), an established promoter of cancer metastasis, and an EWS/ETS-repressed target gene. Loss of TNC function in Ewing sarcoma cells profoundly inhibited their migratory and metastatic potential. Our studies reveal that heterogeneous activation of Wnt/beta-catenin signaling in subpopulations of tumor cells contributes to phenotypic heterogeneity and disease progression in Ewing sarcoma. Significantly, this is mediated, at least in part, by inhibition of EWS/ETS fusion protein function that results in de-repression of metastasis-associated gene programs.

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c-Met activation promotes breast cancer brain metastasis

Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remains poorly understood. Here we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL-8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle which generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention.

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pS473-KAP1 regulates mitochondrial dynamics

Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here we report that KAP1 (TRIM28), a transcriptional co-adaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473-phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live cell imaging and molecular studies revealed that during the first 6-8 hr of glucose starvation mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473-phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress.

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BAFF and APRIL from activin A-treated DC stimulate T-cells

The members of the TGF-β superfamily play a key role in regulating developmental and homeostasis programs by controlling differentiation, proliferation, polarization and survival of different cell types. Although the role of TGF-β1 in inflammation and immunity is well evident, the contribution of other TGF-β family cytokines in the modulation of the antitumor immune response remains less documented. Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and up-regulates production of the TNF-α family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DC up-regulate proliferation and survival of T cells expressing the corresponding receptors - BAFF-R and TACI. In vivo, activin A stimulated DC demonstrate a significantly increased ability to induce tumor-specific CTL and inhibit the growth of melanoma and lung carcinoma, which relays on DC-derived BAFF and APRIL since knockdown of the BAFF and APRIL gene expression in activin A-treated DC blocks augmentation of their antitumor potential. Though systemic administration of activin A, BAFF or APRIL for the therapeutic purposes is not likely due to the pluripotent effects on malignant and non-malignant cells, our data open a novel opportunity for improving the efficacy of DC vaccines. In fact, a significant augmentation of the antitumor activity of DC pre-treated with activin A and the proven role of DC-derived BAFF and APRIL in the induction of antitumor immunity in vivo support this direction.

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Removal of MET kinase inhibition causes tumor rebound

MET oncogene amplification is emerging as a major mechanism of acquired resistance to EGFR-directed therapy in lung and colorectal cancers. Further, MET amplification predicts responsiveness to MET inhibitors currently in clinical trials. Among the anti-MET drugs available, ATP-competitive small molecule kinase inhibitors abrogate receptor autophosphorylation and downstream activation of ERK1/2 and AKT, resulting in cell cycle arrest. However, this anti-proliferative effect allows persistence of a pool of cancer cells that are quiescent but alive. Once the inhibition is removed, rebound activation of MET-driven cell proliferative pathways and tumor growth may occur, an adverse event observed frequently in clinical settings after drug discontinuation. Here we show that inhibitor withdrawal prompts receptor phosphorylation to levels higher than those displayed at steady-state and generates a rebound effect pushing quiescent cancer cells back into the cell cycle, both in vitro and in experimental tumor models in vivo. Mechanistically, we found that inhibitor treatment blocks MET endocytosis, causing a local increase in the number of receptors at the plasma membrane. Upon inhibitor washout, the receptor is readily re-phosphorylated. The initial phosphorylation is not only increased but also prolonged in duration due to downmodulation of a phosphatase-mediated MET negative feedback loop which accompanies receptor internalization. Notably, treatment with a MET therapeutic antibody that induces proteolytic cleavage of the receptor at the cell surface substantially prevents this rebound effect, providing a rationale to combine or alternate these mechanistically different types of MET-targeted therapy.

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Generating cancer stem cells from primary human astrocytes

Cancer stem-like cells (CSC) are thought to drive brain cancer but their cellular and molecular origins remain uncertain. Here we report the successful generation of induced CSC (iCSC) from primary human astrocytes through the expression of defined genetic factors. Combined transduction of four factors - myc, Oct-4, p53DD, and ras - induced efficient transformation of primary human astrocytes into malignant cells with powerful tumor-initiating capabilities. Notably, transplantation of 100 tranduced cells into nude mice was sufficient for tumor formation. The cells showed unlimited self-renewal ability with robust telomerase activities. In addition, they expressed typical glioma stem-like cell markers such as CD133, CD15 and CD90. Moreover, these cells could form spheres in culture and differentiate into neuron-like, astrocyte-like and oligodendrocyte-like cells. Lastly, they also displayed resistance to the widely used brain cancer drug temozolomide. These iCSC could provide important tools for studies of glioma biology and therapeutics development.

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DEP-1 promotes angiogenesis, permeability and metastasis

The protein tyrosine phosphatase PTPRJ/DEP-1 has been implicated in negative growth regulation in endothelial cells, where its expression varies at transitions between proliferation and contact inhibition. However, in the same cells, DEP-1 has also been implicated in VEGF-dependent Src activation, permeability and capillary formation, suggesting a positive role in regulating these functions. To resolve this dichotomy in vivo, we investigated post-natal angiogenesis and vascular permeability in a DEP-1 deficient mouse. In this study, we report that DEP-1 is required for Src activation and phosphorylation of its endothelial cell-specific substrate, VE-cadherin, after systemic injection of VEGF. Accordingly, VEGF-induced vascular leakage was abrogated in the DEP-1 deficient mice. Further, capillary formation was impaired in murine aortic tissue rings or Matrigel plugs infused with VEGF. In the absence of DEP-1, angiogenesis triggered by ischemia or during tumor formation was defective, which in the latter case was associated with reduced tumor cell proliferation and increased apoptosis. Macrophage infiltration was also impaired, reflecting reduced vascular permeability in the tumors or a possible cell autonomous effect of DEP-1. Consequently, the formation of spontaneous and experimental lung metastases was strongly decreased in DEP-1 deficient mice. In clinical specimens of cancer, less vascularized tumors exhibited lower microvascular expression of DEP-1. Altogether, our results established DEP-1 as an essential driver of VEGF-dependent permeability, angiogenesis, and metastasis, suggesting a novel therapeutic route to cancer treatment.

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DESI-MSI of esophageal lymph node metastases

Histopathological assessment of lymph node metastases (LNM) depends on subjective analysis of cellular morphology with inter-/intra-observer variability. In this study, LNM from esophageal adenocarcinoma was objectively detected using desorption electrospray ionization-mass spectrometry imaging (DESI-MSI). Ninety lymph nodes and their primary tumor biopsies from 11 esophago-gastrectomy specimens were examined and analyzed by DESI-MSI. Images from mass spectrometry and corresponding histology were co-registered and analyzed using multivariate statistical tools. The MSIs revealed consistent lipidomic profiles of individual tissue types found within lymph nodes. Spatial mapping of the profiles showed identical distribution patterns as per the tissue types in matched immunohistochemistry images. Lipidomic profile comparisons of LNM versus the primary tumor revealed a close association in contrast to benign lymph node tissue types. This similarity was used for the objective prediction of LNM in mass spectrometry images utilizing the average lipidomic profile of esophageal adenocarcinoma. The multivariate statistical algorithm developed for LNM identification demonstrated a sensitivity, specificity, positive predictive value and negative predictive value of 89.5, 100, 100 and 97.2 per-cent, respectively, when compared to gold-standard immunohistochemistry. DESI-MSI has the potential to be a diagnostic tool for peri-operative identification of LNM and compares favorably with techniques currently used by histopathology experts.

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Nano-Immune Conjugate for Cancer Therapy

Antibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody–chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954–64. ©2016 AACR.

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Omentin as a Novel Biomarker for Colorectal Cancer Risk

Omentin is a novel biomarker shown to exert metabolic, inflammatory, and immune-related properties and thereby could be implicated in the risk of colorectal cancer. So far, the association between omentin and colorectal cancer risk has not been evaluated in prospective cohort studies. We investigated the association between prediagnostic plasma omentin concentrations and risk of colorectal cancer in a case–cohort comprising 251 incident colorectal cancer cases diagnosed over a mean follow-up time of 10.4 years and 2,295 persons who remained free of cancer in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Hazard ratios as a measure of relative risk (RR) and 95% confidence intervals (CI) were computed using a Prentice-modified Cox regression. In a multivariable model adjusted for age, sex, education, dietary and lifestyle factors, body mass index (BMI), and waist circumference, higher omentin concentrations were associated with a higher colorectal cancer risk (RRcontinuously per doubling of omentin concentrations = 1.98; 95% CI, 1.45–2.73). Additional adjustment for metabolic biomarkers, including glycated hemoglobin, high-density lipoprotein cholesterol, and C-reactive protein, did not alter the results. In stratified analyses, the positive association between omentin and colorectal cancer risk was retained in participants with BMI < 30 (RRcontinuously per doubling of omentin concentrations = 2.26; 95% CI, 1.57–3.27), whereas among participants with BMI ≥ 30 no association was revealed (RRcontinuously per doubling of omentin concentrations = 1.07; 95% CI, 0.63–1.83; Pinteraction = 0.005). These novel findings provide the first lines of evidence for an independent association between prediagnostic omentin concentrations and colorectal cancer risk and suggest a potential interaction with the adiposity state of the individual. Cancer Res; 76(13); 3862–71. ©2016 AACR.

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ErbB2 and Breast Cancer

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RAR{gamma} Functions as a Tumor Suppressor in Colorectal Cancer

The Hippo–Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARγ as a regulator of the Hippo–Yap pathway in colorectal tumorigenesis and metastasis. RARγ is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARγ drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo. Mechanistically, RARγ controlled Hippo–Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARγ expression correlated with overall survival outcomes and expression of critical Hippo–Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARγ as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo–Yap pathway, with potential implications for new approaches to colorectal cancer therapy. Cancer Res; 76(13); 3813–25. ©2016 AACR.

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p53 and DNA Damage

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Enhanced Antiproliferative Effects of Mito-Metformin

Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP+). In particular, the analogue Mito-Met10, synthesized by attaching TPP+ to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito-Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904–15. ©2016 AACR.

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OncomiR or Tumor Suppressor? Duplicity of miRNAs in Cancer

MicroRNAs (miRNA) are short, noncoding RNAs whose dysregulation has been implicated in most, if not all, cancers. They regulate gene expression by suppressing mRNA translation and reducing mRNA stability. To this end, there is a great deal of interest in modifying miRNA expression levels for the treatment of cancer. However, the literature is fraught with inconsistent accounts as to whether various miRNAs are oncogenic or tumor suppressive. In this review, we directly examine these inconsistencies and propose several mechanisms to explain them. These mechanisms include the possibility that specific miRNAs can simultaneously produce competing oncogenic and tumor suppressive effects by suppressing both tumor suppressive mRNAs and oncogenic mRNAs, respectively. In addition, miRNAs can modulate tumor-modifying extrinsic factors, such as cancer-immune system interactions, stromal cell interactions, oncoviruses, and sensitivity to therapy. Ultimately, it is the balance between these processes that determines whether a specific miRNA produces a net oncogenic or net tumor suppressive effect. A solid understanding of this phenomenon will likely prove valuable in evaluating miRNA targets for cancer therapy. Cancer Res; 76(13); 3666–70. ©2016 AACR.

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The Role of Mislocalized p27 in Osteosarcoma

Metastatic progression is the major cause of death in osteosarcoma, the most common bone malignancy in children and young adults. However, prognostic biomarkers and efficacious targeted treatments for metastatic disease remain lacking. Using an immunoproteomic approach, we discovered that autoantibodies against the cell-cycle kinase inhibitor p27 (KIP1, CDKN1B) were elevated in plasma of high-risk osteosarcoma patients. Using a large cohort of serum samples from osteosarcoma patients (n = 233), we validated that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival (P < 0.05). Immunohistochemical analysis also showed that p27 was mislocalized to the cytoplasm in the majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 promoted migration and invasion of osteosarcoma cells, whereas shRNA-mediated gene silencing suppressed these effects. In addition, mutations at the p27 phosphorylation sites S10 or T198, but not T157, abolished the migratory and invasive phenotypes. Furthermore, the development of pulmonary metastases increased in mice injected with cells expressing cytoplasmic p27 compared with an empty vector control. Collectively, our findings support further investigation of p27 as a potential prognostic biomarker and therapeutic target in osteosarcoma cases exhibiting aberrant p27 subcellular localization. Cancer Res; 76(13); 4002–11. ©2016 AACR.

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Research Priorities in Cancer-Related Thrombosis

The risk for venous thromboembolism (VTE) is increased in cancer and particularly with chemotherapy, and it portends poorer survival among patients with cancer. However, many fundamental questions about cancer-associated VTE, or Trousseau syndrome, remain unanswered. This report summarizes the proceedings of a working group assembled by the NCI and NHLBI in August 2014 to explore the state of the science in cancer-associated VTE, identify clinically important research gaps, and develop consensus on priorities for future research. Representing a convergence of research priorities between the two NIH Institutes, the workshop addressed epidemiologic, basic science, clinical, and translational issues in cancer-associated VTE. Cancer Res; 76(13); 3671–5. ©2016 AACR.

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MIF-miR-301b-NR3C2 Axis in PDAC Aggressiveness

Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally, and clinically characterized using cell lines, a genetically engineered mouse model, and PDAC patient cohorts. Here, we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF–mir-301b–NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof of principle for candidate therapies to target a newly described MIF–miR-301b–NR3C2 signaling axis for PDAC management. Cancer Res; 76(13); 3838–50. ©2016 AACR.

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Dasatinib/ARID1A Synthetic Lethality in OCCC

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G₁–S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1–13. ©2016 AACR.

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The Cancer Moonshot Summit: Reaching New Heights

Yesterday, I attended the Cancer Moonshot Summit, hosted by Vice President Joe Biden and Dr. Jill Biden, held at Howard University in Washington, DC. In addition to this Summit, there were more than 250 regional summits happening simultaneously, making this truly a national event.

The summits were an opportunity for the Vice President to speak directly to the American public and ask them to "convene under the national charge of doubling the rate of progress toward ending cancer as we know it."

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Issue Information - Ed Board

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The Distress Thermometer for screening for severe fatigue in newly diagnosed breast and colorectal cancer patients

Abstract

Objectiv

Internationally, the Distress Thermometer and associated Problem List are increasingly used in oncology as screening tools for psychological distress. Cancer-related fatigue is common but often overlooked in clinical practice. We examined if severe fatigue in cancer patients can be identified with the fatigue item of the Problem List.

Methods

Newly diagnosed breast (N = 334) and colorectal (N = 179) cancer patients were screened for severe fatigue, which was defined as having a positive score on the fatigue item of the Problem List. The Fatigue Severity subscale of the Checklist Individual Strength was used as gold standard measure for severe fatigue. Results: In total, 78% of breast cancer patients and 81% of colorectal cancer patients were correctly identified with the fatigue item. The sensitivity was 89% in breast cancer patients and 91% in colorectal cancer patients. The specificity was 75% in breast cancer patients and 77% in colorectal cancer patients. The positive predictive value was 53% in breast cancer patients and 64% in colorectal cancer patients, whereas the negative predictive value was 95% in both tumor types.

Conclusions

The fatigue item of the Problem List performs satisfactorily as a quick screening tool for severe fatigue. However, a positive screen should be followed up with a more thorough assessment of fatigue, i.e., a questionnaire with a validated cut-off point. Given time pressure of clinicians, this already implemented and brief screening tool may prevent severe fatigue from going undetected in clinical practice.

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Cancer disclosure–Account from a pediatric oncology ward in egypt

Abstract

Objective

Informing the child about his/her diagnosis and treatment plan is essential; research has shown that it is related to the patient's quality of life and adherence to medication.

Methods

For 7 months during 2008 (February – September), two study-specific questionnaires were constructed and administered to 304 parents of children diagnosed with cancer at the Children's Cancer Hospital, Egypt (CCHE).

Results

Among the 313 eligible parents of children diagnosed with cancer, 304 (97%) answered the first, and 281 (92%) answered the second questionnaire. We found that nearly three quarters (72%) of the parents had their child's cancer diagnosis communicated by the physician. Among the 72%, the rate of the children present with the parent or parents during the disease disclosure conversation was 39 percent (n = 85/219). The majority of the children were in the age group 5–18 years (55%).

Conclusions

Our findings indicate that cancer disclosure at the Children's Cancer Hospital is to a certain degree common, yet even when disclosure does take place; it is mainly in the absence of the child. Moreover, the information provided during the conversation may not be fully comprehended by the parent or the child due to the physician's misleading use of terms when disclosing the disease. Therefore, better practice should be developed for disease disclosure, and proper communication should be established between the patients and the provider; patient autonomy should also have an influence in the clinical practice.

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Multiparametric evaluation of preoperative MRI in early stage breast cancer: prognostic impact of peri-tumoral fat

Abstract

Purpose

Obesity is associated with adverse outcomes in breast cancer patients. Fat-specific cytokines (adipokines) have been proposed as key drivers of breast cancer progression, invasion, and metastasis. We aimed at assessing correlations between peri-tumoral fat, quantified on magnetic resonance imaging (MRI) and pathologic factors potentially impacting therapy recommendations.

Methods

We retrospectively reviewed records of 63 patients with early stage breast cancer who underwent preoperative MRI imaging using appropriately weighted series for breast and tumor contouring. Fat volumes were generated through voxel intensity filtering. The peri-tumoral region was defined as the intersection of a 1-cm spherical extension around the tumor and the breast contour. Peri-tumoral fat was defined as the fraction of a fat content in this volume. Surgical pathology records were used to extract clinical data. Statistical analyses were conducted using Pearson and Spearman correlation coefficients.

Results

Among reviewed patients, 45 had T1 tumors (1.22 ± 0.85 cm diameter) and 18 had T2 tumors (2.08 ± 1.06 cm). Axillary lymph nodes were dissected in 31 and positive in 17 patients analyzed. Peri-tumoral fat ratio ranged between 25 and 99 %. Peri-tumoral fat ratio significantly correlated with the nodal-positive ratio of positive axillary lymph nodes (r = 0.532). Peri-tumoral fat ratio demonstrated optimally prominent correlation among obese patients upon body mass index categorical stratification.

Conclusions

In women with early stage breast cancer, peri-tumoral fat correlates positively with the ratio of pathologically involved axillary nodes. This work highlights a novel method for quantitating peri-tumoral fat content. Preoperative breast MRI may be utilized to predict extent of axillary disease.

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Blood Transfusion is Associated with Increased Perioperative Morbidity and Adverse Oncologic Outcomes in Bladder Cancer Patients Receiving Neoadjuvant Chemotherapy and Radical Cystectomy

Abstract

Purpose

Perioperative blood transfusion (PBT) has been inconsistently associated with adverse outcomes. Bladder cancer patients are unique as they frequently undergo neoadjuvant chemotherapy (NAC) with resulting immunosuppression, which may be exacerbated by transfusion-related immunomodulation. We examined the effect of leukoreduced PBT on oncologic outcomes and perioperative morbidity in radical cystectomy (RC) patients who received NAC, quantifying exposure with a novel dose-index variable.

Methods

The Johns Hopkins Radical Cystectomy database was queried for patients who had undergone NAC followed by RC from 2010 to 2013. Overall, 119 patients had available PBT and survival data. A multivariable Cox model evaluated risk factors, including pathologic stage, Charlson Comorbidity Index, age, race, year of surgery, surgical margin status, PBT, and preoperative hemoglobin for bladder cancer-specific survival (CSS) and overall survival (OS). Logistic regression models determined factors that were independently associated with perioperative morbidity.

Results

Median follow-up was 7.8 months (range 0.2–41.8), and during follow-up there were 25 deaths and 21 cancer deaths. PBT significantly predicted OS (hazard ratio [HR] 1.26, 95 % confidence interval [CI] 1.07–1.49; p = 0.005), CSS (HR 1.32, 95 % CI 1.11–1.57; p = 0.002), and morbidity (odds ratio [OR] 1.67, 95 % CI 1.26–2.21; p = 0.004) in univariate analyses. In multivariable models, PBT was significantly associated with morbidity (OR 1.77, 95 % CI 1.30–2.39; p = 0.0002), but not OS or CSS. Intraoperative transfusion was associated with decreased OS and CSS, and increased morbidity, whereas postoperative transfusion was only associated with increased morbidity.

Conclusions

Intraoperative blood transfusion was associated with increased perioperative morbidity and worsened OS and CSS in patients undergoing RC who had NAC. Although PBT may be life-saving in certain patients, a restrictive transfusion strategy may improve outcomes.

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Genetic Determinants of Nipple Aspiration Fluid Yield

Abstract

Purpose

Nipple aspiration fluid (NAF) is a non-invasively-acquired biosample that can provide a window into the breast environment, but NAF yield is highly variable. Its determinants must be better understood for studies of breast cancer risk. The wet earwax phenotype was identified as one determinant of NAF yield in the 1970s, and is linked to single nucleotide polymorphisms (SNPs) in the ATP-binding cassette transporter gene ABCC11. We have investigated this, as well as SNPs in the prolactin (PRL) and prolactin receptor (PRLR) genes, in relation to NAF yield.

Methods

DNA was extracted from white blood cells of 557 NAF yielders and 359 non-yielders, and was used to genotype ABCC11 (rs17822931), PRL (rs849870, rs849872, rs849886, rs2244502, rs1341239), and PRLR (rs37364, rs34024951, rs1610218, rs9292575, rs7718468) using Taqman genotyping assay. The association between NAF yield and each single SNP was analyzed using logistic regression adjusting for age, race, and menopausal status.

Results

ABCC11 rs17822931 showed a negative association with NAF yield [odds ratio (OR) 0.66, 95 % confidence interval (CI) 0.49–0.88; p = 0.004]. The PRL rs849870 and the haplotype combination with other SNPs showed a marginal association with NAF yield. In addition, the years since last birth also showed negative association with NAF yielding (OR 0.98, 95 % CI 0.96–0.99; p = 0.001). The combination of the years since last birth with ABCC11 SNP revealed significant interaction between reproductive factor and genetic factor.

Conclusions

Our results confirmed the association between NAF yield and earwax phenotype through ABCC11 genotype. Combined with the recency of last birth, ABCC11 genotype should be considered in the design of studies utilizing NAF as a biosample.

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Is Extended Lymphadenectomy Needed for Elderly Patients with Gastric Adenocarcinoma?

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Prostate Health Index and %p2PSA Predict Aggressive Prostate Cancer Pathology in Chinese Patients Undergoing Radical Prostatectomy

Abstract

Purpose

To investigate the performance of prostate health index (PHI) and percentage prostate-specific antigen (PSA) isoform [−2]proPSA (%p2PSA) in predicting pathologic outcomes at radical prostatectomy (RP) in a Chinese population.

Methods

We performed a prospective study of 135 prostate cancer patients with RP. The accuracy of preoperative %p2PSA (= p2PSA/free PSA) and PHI [= (p2PSA/free PSA) × √PSA] in predicting pathologic outcomes of RP including pT3 disease, pathologic Gleason score (pGS) ≥7, Gleason score (GS) upgrade at RP, tumor volume >0.5 ml, and Epstein criteria for significant tumor were calculated using multivariate analyses and area under the curve. The base model in multivariate analysis included age, PSA, abnormal digital rectal examination, and biopsy GS.

Results

PHI was significantly higher in patients with pT3 or pGS ≥ 7 (p < 0.001), pT3 disease (p = 0.001), pGS ≥ 7 (p < 0.001), GS upgrade (p < 0.001), tumor volume >0.5 ml (p < 0.001), and Epstein criteria for significant tumor (p = 0.001). %p2PSA was also significantly higher in all the above outcomes. The risk of pT3 or pGS ≥ 7 was 16.1 % for PHI < 35 and 60.8 % for PHI > 35 (sensitivity 84.2 %, specificity of 60.3 %), and the risk of tumor volume >0.5 ml was 25.5 % for PHI < 35 and 72.6 % for PHI > 35 (sensitivity 79.1 %, specificity 67.2 %). In multivariate analysis, adding %p2PSA or PHI to the base model significantly improved the accuracy (area under the curve) in predicting pT3 or pGS ≥ 7 (by 7.2–7.9 %), tumor volume >0.5 ml (by 10.3–12.8 %), and Epstein criteria for significant tumor (by 13.9–15.9 %). Net clinical benefit was observed in decision curve analyses for prediction of both tumor volume >0.5 ml, and pT3 or pGS ≥ 7.

Conclusions

Both PHI and %p2PSA predict aggressive and significant pathologies in RP in Chinese men. This enabled identification of nonaggressive cancers for better counseling on active surveillance or treatment.

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Survival Following Resection of Intra- and Extra-Hepatic Metastases from Colorectal Cancer: A Phase II Trial

Abstract

Purpose

Metastasectomy for intrahepatic metastases (IHM) from colorectal cancer (CRC) provides excellent 5-year overall survival (OS). Presence of extrahepatic metastases (EHM) has been a historic contraindication to surgery. Due to improved safety of hepatectomy, there is growing interest in multisite metastasectomy for IHM and EHM. The objective of this study was to evaluate the results of metastasectomy for patients with IHM and EHM from CRC.

Methods

A phase II study of metastasectomy for both IHM and EHM from CRC. Eligible patients with any number of IHM and up to three EHM foci, resectable with RO intent, were offered metastasectomy. Clinical, survival, and quality of life (QoL) data were analyzed using standard statistical methods.

Results

Twenty-six patients were enrolled with a median age of 58 (range 32–84) years; 14/26 (54 %) presented with synchronous disease. The lung was the most common EHM site (13/26, 50 %). Protocol surgery was completed in 20/26 (77 %), including 12/26 (46 %) planned sequential resections. Major morbidity and perioperative mortality were 5/26 (19 %) and 1/26 (4 %), respectively. The QoL decline appeared to be transient. All QoL domains returned to baseline by 1-year posttreatment. The median recurrence-free survival (RFS) was 5 months by intent-to-treat analysis. The median OS from the time of CRC diagnosis and metastasectomy were 50 and 38 months (3-year OS 80 and 53 %), respectively.

Conclusions

Complete metastasectomy of multisite CRC is safe, but disease recurs in the majority of patients. Data suggest that aggressive multisite metastasectomy may provide OS benefit for selected patients.

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Training Primary Health Professionals in Breast Cancer Prevention: Evidence and Experience from Mexico

Abstract

To analyze the key successful factors of a national educational strategy for early breast cancer detection developed in Mexico for primary health care personnel from 2008 to 2014, an educational strategy to train physicians, nurses, health promoters, and medical students from local ministries of health with a competency-based approach was developed and implemented using diverse educational modalities, face-to-face, blended, and a massive open online course (MOOC). Formative and summative evaluations were used during the implementation of the course. A total of 19,563 health professionals were trained from 2008 to 2014. The graduation rate, an average of all educational modalities, was 91 %, much higher than those previously reported in the literature. The factors that might have influenced this success were (1) the training strategy, which was designed according to the characteristics and specific needs of the target groups; (2) the political will and commitment of the country's health authorities; (3) the technological and educational models used; and (4) the punctual follow-up of participants. This study shows that carefully designed educational interventions can improve service professionals' competencies and that regardless of the modality, face-to-face, blended learning, or MOOC, high graduation rates can be achieved. Further evaluation is required to demonstrate that the competencies remained in all target groups after 6 months of the intervention and that the women served by the trained personnel were provided accurate information and timely diagnoses of breast cancer.

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Reflections: Spirituality and Cancer Researchers

Abstract

Spirituality is increasingly acknowledged as an essential element to consider within care for cancer and other chronic health conditions. As our colleagues in frontline healthcare roles integrate these concepts into their professional practice, it seems timely for the cancer research community to reflect on the place of spirituality within our work. This reflections article discusses challenges and opportunities for researchers considering spirituality in their own work roles and within broader discussions about health needs, care and research agendas.

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Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis

Systemic mastocytosis is a myeloid neoplasm that is caused by the accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. The KIT D816V mutation, which is detected in approximately 90% of patients, encodes a constitutively activated receptor tyrosine kinase that drives…

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Midostaurin in Advanced Systemic Mastocytosis

To the Editor: Advanced systemic mastocytosis carries a poor prognosis. Midostaurin, an inhibitor of tyrosine kinases, targets KIT mutants associated with mastocytosis. The French National Reference Center for Mastocytosis (CEREMAST) conducted a prospective survey of patients with mastocytosis who…

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Use of glucosamine and chondroitin supplements in relation to risk of colorectal cancer: Results from the Nurses' Health Study and Health Professionals Follow-up Study

Abstract

Recent epidemiologic evidence has emerged to suggest that use of glucosamine and chondroitin supplements may be associated with reduced risk of colorectal cancer (CRC). We therefore evaluated the association between use of these non-vitamin, non-mineral supplements and risk of CRC in two prospective cohorts, the Nurses' Health Study and Health Professionals Follow-up Study. Regular use of glucosamine and chondroitin was first assessed in 2002 and participants were followed until 2010, over which time 672 CRC cases occurred. Cox proportional hazards regression was used to estimate relative risks (RRs) within each cohort, and results were pooled using a random effects meta-analysis. Associations were comparable across cohorts, with a RR of 0.79 (95% CI: 0.63-1.00) observed for any use of glucosamine and a RR of 0.77 (95% CI: 0.59-1.01) observed for any use of chondroitin. Use of glucosamine in the absence of chondroitin was not associated with risk of CRC, whereas use of glucosamine + chondroitin was significantly associated with risk (RR: 0.77; 95% CI: 0.58-0.999). The association between use of glucosamine + chondroitin and risk of CRC did not change markedly when accounting for change in exposure status over follow-up (RR: 0.75; 95% CI: 0.58-0.96), nor did the association significantly vary by sex, aspirin use, body mass index, or physical activity. The association was comparable for cancers of the colon and rectum. Results support a protective association between use of glucosamine and chondroitin and risk of CRC. Further study is needed to better understand the chemopreventive potential of these supplements. This article is protected by copyright. All rights reserved.

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Comparison of outcomes after umbilical cord blood and unmanipulated haploidentical hematopoietic stem cell transplantation in children with high-risk acute lymphoblastic leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for children with high-risk acute lymphoblastic leukemia (ALL). Human leukocyte antigen (HLA)-haploidentical HSCT (haplo-HSCT) or umbilical cord blood transplantation (UCBT) are both important alternative sources of stem cells for those without an HLA-identical sibling donor or unrelated matched donor. We aimed to compare the therapeutic effects of single UCBT and unmanipulated haplo-HSCT in high-risk ALL children (n = 129). Hematopoietic recovery was significantly faster in haplo-HSCT recipients than in UCBT recipients. The 2-year cumulative incidences of relapse in the haplo-HSCT and UCBT groups were 16.1% and 24.1%, respectively (P = 0.169). The 2-year cumulative incidences of non-relapse mortality in the haplo-HSCT and UCBT groups were 12.8% and 18.8%, respectively (P = 0.277). The 2-year probabilities of overall survival in the haplo-HSCT and UCBT groups were 82.0% and 69.6%, respectively (P = 0.071), and the 2-year probability of disease-free survival in the haplo-HSCT group was higher than in the UCBT group (71.0% vs. 57.2%, P = 0.040). However, several variables (such as leukocyte count and cytogenetics at diagnosis) were different between the groups, and a possible center effect should also be considered. In addition, only mild and moderate chronic GVHD was associated with significantly improved survival compared to those without chronic GVHD in multivariate analysis. Thus, our results show that both unmanipulated haplo-HSCT and UCBT are valid for high-risk ALL children lacking a HLA matched donor, and both strategies expand the donor pool for children in need. This article is protected by copyright. All rights reserved.

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A model to predict the risk of lethal nasopharyngeal necrosis after re-irradiation with intensity-modulated radiotherapy in nasopharyngeal carcinoma patients

Abstract

Background

For patients with nasopharyngeal carcinoma (NPC) who undergo re-irradiation with intensity-modulated radiotherapy (IMRT), lethal nasopharyngeal necrosis (LNN) is a severe late adverse event. The purpose of this study was to identify risk factors for LNN and develop a model to predict LNN after radical re-irradiation with IMRT in patients with recurrent NPC.

Methods

Patients who underwent radical re-irradiation with IMRT for locally recurrent NPC between March 2001 and December 2011 and who had no evidence of distant metastasis were included in this study. Clinical characteristics, including recurrent carcinoma conditions and dosimetric features, were evaluated as candidate risk factors for LNN. Logistic regression analysis was used to identify independent risk factors and construct the predictive scoring model.

Results

Among 228 patients enrolled in this study, 204 were at risk of developing LNN based on risk analysis. Of the 204 patients treated, 31 (15.2%) developed LNN. Logistic regression analysis showed that female sex (P = 0.008), necrosis before re-irradiation (P = 0.008), accumulated total prescription dose to the gross tumor volume (GTV) ≥145.5 Gy (P = 0.043), and recurrent tumor volume ≥25.38 cm³ (P = 0.009) were independent risk factors for LNN. A model to predict LNN was then constructed that included these four independent risk factors.

Conclusions

A model that includes sex, necrosis before re-irradiation, accumulated total prescription dose to GTV, and recurrent tumor volume can effectively predict the risk of developing LNN in NPC patients who undergo radical re-irradiation with IMRT.

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Protein stability regulators screening assay (Pro-SRSA): protein degradation meets the CRISPR–Cas9 library

Abstract

The regulation of protein stability is a fundamental issue for biophysical processes, but there has not previously been a convenient and unbiased method of identifying regulators of protein stability. However, as reported in the article entitled "A genome-scale CRISPR–Cas9 screening method for protein stability reveals novel regulators of Cdc25A," recently published in Cell Discovery, our team developed a protein stability regulators screening assay (Pro-SRSA) by combining the whole-genome clustered regularly interspaced short palindromic repeats Cas9 (CRISPR–Cas9) library with a dual-fluorescence-based protein stability reporter and high-throughput sequencing to screen for regulators of protein stability. Based on our findings, we are confident that this efficient and unbiased screening method at the genome scale will be used by researchers worldwide to identify regulators of protein stability.

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Low expression of centrosomal protein 78 (CEP78) is associated with poor prognosis of colorectal cancer patients

Abstract

Background

Centrosomal protein 78 (CEP78) has been characterized as a component of the centrosome required for the regulation of centrosome-related events during the cell cycle, but its role in human cancers remains unclear. This study aimed to investigate the role and the clinical value of CEP78 in colorectal cancer (CRC).

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to examine CEP78 expression in CRC tissues and adjacent noncancerous tissues. The association between CEP78 expression and clinical outcomes of CRC patients was determined. The effect of CEP78 on cell growth was examined in vitro by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, colony formation, and flow cytometry assays and in vivo using a nude mouse model.

Results

The expression level of CEP78 was significantly lower in tumor tissues than in the adjacent normal tissues (P < 0.01). Low CEP78 expression was significantly associated with poor differentiation (P = 0.003), large tumor size (P = 0.017), lymphatic metastasis (P = 0.034), distant metastasis (P = 0.029), and advanced stage (P = 0.011). Kaplan–Meier analysis indicated that patients with low CEP78 expression had shorter survival than those with high CEP78 expression (P < 0.01). Overexpression of CEP78 in CRC cells significantly reduced cell viability and colony formation in vitro and halted tumor growth in vivo. Further study showed that CEP78 reintroduction in CRC cells resulted in G₂/M phase arrest rather than cell apoptosis.

Conclusions

CEP78 might function as a tumor suppressor and serve as a novel prognostic marker in CRC.

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Palliative primary tumor resection provides survival benefits for the patients with metastatic colorectal cancer and low circulating levels of dehydrogenase and carcinoembryonic antigen

Abstract

Background

It remains controversial whether palliative primary tumor resection (PPTR) can provide survival benefits to the patients with metastatic colorectal cancer (mCRC) who have unresectable metastases. The aim of this study was to evaluate whether PPTR could improve the survival of patients with mCRC.

Methods

We conducted a retrospective study on consecutive mCRC patients with unresectable metastases who were diagnosed at Sun Yat-sen University Cancer Center in Guangzhou, Guangdong, China, between January 2005 and December 2012. Overall survival (OS) and progression-free survival (PFS) after first-line chemotherapy failure were compared between the PPTR and non-PPTR patient groups.

Results

A total of 387 patients were identified, including 254 who underwent PPTR and 133 who did not. The median OS of the PPTR and non-PPTR groups was 20.8 and 14.8 months (P < 0.001), respectively. The median PFS after first-line chemotherapy was 7.3 and 4.8 months (P < 0.001) in the PPTR and non-PPTR groups, respectively. A larger proportion of patients in the PPTR group (219 of 254, 86.2%) showed local progression compared with that of patients in the non-PPTR group (95 of 133, 71.4%; P < 0.001). Only patients with normal lactate dehydrogenase (LDH) levels and with carcinoembryonic antigen (CEA) levels <70 ng/mL benefited from PPTR (median OS, 22.2 months for the PPTR group and 16.2 months for the non-PPTR group; P < 0.001).

Conclusions

For mCRC patients with unresectable metastases, PPTR can improve OS and PFS after first-line chemotherapy and decrease the incidence of new organ involvement. However, PPTR should be recommended only for patients with normal LDH levels and with CEA levels <70 ng/mL.

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Combination therapy in cancer: effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

Abstract

Validated preclinical studies have provided evidence that anti-vascular endothelial growth factor (VEGF) compounds enhance the activity of subsequent antitumor therapy, but the mechanism of this potentiation is far from clear. The most widespread explanation is enhanced delivery of therapeutics due to vascular remodeling, lower interstitial pressure, and increased blood flow. While the antiangiogenic effects on vascular morphology have been fairly consistent in both preclinical and clinical settings, the improvement of tumor vessel function is debated. This review focuses on the effect of anti-VEGF therapy on tumor microenvironment morphology and functions, and its therapeutic benefits when combined with other therapies. The uptake and spatial distribution of chemotherapeutic agents into the tumor after anti-VEGF are examined.

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Fish-Derived Omega-3 Fatty Acids and Prostate Cancer: A Systematic Review

Background. The use of natural health products in prostate cancer (PrCa) is high despite a lack of evidence with respect to safety and efficacy. Fish-derived omega-3 fatty acids possess anti-inflammatory effects and preclinical data suggest a protective effect on PrCa incidence and progression; however, human studies have yielded conflicting results. Methods. A search of OVID MEDLINE, Pre-MEDLINE, Embase, and the Allied and Complementary Medicine Database (AMED) was completed for human interventional or observational data assessing the safety and efficacy of fish-derived omega-3 fatty acids in the incidence and progression of PrCa. Results. Of 1776 citations screened, 54 publications reporting on 44 studies were included for review and analysis: 4 reports of 3 randomized controlled trials, 1 nonrandomized clinical trial, 20 reports of 14 cohort studies, 26 reports of 23 case-control studies, and 3 case-cohort studies. The interventional studies using fish oil supplements in patients with PrCa showed no impact on prostate-specific antigen levels; however, 2 studies showed a decrease in inflammatory or other cancer markers. A small number of mild adverse events were reported and interactions with other interventions were not assessed. Cohort and case-control studies assessing the relationship between dietary fish intake and the risk of PrCa were equivocal. Cohort studies assessing the risk of PrCa mortality suggested an association between higher intake of fish and decreased risk of prostate cancer–related death. Conclusions. Current evidence is insufficient to suggest a relationship between fish-derived omega-3 fatty acid and risk of PrCa. An association between higher omega-3 intake and decreased PrCa mortality may be present but more research is needed. More intervention trials or observational studies with precisely measured exposure are needed to assess the impact of fish oil supplements and dietary fish-derived omega-3 fatty acid intake on safety, PrCa incidence, treatment, and progression.

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p27 KIP1 and PTEN cooperate in myeloproliferative neoplasm tumor suppression in mice

Abstract

PTEN acts as a phosphatase for PIP3 and negatively regulates the PI3K/AKT pathway, and p27^KIP1 is a cyclin-dependent kinase inhibitor that regulates the G1 to S-phase transition by binding to and regulating the activity of cyclin-dependent kinases. Genetic alterations of PTEN or CDKN1B (p27^KIP1) are common in hematological malignancies. To better understand how mutations in these two genes might cooperate in leukemogenesis, we inactivated both genes in the hematological compartment in mice. Here, we show that the combined inactivation of Pten and Cdkn1b results in a more severe myeloproliferative neoplasm phenotype associated with lower hemoglobin, enlarged spleen and liver, and shorter lifespan compared to inactivation of Pten alone. More severe anemia and increased myeloid infiltration and destruction of the spleen contributed to the earlier death of these mice, and elevated p-AKT, cyclin D1, and cyclin D3 might contribute to the development of this phenotype. In conclusion, PTEN and p27^KIP1 cooperate in tumor suppression in the hematological compartment.

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First-line therapy in HER2 positive metastatic breast cancer: is the mosaic fully completed or are we missing additional pieces?

Abstract

The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for women with early-stage and advanced HER2-positive breast cancer (BC).

HER-2 targeted therapies represent a major step forward in achieving the goal of delivering individualized targeted therapy for BC, and trastuzumab was the first anti-HER-2 strategy to be approved for treatment of HER-2 positive BC.

This review discusses the treatment of metastatic HER2-positive BC and describes efficacy and safety of novel anti-HER2 target therapies in first-line metastatic settings and the future challenges include refining such treatments, reducing toxicity and simultaneously developing innovative therapies. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.

In the next future will be possible to use an ample armamentarium of combination therapies directed against HER2 and key signaling components integrated in the HER network. This approach will allow clinicians to tailor the management of the individual patient on the basis of tumor- specific biomarker profiles.

There is an urgent need for prospective biomarker-driven trials to identify patients for whom targeting is cost-effective.

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