Tailoring treatment of salivary duct carcinoma (SDC) by liquid biopsy: ARv7 expression in circulating tumor cells

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Sodium 4-Carboxymethoxyimino-(4-HPR) a Novel Water-Soluble Derivative of 4-Oxo-4-HPR Endowed with In Vivo Anticancer Activity on Solid Tumors

4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), an active polar metabolite of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR), was shown to exert promising antitumor activity through at least two independent mechanisms of action. Specifically, differently from 4-HPR and other retinoids, 4-oxo-4-HPR targets microtubules and inhibits tubulin polymerization causing mitotic arrest and on the other hand, analogously to the parent drug, it induces apoptosis through the activation of a signaling cascade involving the generation of reactive oxygen species (ROS). However, the potential in vivo use of 4-oxo-4-HPR is impaired by its poor solubility. By chemical modification of 4-oxo-4-HPR, a new class of compounds with improved solubility and in vivo bioavailability was obtained. We demonstrated here that, among them, the most promising molecule, sodium 4-carboxymethoxyimino-(4-HPR), was endowed with in vitro antitumor efficacy and entirely preserved the double mechanism of action of the parent drug in cancer cells of different histotypes. In fact, the retinoid induced the activation of the apoptotic cascade related to the generation of ROS through endoplasmic reticulum stress response and upregulation of phospho c-Jun N-terminal kinases and PLAcental Bone morphogenetic protein, leading to cell death through caspase-3 cleavage. Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization. To assess the compound antitumor activity, in vivo experiments were performed in three mouse xenograft models (ovarian and breast cancers and mesothelioma). The in vivo results demonstrated that retinoid administration as single agent significantly increased the survival in ovarian cancer xenografts, induced a statistically significant decrease in tumor growth in breast cancer xenografts, and caused a 30% reduction in tumor growth in a mesothelioma mouse model. Even though further studies investigating sodium 4-carboxymethoxyimino-(4-HPR) toxicity and in vitro and in vivo activities in combination with other drugs are required, the double mechanism of action of the retinoid coupled with its in vivo antitumor efficacy and potential low toxicity suggest a promising therapeutic potential for the compound in different solid tumors

Head and neck cancer subtypes with biological and clinical relevance : meta-analysis of gene-expression data

Head and neck squamous cell carcinoma (HNSCC) is a disease with heterogeneous clinical behavior and response to therapies. Despite the introduction of multimodality treatment, 40-50% of patients with advanced disease recur. Therefore, there is an urgent need to improve the classification beyond the current parameters in clinical use to better stratify patients and the therapeutic approaches. Following a meta-analysis approach we built a large training set to whom we applied a Disease-Specific Genomic Analysis (DSGA) to identify the disease component embedded into the tumor data. Eleven independent microarray datasets were used as validation sets. Six different HNSCC subtypes that summarize the aberrant alterations occurring during tumor progression were identified. Based on their main biological characteristics and de-regulated signaling pathways, the subtypes were designed as immunoreactive, inflammatory, human papilloma virus (HPV)-like, classical, hypoxia associated, and mesenchymal. Our findings highlighted a more aggressive behavior for mesenchymal and hypoxia-associated subtypes. The Genomics Drug Sensitivity Project was used to identify potential associations with drug sensitivity and significant differences were observed among the six subtypes. To conclude, we report a robust molecularly defined subtype classification in HNSCC that can improve patient selection and pave the way to the development of appropriate therapeutic strategies

Cell cycle dependent oscillatory expression of estrogen receptor-α links Pol II elongation to neoplastic transformation

Decades of studies provided a detailed view of the mechanism of estrogen receptor-\u3b1 (ER\u3b1) regulated gene transcription and the physio-pathological relevance of the genetic programs controlled by this receptor in a variety of tissues. However, still limited is our knowledge on the regulation of ER\u3b1 synthesis. Preliminary observations showed that the expression of ER\u3b1 is cell cycle regulated. Here, we have demonstrated that a well described polymorphic sequence in the first intron of ER\u3b1 (PvuII and XbaI) has a key role in regulating the ER\u3b1 content in cycling cells. We have shown that the RNA Pol II (Pol II) elongation is blocked at the polymorphic site and that the proto-oncogene c-MYB modulates the release of the pausing polymerase. It is well known that the two SNPs are associated to an increased risk, progression, survival and mortality of endocrine-related cancers, here we have demonstrated that the c-MYB-dependent release of Pol II at a specific phase of the cell cycle is facilitated by the px haplotype, thus leading to a higher ER\u3b1 mitogenic signal. In breast cancer, this mechanism is disrupted when the hormone refractory phenotype is established; therefore, we propose this oscillator as a novel target for the development of therapies aimed at sensitizing breast cancer resistant to hormonal treatments. Because PvuII and XbaI were associated to a broad range physio-pathological conditions beside neoplastic transformation, we expect that the ER\u3b1 oscillator contributes to the regulation of the estrogen signal in several tissues

A model of study for human cancer: Spontaneous occurring tumors in dogs. Biological features and translation for new anticancer therapies

Murine cancer models have been extremely useful for analyzing the biology of pathways involved in cancer initiation, promotion, and progression. Interestingly, several murine cancer models also exhibit heterogeneity, genomic instability and an intact immune system. However, they do not adequately represent several features that define cancer in humans, including long periods of latency, the complex biology of cancer recurrence and metastasis and outcomes to novel therapies. Therefore, additional models that better investigate the human disease are needed. In the pet population, with special references to the dog, cancer is a spontaneous disease and dogs naturally develop cancers that share many characteristics with human malignancies More than 40 years ago, optimization of bone marrow transplantation protocols was undertaken in dogs and recently novel targeted therapies such as liposomal muramyl tripeptide phosphatidylethanolamine and several tyrosine kinase inhibitors, namely masitinib (AB1010) and toceranib phosphate (SU11654), have been developed to treat dog tumors which have then been translated to human clinical trials. In this review article, we will analyze biological data from dog tumors and comparative features with human tumors, and new therapeutic approaches translated from dog to human cancer

DRUG SENSITIVITY OF DIFFERENT TUMOR LESIONS FROM THE SAME PATIENT EVALUATED BY A SHORT-TERM ASSAY

A short-term antimetabolic assay, which considers the interference with [3H]thymidine incorporation as an indicator of drug effect, has been used to comparatively assess the chemosensitivity of different tumor lesions from the same patient. The analysis was performed on primary tumors and their synchronous metastases from 67 patients with breast, ovarian, gastrointestinal and germ cell testicular tumors. A remarkable difference in sensitivity to cytostatic drugs was observed between the two lesions. In contrast, a strong association in chemosensitivity (81.7% agreement rate; p less than 0.01) was observed between two synchronous metastases from 17 patients with breast, ovarian, germ cell testicular tumors or malignant melanoma. In addition, the predictive relevance of the antimetabolic assay on clinical response to chemotherapy was analyzed in relation to the type of tumor lesion tested in vitro in a retrospective correlative study on 57 patients with advanced ovarian and germ cell testicular tumors. The objective clinical response was significantly correlated to the in vitro sensitivity of metastases (83.7% agreement rate; p less than 0.01), but not to that of the primary tumor

Biomolecular features of clinical relevance in breast cancer.

Contains fulltext : 57604.pdf (publisher's version ) (Closed access)Breast cancer is a heterogeneous disease and its consequent complexity is a major challenge for physicians and biologists. Notwithstanding its potential curability due to the availability of treatment modalities which are effective in the presence of favourable clinical or pathobiological features, there is still a great deal of controversy over its clinical management. In recent decades, tumour biomarkers that are indicative of or related to cell traits characterising malignancy--that is self-sufficiency in proliferative growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, and activation of pathways leading to neo-angiogenesis, invasion and metastasis--have provided information that has been proven to be associated with disease progression. However, when these biomarkers have been analysed individually, their prognostic relevance has been found to be modest, the only remaining clinically useful biomarkers being cell proliferation and plasminogen activation-related factors for prognosis, and steroid hormone receptors and the oncogene HER2/neu for prediction of response to hormonal therapy or to the novel targeted anti-HER2/neu therapy. It therefore remains necessary to reduce the intrinsic complexity of breast cancer in order to improve its clinical outcome. One way to achieve this objective derives directly from the concept that cancer is a genetic disease at the somatic level and from the recent availability of high-throughput post-genomic analytical tools such as gene and protein expression techniques for global gene expression analysis. Following these novel approaches, a number of recent studies have produced gene expression profiles in breast cancer that are markedly associated with disease progression and directed to answer different clinical and biological questions. However, the outcome of these novel studies still needs to be validated, which will entail cooperation between different specialists and integration of all the different skills involved in translational research in oncology

Identification, validation, and clinical implementation of tumor-associated biomarkers to improve therapy concepts, survival, and quality of life of cancer patients: tasks of the Receptor and Biomarker Group of the European Organization for Research and Treatment of Cancer.

Guiding principles are provided and discussed on how to inform the physician scientist and cancer researcher about quality control systems to enable a consistent assessment of the clinical value of tumor-associated biomarkers. Next to cancer research itself, the Receptor and Biomarker Group of the European Organization for Research and Treatment of Cancer (RBG-EORTC) advises on methodologies, test kits and test reagents utilized for tumor biomarker determination. Tumor-associated biomarkers are important and clinically useful tools which can aid the early diagnosis of cancer, determine prognosis, predict therapy response, and monitor disease. With regard to clinical use of tumor-associated bio-markers, quality assessment and quality assurance programs of the RBG-EORTC are crucially important issues. Test reagents, assays, and procedures for tumor sample collection and handling should be standardized. Furthermore, standard operating procedures (SOPs) should be developed for each type of tumor specimen. Assay formats and the quality of the tumor biomarker assay results have to be monitored by continuous within- and inter-laboratory proficiency testing. With this approach, a major step forward in the knowledge and understanding of the biological role and the clinical utility of tumor-associated biomarkers would be anticipated