Inhibition of the angiotensin II type 2 receptor ATR is a novel therapeutic strategy for glioblastoma.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (ATR) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through ATR. We repurposed EMA401, an ATR antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of ATR-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity.

The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention.

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2).

Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma.

Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl 3-hydroxylase family exemplified by Leprel1 and Leprel2 is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function.

methylation is a candidate biomarker of outcome in head and neck cancer.

Background: Biomarkers predictive of response to chemoradiotherapy (CRT) regimens for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are urgently required to identify patients in whom this approach is likely to be effective. TP53 mutations and epidermal growth factor (EGFR) overexpression are common markers of disease. Dual-specificity-phosphatase-2 (DUSP2) has an essential role in cell proliferation, cancer and immune responses.

Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy.

Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) may contribute to the antitumor activity of cetuximab. However, the extent of this contribution is unclear. In this study, we investigated the impact of baseline ADCC on the outcome of patients with locally advanced squamous cell carcinoma treated with cetuximab and radiotherapy.

Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015.

MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A.

Inhibition of the Polyamine Synthesis Pathway Is Synthetically Lethal with Loss of Argininosuccinate Synthase 1.

Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of tumor types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinical setting.

Reoxygenation Reverses Hypoxia-related Radioresistance in Head and Neck Cancer Cell Lines.

Background/aim: Head and neck cancer (HNC) is characterized by epidermal growth factor receptor (EGFR) overexpression and radiotherapy (RT) resistance. Cancer cells are able to survive and proliferate in hypoxic conditions. Hypoxia can be transiently interrupted by phases of reoxygenation.

E1 detection as prognosticator in human papillomavirus-positive head and neck cancers.

Purpose: HPV-related locally advanced head and neck cancers (LA-HNCs) show a good prognosis. This study aimed to investigate the HPV prevalence in LA-HNCs and compare the prognostic value of E1, E6 and L1 genomic viral fragments and p16, individually and in combination, in order to find the best prognosticator in terms of overall survival (OS) and progression-free survival (PFS).

Patients And Methods: HPV16 was searched in 255 LA-HNC formalin-fixed paraffin-embedded tumor tissues, 89 oropharyngeal cancers (OPCs), and 166 non-OPCs by DNA-PCR with 3 primer pairs.

Schedule-dependent interaction between temsirolimus and cetuximab in head and neck cancer: a preclinical study.

Aberrant epidermal growth factor receptor (EGFR) signaling is associated with tumor growth in head and neck squamous cell carcinoma (HNSCC) and is a major focus of targeted therapy. The phosphatidylinositol-3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is frequently mutated in HNSCC and is involved in disease progression and resistance to EGFR inhibitors. The aim of this study was to assess the antiproliferative effects of mTOR inhibition (temsirolimus) combined with the anti-EGFR monoclonal antibody cetuximab, administered according to different combination schedules.

Correlation of TP53 and MDM2 genotypes and clinical outcome in platinum-treated head and neck cancer patients with more than 10 years' follow-up.

Purpose: Adequate biomarkers are still required to optimize therapy in patients with locally advanced head and neck squamous carcinomas (HNSCC) treated with chemoradiotherapy (CRT).

Methods: We updated the follow-up of 66 HNSCC patients treated with CRT we described more than 10 years ago, focusing on SNP Arg/Pro (R/P) at codon 72 and somatic mutations in TP53 and on SNP309 in the MDM2 gene.

Results: In wild-type TP53 cases, overall survival (OS) was longer in 72RR and less favorable in 72PP (p = 0.

The effect of paclitaxel and nab-paclitaxel in combination with anti-angiogenic therapy in breast cancer cell lines.

Taxanes represent a treatment of choice for metastatic breast cancer. Their combination with bevacizumab improved response rate and progression-free survival. We studied in vitro the effect on cell survival of the combination of either paclitaxel or nab-paclitaxel with bevacizumab and we investigated the biological factors involved in the response to treatments.

The relevance of ADCC for EGFR targeting: A review of the literature and a clinically-applicable method of assessment in patients.

Background: Advances in the understanding of tumor biology have led to the development of targeted therapies as monoclonal antibodies (MoAbs) in clinical oncology. Among their suggested mechanisms of action monoclonal antibodies (IgG1) selectively directed against tumor membrane receptors mediate of antibody-dependent cellular cytotoxicity (ADCC) by triggering Fc-γRIII on natural killer (NK) cells.

Methods: This study reviews the clinical context of ADCC measurement with a particular focus on EGFR targeting and describes an ex vivo ADCC method applied to MoAbs (cetuximab and panitumumab), against epidermal growth factor receptor (EGFR).

Treatment effect of buparlisib, cetuximab and irradiation in wild-type or PI3KCA-mutated head and neck cancer cell lines.

Introduction In complement to anti-EGFR therapy, the targeting of PI3K/AKT/mTOR signaling pathway is of particular interest in the management of Head and Neck Squamous Cell Carcinoma (HNSCC). Here, we assess the effects of PI3K inhibition combined with anti-EGFR monoclonal antibody cetuximab and/or irradiation (RT). Material and methods Anti-proliferative effects of the combination of buparlisib (a specific PI3K inhibitor), cetuximab and RT was determined in two HNSCC cell lines (CAL33, PI3KCA H1047R-mutated and CAL27, PI3KCA wild-type).

MGMT promoter methylation and glioblastoma: a comparison of analytical methods and of tumor specimens.

It is already well known that hypermethylation of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is a predictive biomarker of response to temozolomide treatment and of favorable outcomes in terms of overall survival (OS) and progression-free survival (PFS) in glioblastoma (GBM) patients. Nevertheless, MGMT methylation status has not currently been introduced into routine clinical practice, as the choice of the ideal technique and tissue sample specimen is still controversial. The aim of this study was to compare 2 analytical methods, methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ), and their use on 2 different tissue type samples, snap-frozen and formalin-fixed paraffin-embedded (FFPE), obtained from a single-center and uniformly treated cohort of 46 GBM patients.

Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging.

Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion.

A PNA-mediated clamping PCR for routine detection of KRAS mutations in colorectal carcinoma.

The detection of somatic mutations in a tumor represents a valuable tool for tumor characterization and provides the clinicians with information for setting up the most appropriate therapy. KRAS mutations in codons 12 and 13 are important biomarkers routinely analyzed in the clinic for the management of anti-EGFR treatment in colorectal carcinoma (CRC). Here we report a sensitive and inexpensive assay for KRAS mutations based on a PNA-mediated PCR clamping.

Role of IL-8 induced angiogenesis in uveal melanoma.

Introduction Uveal melanoma (UM) is a highly vascularised tumour generally treated with radiotherapy (RT). A recent preclinical study from our group [1] demonstrated that RT-associated anti-angiogenic therapy has more than additive effects on cell growth, by modulating vascular endothelial growth factor (VEGF) levels. The pro-angiogenic interleukin-8 (IL-8) is highly expressed in both tumour and endothelial cells and is associated with resistance to VEGF-targeted therapies in various tumour types.

Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma.

Transcriptional silencing of tissue factor pathway inhibitor 2 (TFPI2) occurs in several human tumors including melanoma. We investigated methylated TFPI2 as a biomarker of metastatic melanoma using qRT-PCR to assess TFPI2 expression and pyrosequencing to analyze CpG island methylation in malignant melanoma cell lines, in benign nevi, in 112 primary and metastatic melanomas, and in serum from 6 healthy individuals and 35 patients: 20 patients with primary and 15 patients with metastatic melanoma. The TFPI2 CpG island is unmethylated in nevi but methylation is associated with metastatic melanoma.

Differential molecular mechanism of docetaxel-octreotide combined treatment according to the docetaxel-resistance status in PC3 prostate cancer cells.

To examine the effect and the molecular mechanisms of the combined treatment of the somatostatin (SST) analogue octreotide with docetaxel: analysis of proliferation, apoptosis and migration in the human prostate cancer cell line PC3, either sensitive (PC3wt) or made resistant to docetaxel (PC3R). We examined the effect of the two drugs individually or in combination on cell proliferation and migration by analysis of apoptosis and cell cycle proteins. The role of octreotide in modulating P-glycoprotein function was examined together with the modulation of SST receptors type 2 and 5 (SSTR2 and SSTR5).

Combination of bevacizumab and irradiation on uveal melanoma: an in vitro and in vivo preclinical study.

Background: Radiotherapy (RT) is the standard treatment for uveal melanoma. However it can cause damage to the retina and optic nerve. This study examined the in vitro and in vivo effects of the anti-VEGF monoclonal antibody bevacizumab associated with radiotherapy (RT) on tumor growth and tumor proliferation and vasculature on OCM-1 human uveal melanoma cell line.

Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines.

Objectives: Overexpression of epidermal growth factor receptor (EGFR) and angiogenic factors is associated with the progression of androgen-independent prostate cancer (AIPC). We examined the effects of vandetanib, an inhibitor of vascular endothelial growth factor (VEGFR), EGFR, and rearranged during transfection (RET) tyrosine-kinase activities, alone or combined with docetaxel, on PC3 docetaxel-sensitive (PC3wt) or docetaxel-resistant (PC3R) AIPC cell growth in vivo and in vitro.

Methods: Mice bearing PC3wt or PC3R tumors were treated for 3 weeks with vandetanib (25 or 50 mg/kg/d p.

MDM2 309 polymorphism predicts outcome in platinum-treated locally advanced head and neck cancer.

Chemo-radiotherapy (CRT) with cisplatin-based regimens is curative in a subset of patients with locally advanced (stage III and IV) squamous carcinomas of the head and neck (LAHNSCC), but causes considerable toxicity. To seek predictive biomarkers, we analysed single nucleotide polymorphisms (SNPs) in the p53 and MDM2 genes in LAHNSCC patients treated with cisplatin-based CRT. We analysed germ-line p53 72 Arg/Pro (R/P) and MDM2 309 SNPs and somatic p53 mutational status in 140 LAHNSCC and determined their utility as predictive biomarkers.

Bcl2-interacting killer CpG methylation in multiple myeloma: a potential predictor of relapsed/refractory disease with therapeutic implications.

BIK (bcl2-interacting killer) is the founding member of the BH3-only bcl-2 family of pro-apoptotic proteins, which is suppressed in various cancers. In multiple myeloma (MM), BIK has been shown to be epigenetically silenced in vitro, but there is a lack of clinical data. We investigated the CpG methylation status of the BIK promoter in a well-characterized clinical series of patients with MM and investigated its clinical relevance.

Expression profiling and long lasting responses to chemotherapy in metastatic gastric cancer.

Current palliative chemotherapy (CT) regimens achieve clinical benefits in less than 50% of patients treated for metastatic gastric cancers, and long-term survivals are anecdotical. Genetic polymorphisms and differences at the level of transcription in genes involved in biological processes of drug metabolism, DNA repair and drug resistance can explain the observed individual differences in response to drugs, in survival and in different susceptibility to the toxic effects of CT. The possibility to classify patients on the basis of genetic signatures could help in choosing the CT regimen.