Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma

Abstract

Circulating biomarker for malignant gliomas could improve both differential diagnosis and clinical management of brain tumor patients. Among all gliomas, glioblastoma (GBM) is considered the most hypervascularized tumor with activation of multiple proangiogenic signaling pathways that enhance tumor growth. To investigate whether preoperative antigen plasma level of von Willebrand Factor (VWF:Ag) might be possible marker for GBM onset, progression, and prognosis, we retrospectively examined 57 patients with histological diagnosis for GBM and 23 meningiomas (MNGs), benign intracranial expansive lesions, enrolled as controls. Blood samples were collected from all the patients before tumor resection. Plasma von Willebrand Factor (VWF):Ag levels were determined by using a latex particle-enhanced immunoturbidimetric assay. The median levels of vWF:Ag were significantly higher in GBMs than in meningiomas (MNGs) (183 vs. 133 IU/dL, P = 0.01). The cumulative 1-year survival was significantly shorter in patients with VWF:Ag levels >200 IU/dL than in those with levels <200 IU/dL and increased VWF levels were associated with a threefold higher risk of death in GBM patients. Our data suggest that VWF:Ag could be a circulating biomarker of disease malignancy, that could be considered, in association with other genetic and epigenetic factors, currently available in the GBM management. Future studies should investigate whether plasma VWF:Ag levels could also be used to monitor therapeutic effects and whether it may have a prognostic value.

Circulating biomarker for malignant glioblastoma could improve both differential diagnosis and clinical management of brain tumor patients. Plasma von Willebrand Factor (VWF):Ag levels were determined in 80 patients (57 glioblastoma and 23 meningiomas). The median levels of vWF:Ag were significantly higher in glioblastoma (GBMs) than in meningiomas (MNGs) and the cumulative 1-year survival was significantly shorter in patients with VWF:Ag levels >200 IU/dL than in those with levels <200 IU/dL and increased VWF levels were associated with a threefold higher risk of death in GBM patients. Our data suggest that VWF:Ag could be a circulating biomarker of disease malignancy, that could be considered, in association with other genetic and epigenetic factors, currently available in the GBM management.

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Acute hemolysis in a patient with a newly diagnosed glioblastoma

CNS Oncology Ahead of Print.


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Anaplastic astrocytoma

CNS Oncology Ahead of Print.


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Sox2: regulation of expression and contribution to brain tumors

CNS Oncology Ahead of Print.


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Our panel of experts highlights the most important research articles across the spectrum of topics relevant to the field of CNS oncology

CNS Oncology Ahead of Print.


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A selected review of abstracts from the 20th Annual Meeting of the Society for Neuro-Oncology (SNO)

CNS Oncology Ahead of Print.


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Disulfiram/Copper Enhance Temozolomide Treatment for Glioblastoma

Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor–initiating cells (BTIC) that confer resistance to conventional therapies.

Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.

Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).

Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings. Clin Cancer Res; 1–16. ©2016 AACR.

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TIL Therapy for Melanoma Patients with Attenuated IL2 Dose

Purpose: Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen.

Experimental Design: Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625).

Results: Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment.

Conclusions: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res; 1–12. ©2016 AACR.

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Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer

Publication date: July 2016
Source:European Journal of Cancer, Volume 62
Author(s): Takaki Yoshikawa, Satoshi Morita, Kazuaki Tanabe, Kazuhiro Nishikawa, Yuichi Ito, Takanori Matsui, Kazumasa Fujitani, Yutaka Kimura, Junya Fujita, Toru Aoyama, Tsutomu Hayashi, Haruhiko Cho, Akira Tsuburaya, Yumi Miyashita, Junichi Sakamoto
BackgroundThe prognosis for stage III gastric cancer is unsatisfactory by D2 gastrectomy and S-1 adjuvant chemotherapy. Both S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) are promising regimens as neoadjuvant chemotherapy; however, the optimal duration remains unclear.Patients and methodsIn this 2×2 randomised phase II trial, stage III gastric cancer patients, those with a prognosis corresponding to stage III, and macroscopically resectable stage IV cases were randomised to two or four courses of S-1 (80 mg/m² for 21 d with 1 week rest)/cisplatin (60 mg/m² at day 8) or PC (80 and 25 mg/m², respectively, on days 1, 8, and 15 with 1 week rest) as neoadjuvant chemotherapy. The primary end-point was the 3-year overall survival (OS).ResultsBetween October 2009 and July 2011, 83 patients received 2 courses of SC (n=21), 4 courses of SC (n=20), 2 courses of PC (n=21) and 4 courses of PC (n=21). The 3-year OS was 60.9% for SC and 64.3% for PC and 64.3% for the two courses and 61.0% for the four courses. Subset analyses demonstrated no subgroup which showed any potential survival benefit by PC in comparison to SC or by four courses as in comparison to two courses.ConclusionsTwo courses of SC as neoadjuvant chemotherapy are recommended as a test arm of a future phase III study for patients with locally advanced gastric cancer.Clinical trial numberUMIN-000002595.



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Impact of Molecular Predictors on the Response Rates in Head and Neck Cancer Patients – an Observational Study

Abstract

Squamous cell carcinoma of head and neck region account for more than 25 % of male and more than 10 % of female cancers in India (1). Head and neck cancer treatment includes a multidisciplinary approach involving all specialties. Concurrent chemo-radiation is the standard of care in most of the subsites (2). Inspite of the multi-disciplinary approach, a plateau has been reached in terms of results with 5 year survival of locally advanced disease of around 30 % (3). In order to improve outcomes, there has been considerable interest in molecular profiling of head and neck cancers 4-10. However there is still significant paucity in terms of Indian data, hence the need for the study. The objectives are to assess the HPV-p16, EGFR and p53 status, to correlate HPV-p16, EGFR and p53 status with the response rates, to correlate HPV-p16,EGFR and p53 status with other factors like age, sex, tobacco use. Twenty five consecutive cases of histopathologically proven head and neck cancers were accrued. All patients were treated with external radiation to a dose of 66Gy in 33 fractions along with concurrent weekly cisplatin chemotherapy at a dose of 40mg/sqm. HPV-p16, EGFR and p53 mutation analysis was done on paraffin embedded histopathological blocks. PCR technique used for HPV-p16, EGFR and p53 status detection. Response assessment was done based on RECIST criteria. Correlation of HPV, EGFR and p53 status on response was done. The EGFR positivity rate was 84 %, the p53 positivity rate was 76 % and the HPV p-16 positivity rate was 28 %. Out of 25 patients, 13(52%) had complete response, 7(28 %) had partial response, 3(12 %) had stable disease and 2(8 %) had progressive disease. On correlation of molecular profile with response, there was no statistical significance between EGFR status and response (p 0.5) or HPV-p16 and response (p 0.8). However, p53 positivity was approaching significance with respect to good response (p 0.07).

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Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Cancer: a Bayesian Network Meta-Analysis

Abstract

Fluoropyrimidine-based regimens are the most common treatments in advanced gastric cancer. We used a Bayesian network meta-analysis to identify the optimal fluoropyrimidine-based chemotherapy by comparing their relative efficacy and safety. We systematically searched databases and extracted data from randomized controlled trials, which compared fluoropyrimidine-based regimens as first-line treatment in AGC. The main outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 adverse events (AEs). A total of 12 RCTs of 4026 patients were included in our network meta-analysis. Pooled analysis showed S-1 and capecitabine had a significant OS benefit over 5-Fu, with hazard ratios of 0.90 (95%CI = 0.81–0.99) and 0.88 (95%CI = 0.80–0.96), respectively. The result also exhibited a trend that S-1 and capecitabine prolonged PFS in contrast to 5-Fu, with hazard ratios of 0.84 (95%CI = 0.66–1.02) and 0.84 (95%CI = 0.65–1.03), respectively. Additionally, all the three fluoropyrimidine-based regimens were similar in terms of ORR and grade 3 or 4 AEs. Compared with regimens based on 5-Fu, regimens based on S-1 or capecitabine demonstrated a significant OS improvement without compromise of AEs as first-line treatment in AGC in Asian population. S-1 and capecitabine can be interchangeable according their different emphasis on AEs.

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Primary Hepatic Lymphoma: the Importance of Liver Biopsy

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The association between social support and smoking status in cancer survivors with frequent and infrequent mental distress: results from 10 US states, 2010

Abstract

Purpose

This study examined the association between social support and smoking status among adult cancer survivors, with special emphasis on mental health differences using data from 10 US states.

Methods

Cross-sectional data from the 2010 Behavioral Risk Factor Surveillance System, Cancer Survivorship module on 8055 cancer survivors were analyzed. Sample weights were applied for the generalization of results to 2.6 million cancer survivors.

Results

In 2010, 15.6 % (418,700) were current, 38.4 % (1.03 million) former, and 46.0 % (1.2 million) never smokers. About 18.0 % of cancer survivors reported receiving the lowest level of social support and 12.1 % reported experiencing frequent mental distress in the past 30 days. Participants' mean age at the time of the first cancer diagnosis was 51.0 (standard error (SE) = 0.33) and mean time since their diagnosis was 11.3 years (SE = 0.18). Compared to those with infrequent mental distress, cancer survivors with frequent mental distress were diagnosed at a younger age (45.0 vs. 51.8), more likely to be current smokers (36.8 vs. 12.7 %), and less likely to always receive social support they needed (33.4 vs. 56.3 %). Cancer survivors who received higher levels of social support were less likely to be current smokers than those who received the lowest level of social support they needed. Among cancer survivors who reported frequent mental distress, non-Hispanic blacks were more likely to be current smokers than non-Hispanic whites.

Conclusions

Rates of current smokers were lower among cancer survivors who received social support and reported infrequent mental distress.

Implications for Cancer Survivors

Psychosocial screening may help health care professional identify smokers with frequent mental distress who require more intensive smoking cessation interventions.

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Malignant gliomas induce and exploit astrocytic mesenchymal-like transition by activating canonical Wnt/β-catenin signaling

Abstract

The complex microenvironment of malignant gliomas plays a dynamic and usually cancer-promoting role in glioma progression. Astrocytes, the major stromal cells in the brain, can be activated by glioma microenvironment, resulting in a layer of reactive astrocytes surrounding the gliomas. Reactive astrocytes are universally characterized with the upregulation of glial fibrillary protein and glycoprotein podoplanin. In this work, we investigated the role of reactive astrocytes on malignant glioma microenvironment and the potential mechanism by which glioma cells activated the tumor-associated astrocytes (TAAs). The reactive astrocytes were observed around gliomas in the intracranial syngeneic implantation of rat C6 and mouse GL261 glioma cells in vivo, as well as primary astrocytes cultured with glioma cells condition medium in vitro. Besides, reactive astrocytes exhibited distinct epithelial-to-mesenchymal (-like) transition and enhanced migration and invasion activity, with the decrease of E-cadherin and concomitant increase of vimentin and matrix metalloproteinases. Furthermore, canonical Wnt/β-catenin signaling was activated in TAAs. The Wnt/β-catenin pathway inhibitor XAV939 and β-catenin plasmid were used to verify the regulation of Wnt/β-catenin signaling on TAAs and their invasion ability. Taken together, our findings established that glioma cells remarkably activated astrocytes via upregulating Wnt/β-catenin signaling, with obviously mesenchymal-like transition and increased migration and invasion ability, indicating that glioma cells may stimulate adjacent astrocytes to degrade extracellular matrix and thereby promoting tumor invasiveness.

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Synchronous Papillary Carcinoma of Thyroid and Lung

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Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness

Abstract

Background

Angiopoietin-2 is a growth factor involved in the pathophysiology of vascular and inflammatory diseases such as arteriosclerosis. Carotid or aortic scans provide noninvasive screening tools for assessment of preclinical atherosclerosis in high-risk children.

Aim

We assessed serum angiopoietin-2 in children and adolescents with type 1 diabetes mellitus as a potential marker for vascular complications in relation to glycemic control, inflammation and vascular structure.

Methods

Sixty patients with type 1 diabetes were divided into 2 groups according to the presence of micro-vascular complications and compared with 30 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), urinary albumin/creatinine ratio, serum angiopoietin-2, carotid and aortic intima-media thickness (CIMT and AIMT) were measured.

Results

CIMT, AIMT and serum angiopoietin-2 levels were significantly increased in patients with and without micro-vascular complications compared with controls, and the highest levels were in patients with complications (p < 0.001). Angiopoietin-2 was higher in patients with microalbuminuria than normoalbuminuric group (p < 0.001). Fasting blood glucose, HbA1c, hs-CRP, CIMT and AIMT were independently related to angiopoietin-2 in multiple regression analysis. Disease duration, hyperglycemia, poor glycemic control, hypercholesterolemia, inflammation and angiopoietin-2 were independent factors contributing to atherosclerosis risk.

Conclusion

The relation between angiopoietin-2 and assessed parameters of vascular structure in type 1 diabetes reflects a state of endothelial injury and highlights the role of disturbed angiogenesis and vascular inflammation in the occurrence of diabetic complications.

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Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort

Abstract

Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome towards NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene P-values derived from differential expression values from GEO2R. Our study identified NPC association in the Gene Ontology (GO) axonemal dynein complex pathway (P_GWAS-GSEA=1.98x10⁻²; P_Expr-GSEA=1.27x10⁻²⁴; P_{Bonf-Combined}=4.15x10⁻²¹). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (P_{AmpliSeq-GSEA}=6.56x10⁻⁴). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort. This article is protected by copyright. All rights reserved.

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Genetic mutations in high grade gliomas of the adult spinal cord

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The survival outcome and prognostic factors for distal cholangiocarcinoma following surgical resection: a meta-analysis for the 5-year survival

Abstract

Purpose

To assess the available evidence on the prognostic factors for the 5-year survival for patients with distal cholangiocarcinoma (DCC) following surgical resection.

Methods

We performed a comprehensive search of abstracts included in databases where relevant studies were published between January 2000 and August 2015. Risk ratios (RRs), 95 % confidence intervals (95 % CIs), and random-effects model were calculated using RevMan 5.3 software.

Results

A total of 23 observational studies involving 2063 patients with DCC were analyzed. The meta-analysis showed that postoperative adjuvant chemotherapy was not confirmed as a prognostic factor, with similar 5-year survival rates between those receiving and not receiving chemotherapy (RR 0.71; 95 % CI 0.21–2.36; P = 0.57). Perineural invasion (RR 0.51; 95 % CI 0.40–0.64; P < 0.00001), lymph node metastasis (RR 0.51; 95 % CI 0.38–0.70; P < 0.0001), positive resection margin status (RR 2.11; 95 % CI 1.36–3.30; P = 0.001), and not-well-differentiated adenocarcinoma (RR 1.77; 95 % CI 1.39–2.25; P < 0.00001) were associated with shorter survival.

Conclusions

Perineural invasion, lymph node metastasis, resection margin status, and tumor differentiation were the significant prognostic factors for the 5-year survival.

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Clinical results of mean GTV dose optimized robotic guided SBRT for liver metastases

Abstract

Background

We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases.

Methods

Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED₁₀) was 142.1 Gy₁₀ (range, 60.2 Gy₁₀ –165.3 Gy₁₀) and the prescribed PTV BED₁₀ ranged from 40.6 Gy₁₀ to 112.5 Gy₁₀ (median, 86.1 Gy₁₀). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity.

Results

Median follow-up was 17 months (range, 2–49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED₁₀ (HR 0.95, CI 0.91–0.98, p = 0.002) and GTV mean BED₁₀ (HR 0.975, CI 0.954–0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade ≥ 2.

Conclusions

Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions.

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Volumetric-modulated arc therapy (VMAT) versus 3D-conformal radiation therapy in supra-diaphragmatic Hodgkin’s Lymphoma with mediastinal involvement: A dosimetric comparison

Publication date: Available online 27 May 2016
Source:Journal of the Egyptian National Cancer Institute
Author(s): Christine Higby, Yasser Khafaga, Mohammad Al-Shabanah, Amr Mousa, Mohamed Ilyas, Ghadeer Nazer, Ehab M. Khalil
PurposeTo compare volumetric-modulated arc therapy (VMAT) with 3D-conformal radiation therapy (3D-CRT) mediastinal irradiation for stage I–II supra-diaphragmatic Hodgkin's Lymphoma (HL).Patients and methodsEleven patients were planned for RT after 4–6 cycles of ABVD chemotherapy: conventional 3D-CRT (AP/PA) and VMAT plans were conformed to the same PTV. Objective was to choose the best PTV coverage plan with the least OAR dose. The 2 plans were compared for: PTV coverage, mean dose and V5,V20lung, mean dose and V30heart, V5, V10, V15breast (female patients), and the integral body dose.ResultsBoth techniques achieved adequate PTV coverage. Mean lung and heart dose was consistently lower in VMAT plans. The lung V20 dose was acceptable for VMAT, but exceeded the tolerance threshold in 6 cases with 3DCRT plans. A mean difference of 15.9% for both lungs V20 favored VMAT plans; average MLD difference was 2.3Gy less for VMAT plans. Similarly, lower maximum and mean heart doses with a 3.3Gy dose reduction and a 9.4% difference in V30 favored VMAT plans. Mean V5lung/female breast and integral dose were invariably higher in VMAT plans because of the low-dose spread.ConclusionsVMAT is a valuable technique for treatment of large mediastinal HL. VMAT spares the lung and heart compared to 3DCRT using ISRT in select HL cases. VMAT allows dose escalation for post-chemotherapy residual disease with minimal dose to OARs. VMAT low radiation dose (V5) to the normal tissues, and the increased integral dose should be considered.



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Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance

Publication date: Available online 26 May 2016
Source:Cancer Cell
Author(s): Michaël Cerezo, Abdelali Lehraiki, Antoine Millet, Florian Rouaud, Magali Plaisant, Emilie Jaune, Thomas Botton, Cyril Ronco, Patricia Abbe, Hella Amdouni, Thierry Passeron, Veronique Hofman, Baharia Mograbi, Anne-Sophie Dabert-Gay, Delphine Debayle, Damien Alcor, Nabil Rabhi, Jean-Sébastien Annicotte, Laurent Héliot, Mariano Gonzalez-Pisfil, Caroline Robert, Solange Moréra, Armelle Virougoux, Philippe Gual, Maruf M.U. Ali, Corine Bertolotto, Paul Hofman, Robert Ballotti, Rachid Benhida, Stéphane Rocchi
We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.

Graphical abstract

Teaser

Cerezo et al. show that HA15, the lead compound of a series of thiazole benzenesulfonamides that they have developed, kills cancer cells by targeting BiP to increase ER stress. HA15 exhibits strong efficacy in melanoma cells, including those resistant to BRAF inhibitors.


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TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

Publication date: Available online 26 May 2016
Source:Cancer Cell
Author(s): Anna C. Groner, Laura Cato, Jonas de Tribolet-Hardy, Tiziano Bernasocchi, Hana Janouskova, Diana Melchers, René Houtman, Andrew C.B. Cato, Patrick Tschopp, Lei Gu, Andrea Corsinotti, Qing Zhong, Christian Fankhauser, Christine Fritz, Cédric Poyet, Ulrich Wagner, Tiannan Guo, Ruedi Aebersold, Levi A. Garraway, Peter J. Wild, Jean-Philippe Theurillat, Myles Brown
Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.

Graphical abstract

Teaser

Groner et al. show that recurrent prostate cancer-driver mutations in SPOP stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling; AR and TRIM24 co-activated genes are upregulated in the castration-resistant state and are predictive of disease recurrence.


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