Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but it is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities. Cancer Res; 76(4); 796–804. ©2015 AACR.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Κυριακή 14 Φεβρουαρίου 2016
Metabolic Biomarkers for Ovarian High-Grade Serous Ovarian Carcinomas
Imaging Tumor Hypoxia In Vivo with Oxygen-Enhanced MRI
There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast–enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic. Cancer Res; 76(4); 787–95. ©2015 AACR.
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High-Throughput Ex Vivo Transposon Mutagenesis
Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development. Cancer Res; 76(4); 773–86. ©2015 AACR.
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3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal cells but Sensitivity to Histone Deacetylase Inhibitors
There is a growing recognition that current pre-clinical models do not reflect the tumor microenvironment in cellular, biological and biophysical content and this may have a profound effect on drug efficacy testing especially in the era of molecular-targeted agents. Here we describe a method to directly embed low passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by co-culture with patient-derived cancer-associated fibroblasts (CAFs). A range of solid tumors proved amenable to growth and pharmacological testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standards-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers.
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Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience
By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a "matched" versus "unmatched" therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a "matched" therapy; 93 (26.8%) with an "unmatched" therapy. More patients in the matched group achieved [SD≥6 months/PR/CR] (34.5% versus 16.1%, (P≤0.020 multivariable or propensity score methods). Matched patients had a longer median PFS (4.0 versus 3.0 months, P=0.039 in Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P=0.009); however, this shortening was not observed in the matched patients (P=0.595). Furthermore, 45.3% of the matched patients (24/53) had a PFS2/PFS1 ratio ≥1.3 compared to 19.3% of patients (11/57) in the unmatched group (P=0.004 univariable and P≥0.057 in multivariable/propensity score analysis). Patients with a "matching-score" (the number of matched drugs divided by the number of aberrations; unmatched patients had a score of zero) >0.2 had a median overall survival of 15.7 months compared to 10.6 months when their matching-score was ≤0.2, (P=0.040 in Cox regression model). Matched versus unmatched patients had higher rates of SD≥6 months/PR/CR and longer PFS, and improvement in OS correlated with a higher matching score in multivariable analysis.
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Pre-Clinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies
Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side effect profile. In this current study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo. We successfully demonstrated decreased cellular proliferation, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should further be investigated as a developing therapeutic in these rare and difficult to treat, pediatric solid organ tumors.
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Applying Small Molecule Signal Transducer and Activator of Trancription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics
Constitutively activated Signal Transducer and Activator of Transcription 3 (STAT3) protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low µM range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nM by SPR, showed no effect in a kinome screen (> 100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized 3-Dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAFs). In this co-culture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D co-cultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells.
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High expression of miR-532-5p, a tumor suppressor, leads to better prognosis in ovarian cancer both in vivo and in vitro
Ovarian cancer is the leading cause of death for gynaecological cancers, ranking fifth overall for cancer-related death among women. The identification of biomarkers and the elucidation of molecular mechanisms for improving treatment options have received extensive efforts in ovarian cancer research. MicroRNAs (miRNAs) have high potential to act as both ovarian cancer biomarkers and as critical regulators of ovarian tumor behavior. We comprehensively analyzed global messenger RNA (mRNA), miRNA expression, and survival data for ovarian cancer from the Cancer Genome Atlas (TCGA) to pinpoint miRNAs that play critical roles in ovarian cancer survival through their effect on mRNA expression. We performed miRNA overexpression and gene knockdown experiments to confirm mechanisms predicted in our bioinformatics approach. We established that overexpression of miR-532-5p in OVCAR-3 cells resulted in a significant decrease in cell viability over a 96-hour time period. In the TCGA ovarian cancer data set, we found 67 genes whose expression levels were negatively correlated with miR-532-5p expression and correlated with patient survival, such as WNT9A, CSNK2A2, CHD4, and SH3PXD2A. The potential miR-532-5p-regulated gene targets were found to be enriched in the Wnt pathway. Overexpression of miR-532-5p through miRNA mimic caused downregulation of CSNK2A2, CHD4, and SH3PXD2A in the OVCAR-3 cell line. We have discovered and validated the tumor-suppressing capabilities of miR-532-5p both in vivo through TCGA analysis and in vitro through ovarian cancer cell lines. Our work highlights the potential clinical importance of miR-532-5p expression in ovarian cancer patients.
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Oncolytic adenovirus loaded with L-carnosine as novel strategy to enhance the anti-tumor activity
Oncolytic viruses are able to specifically replicate, infect and kill only cancer cells. Their combination with chemotherapeutic drugs have shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In the present study we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction and used this strategy to deliver an active anti-tumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant anti-proliferative activity. An ad-hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus-carnosine complex. This complex showed enhanced anti tumor efficacy in vitro and in vivo in different tumor models. In HCT116 colorectal and A549 lung cancer cells the complex showed higher transduction ratio and infectious titer compared to an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cells lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs.
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Linalool-incorporated nanoparticles as a novel anticancer agent for epithelial ovarian carcinoma
Although cytotoxic chemotherapy is widely used against epithelial ovarian cancer (EOC), adverse side effects and emergence of resistance can limit its utility. Therefore, new drugs with systemic delivery platforms are urgently needed for this disease. In this study, we developed linalool-incorporated nanoparticles (LIN-NPs) as a novel anticancer agent. We prepared LIN-NPs by the self-assembly water-in-oil-in-water (w/o/w) emulsion method. LIN-NP-mediated cytotoxicity and apoptosis was assessed in EOC cells and the role of reactive oxygen species (ROS) generation as the mechanism of action was evaluated. In addition, therapeutic efficacy of LIN-NP was assessed in cell lines and patient-derived xenograft (PDX) models for EOC. LIN-NPs had significant cytotoxicity and apoptotic activity against EOC cells including A2780, HeyA8, and SKOV3ip1. LIN-NP treatment increased apoptosis in EOC cells through ROS generation and a subsequent decrease in mitochondrial membrane potential and increase in caspase-3 levels. In addition, 100 mg/kg LIN-NPs significantly decreased tumor weight in the HeyA8 (P < 0.001) and SKOV3ip1 (P = 0.006) in vivo models. Although treatment with 50 mg/kg LIN-NP did not decrease tumor weight compared to the control group, combination treatment with paclitaxel significantly decreased tumor weight compared with paclitaxel alone in SKOV3ip1 xenografts (P = 0.004) and the patient-derived xenograft model (P = 0.020). We have developed LIN-NPs that induce ROS generation as a novel anti-cancer agent for EOC. These findings have broad applications for cancer therapy.
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Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of osteoclast Recruitment, Giant Cell Formation and Bone Resorption
Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor usually leads to an extensive bone lesion. The purpose for this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-B signaling-related cytokines including TNF-α, MCP-1, IL-1α, and IL-17A were significantly increased in GCTB patients. The results were confirmed by immunohistochemistry that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-B inhibitors tested suppressed GCTB cell growth, and Bortezomib (BZB), the well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that BZB not only induced GCTB neoplastic stromal cells (NSCs) apoptosis, but also suppressed GCTB NSCs-induced giant cell differentiation, formation and resorption. Moreover, BZB specifically suppressed GCTB NSCs-induced pre-osteoclast recruitment. Furthermore, BZB ameliorated GCTB cells induced bone destruction in vivo. As a result, BZB suppressed NF-B-regulated gene expression in GCTB NSCs apoptosis, monocyte migration, angiogenesis and osteoclastogenesis. Particularly, the inhibitory effects of BZB were much better than the zoledronic acid, (ZA), a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-B signaling pathway is highly activated in GCTB and BZB could suppress GCTB and osteolysis in vivo and in vitro, indicating that BZB is a potential agent in the treatment of GCTB.
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Prognostic factors in patients with poor risk germ cell tumors: a retrospective analysis of the Indiana University experience from 1990-2014
Survival outcomes for poor risk germ cell tumor treated at Indiana University (1990-2014) were improved from historical IGCCCG group of patients (1975-1990). Among the poor risk category, patients with primary mediastinal non-seminomatous germ cell tumor, brain metastasis, or increasing age have a worse overall survival.
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Molecular Classification of Gastric Cancer
Gastric cancers are currently classified using clinicopathologic criteria, however existing classification systems are inadequate for guiding the treatment of individual patients. Understanding the genomic and epigenomic basis of gastric cancer may facilitate the molecular subtyping of gastric cancer patients and the development of novel drug treatments. Such information has already enhanced our understanding of gastric carcinogenesis, and may ultimately improve the medical management of gastric cancer patients in the future.
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FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials
In the present study, we aim at providing an estimation of the impact of adding bevacizumab to FOLFOXIRI in an adjusted pooled analysis of two consecutive randomized trials in the first-line treatment of mCRC. Improved PFS and OS were reported with FOLFOXIRI plus bevacizumab when compared with FOLFOXIRI alone, with no differences in term of response rate, early response rate and depth of response.
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Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor positive breast cancer (ANZ0501 LATER): An open-label randomised controlled trial
Postmenopausal women who had completed at least 4 years of any standard endocrine therapy, at least one year prior, were randomised to observation or 5 years of letrozole 2.5mg daily. At a median of 3.9 years of follow-up, 2/181 (1.1%) patients allocated letrozole experienced an invasive breast cancer event, compared with 17/179 (9.5%) patients allocated to observation (P=0.0004). This suggests a potential benefit to reintroduction of letrozole in this setting.
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Cancer associated Toll like receptor modulation and insinuation in infection susceptibility: association or coincidence?
TLR are microbial sensing proteins and their modulation during cancer is very common and has several implications. Present article discusses about altered infection susceptibility in cancer patients due to these associated TLR modulations. It concludes that knowledge of these associations can help to predict infection risk in certain cancer patients and development of proper management strategies.
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Statistical Controversies in Clinical Research: Statistical significance - too much of a good thing...
P-values are useful as a pragmatic guide to interpret the results of a clinical trial, not as a strict binary boundary that separates real treatment effects from lack thereof.
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The Impact of Postmastectomy and Regional Nodal Radiation after Neoadjuvant Chemotherapy for Clinically Lymph Node Positive Breast Cancer: A National Cancer Database (NCDB) Analysis
No randomized data are available to characterize the overall survival (OS) impact of postmastectomy radiation (PMRT) and regional nodal irradiation (RNI) after neoadjuvant chemotherapy for breast cancer. In a study of over 15,000 cN1 women in the NCDB, PMRT was associated with improved OS for all pathologic nodal subgroups (ypN0, ypN1, ypN2-3); no OS differences were observed with RNI.
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A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas
Everolimus plus CHOP is effective for newly diagnosed, chemotherapy-naïve peripheral T-cell lymphoma patients with acceptable toxicity.
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Developing a core set of patient-reported outcomes in pancreatic cancer: A Delphi survey
Publication date: April 2016
Source:European Journal of Cancer, Volume 57
Author(s): Arja Gerritsen, Marc Jacobs, Inge Henselmans, Jons van Hattum, Fabio Efficace, Geert-Jan Creemers, Ignace H. de Hingh, Miriam Koopman, I.Quintus Molenaar, Hanneke W. Wilmink, Olivier R. Busch, Marc G. Besselink, Hanneke W. van Laarhoven
BackgroundPatient-reported outcomes (PROs) are amongst the most relevant outcome measures in pancreatic cancer care and research. However, it is unknown which out of the numerous PROs are most important to patients and health care professionals (HCPs) in this setting. The aim of this study was to identify a core set of PROs to be incorporated in a nationwide prospective multidisciplinary pancreatic cancer registry.Patients and methodsWe performed a two-round Delphi survey among 150 patients diagnosed with pancreatic or periampullary cancer (treated either with curative intent or in palliative setting) and 78 HCPs (surgeons, medical oncologists, gastroenterologists, radiotherapists, nurses, and dietitians) in The Netherlands. In round 1, participants were invited to rate the importance of 53 PROs, which were extracted from 17 different PRO measures and grouped into global domains, on a 1–9 Likert scale. PROs rated as very important (score 7–9) by the majority (≥80%) of curative and/or palliative patients as well as HCPs were considered sufficiently important to be incorporated in the core set. PROs not fulfilling these criteria in round 1 were presented again to the participants in round 2 along with individual and group feedback.ResultsA total of 97 patients (94%) in curative-intent setting, 38 patients (81%) in palliative setting and 73 HCPs (94%) completed both rounds 1 and 2. After the first round, 7 PROs were included in the core set: general quality of life, general health, physical ability, satisfaction with caregivers, satisfaction with services and care organisation, coping and defecation. After the second round, 10 additional PROs were added: appetite, ability to work/do usual activities, medication use, weight changes, fatigue, negative feelings, positive feelings, fear of recurrence, relationship with partner/family, and pancreatic enzyme replacement therapy use.ConclusionThis study provides a core set of PROs selected by patients and HCPs, which may be incorporated in pancreatic cancer care and research. Validation outside the Dutch context is recommended for generalisation and use in international studies.
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