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Borchiellini D.,Oncopharmacology Unit | Borchiellini D.,Center Antoine Lacassagne | Etienne-Grimaldi M.-C.,Oncopharmacology Unit | Thariat J.,Center Antoine Lacassagne | Milano G.,Oncopharmacology Unit
Cancer Treatment Reviews | Year: 2012

More than half of cancer patients are treated by radiation therapy, with a wide inter-patient variability in tumour response. Recent advances have been made in understanding molecular mechanisms that govern the behaviour of tumour cells and tissues exposed to ionizing radiation. Accumulating data suggest an important role of DNA damage response genes, including DNA repair (especially double-strand breaks), apoptosis and cell-cycle control genes. It has been hypothesized that frequent germinal polymorphisms, most often single-nucleotide polymorphisms, in DNA damage response genes may impact tumour response and clinical outcome for patients receiving a radiotherapy-based treatment. We reviewed literature covering the relationships between candidate gene polymorphisms in DNA damage response and the efficacy of a radiation-based treatment. Although several methodological limitations may preclude a definitive conclusion, single nucleotide polymorphisms of several candidate genes such as ERCC- or XRCC-family genes seem to be potential predictive biomarkers of radiotherapy efficacy, even though not strictly involved in radiotherapy-induced double-strand breaks repair. In order to improve the relevance of clinical results, and our interpretation of them, we draw a parallel between clinical findings and available preclinical data on polymorphism functionality. Clinical findings require validation in larger replication studies and open the prospect of future clinical trials. © 2012 Elsevier Ltd.


Bozec A.,Head and Neck Surgery Unit | Etienne-Grimaldi M.-C.,Oncopharmacology Unit | Fischel J.-L.,Oncopharmacology Unit | Sudaka A.,Pathology Unit | And 3 more authors.
Oral Oncology | Year: 2011

We previously reported on head and neck tumor xenografts that the tumor regression induced by a triple combination of irradiation (RT), anti-EGFR and anti-angiogenic therapies was followed, after treatment arrest, by tumor re-growth characterized by activation of the AKT signaling pathway. Since mTOR is the main AKT-related messenger, the aim of this study was to add the mTOR inhibitor temsirolimus to a tri-therapy with RT plus anti-EGFR and anti-angiogenic drugs in order to improve anti-tumor effects. The human head and neck cancer cell line CAL33 (over-expressing EGFR and secreting VEGF-A) was xenografted in nude mice. Treatment (20 mice per treatment group) was administered for 2 weeks and consisted of either vehicle (control), temsirolimus (5 mg/kg i.p. five times a week), tri-therapy with RT (6 Gy three times a week) combined with cetuximab (0.5 mg/kg i.p. five times a week) and bevacizumab (5 mg/kg i.p. five times a week) or the temsirolimus-tri-therapy association. The time to reach a tumor volume of 2000 mm3 was significantly different between the four treatment groups (Log Rank p < 0.0001), with a median of 29.5, 44.5, 67.0 and 70.0 days for control, temsirolimus, tri-therapy and combination groups, respectively. The combination of temsirolimus plus tri-therapy produced the longest growth-inhibiting effects (tri-therapy versus combination, p = 0.01). No significant interaction was observed between temsirolimus and the tri-therapy, suggesting that temsirolimus, on the one hand, and RT-cetuximab-bevacizumab, on the other, exert additive effects on tumor growth inhibition. These decreases observed on tumor growth were corroborated by the parallel decreases observed on tumor proliferation (Ki67) and on anti-apoptotic markers (Bcl2). These results suggest that temsirolimus exhibits synergistic antiproliferative effects when administered in combination with irradiation, anti-EGFR and anti-angiogenic therapies in head and neck cancer patients. © 2011 Elsevier Ltd. All rights reserved.


Fanciullino R.,La Conception University Hospital of Marseille | Ciccolini J.,Aix - Marseille University | Milano G.,Oncopharmacology Unit
Critical Reviews in Oncology/Hematology | Year: 2013

Improving the efficacy-toxicity balance of anticancer agents remains an ongoing challenge in oncology. Beside the ever-growing development of innovative drugs addressing newly discovered molecular targets, nanotechnologies provide today a promising and exciting strategy to achieve this goal. The idea of carrying active compounds to their respective targets so as to improve their efficacy while sparing healthy tissue and reducing side-effects is not new. However, this area of research is in constant rise, and benefits from the latest advances in the field of biopharmaceutics, medicinal chemistry and nanomedicine. In addition to anthracyclines already widely present as liposomal drugs on the shelves, a variety of anticancer drugs can be now encapsulated into different chemical of structures so as to enhance their specificity toward malignant cells, mainly through improved pharmacokinetics profiles. Indeed, the recent advances in chemistry allow now a wide variety of scaffolds to be used as drug-carriers, so as optimize the delivery of cytotoxics. Even more recently, conjugated-drugs such as nanoalbumin (Nab) conjugates have emerged as a new promising alternative to improve both anticancer drugs distribution in the body and efficacy/toxicity balance eventually. This review covers the achievements and current limits of nanoparticles in oncology, with a special focus on nab-paclitaxel as a paradigmatic drug for this new generation of conjugated entities. © 2013 Elsevier Ireland Ltd.


Lattanzio L.,S Croce General Hospital | Tonissi F.,S Croce General Hospital | Monteverde M.,S Croce General Hospital | Milano G.,Oncopharmacology Unit | And 2 more authors.
Anti-Cancer Drugs | Year: 2013

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). We observed an enhanced effect of docetaxel and octreotide given in combination or in sequence compared with either agent alone; this result was particularly evident when docetaxel was given before octreotide in PC3wt and when the two drugs were given together in PC3R cells. In contrast to lanreotide, our data indicate that octreotide does not act as a P-glycoprotein inhibitor in PC3R cells. A role of docetaxel and combined treatment in regulating SSTR2, SSTR5, proliferation and apoptosis gene expression is suggested as the possible mechanism for the enhanced effect observed. In addition, an evaluation of the effect of the combined treatment on cellular migration was examined, showing a moderate loss of invasive properties in PC3R cells. The present results confirm that SST analogues may be combined with docetaxel to increase the antitumour effect in patients with advanced prostate carcinoma. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.


Monteverde M.,S Croce General Hospital | Milano G.,Oncopharmacology unit | Strola G.,S Croce General Hospital | Maffi M.,S Croce General Hospital | And 5 more authors.
Critical Reviews in Oncology/Hematology | Year: 2015

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). The test performance was evaluated on different target cells lines (CAL166, A431, HNO91, CAL27), with different effector cells (peripheral blood mononuclear cells or natural killers -NK-) and in various experimental conditions, in order to establish a truly clinically applicable method. Results: Using the experience available in the published literature, we optimized all variables involved in the experimental design: target cells type, numbers and ratio target cells and NK cells (effector cells) per well, time of exposure and repeatability. Conclusion: ADCC measurement may be of clinical relevance in the context of treatment with MoAbs. This study describes a non-radioactive method which has proven satisfactory in terms of sensitivity, reproducibility, feasibility and cost effectiveness for the measurement of ADCC activity mediated by NK with an orientation towards the EGFR target. © 2015 Elsevier Ireland Ltd.


Bozec A.,Center Antoine Lacassagne | Bozec A.,Oncopharmacology Unit | Peyrade F.,Center Antoine Lacassagne | Milano G.,Oncopharmacology Unit
Anti-Cancer Agents in Medicinal Chemistry | Year: 2013

Current development of molecular targeted therapies in oncology is particularly active. This paper is a review of the recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). We analyze not only the recently published and ongoing clinical trials, but also the relevant preclinical studies, in order to identify the future directions of research in the field of HNSCC. As epidermal growth factor receptor (EGFR) signaling pathway plays a key role in the growth of HNSCC, EGFR, with its downstream effectors, represents the main target of the new therapeutic agents currently in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic disease, in association with platinum-based chemotherapy. Future advances are expected with the integration of cetuximab and other anti-EGFR agents into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors. Besides EGFR inhibition, new molecular targeted therapies such as mTOR, Src kinase, or IGF-1R inhibitors, acting on other activated molecular signaling pathways, are being developed. As these innovative molecules are beginning to be used in clinical practice, the identification of predictive markers for efficacy and toxicity is now a crucial issue. © 2013 Bentham Science Publishers.


Milano G.A.,Oncopharmacology Unit
Chinese Clinical Oncology | Year: 2015

The main molecular targeting of lung cancer [non-small cell lung cancer (NSCLC)] concerns mutations of epidermal growth factor receptor (EGFR). The awaited responsiveness of tumors carrying these mutations is high with for instance 60% to 80% with tyrosine kinase inhibitors hitting EGFR mutations. The EGFR T790M as a secondary mutation is responsible for the occurrence of a resistance phenomenon. A multitude of drugs have been produced and tested with the property of a specific binding at the EGFR T790M site. There is currently an evolution oriented to a robust genotyping methods allowing the identification of given molecular anomalies (pyrosequencing for instance) towards the consideration of a much larger set of molecular anomalies under the form of a global genotyping realized with the use of next-generation sequencing (NGS). This phase of whole genome analysis necessitates the introduction of a specialized staff for data treatment. A possible substitution plasma/tumor for the mutation analyses is perceptible in lung cancer, a preference being however given to the intratumoral direct investigation when this is feasible. EGFR mutations as targetable anomalies are illustrative examples, that the management of NSCLC is currently drawing a significant benefit from personalized therapy. © Chinese Clinical Oncology.


PubMed | Laboratoire Of Pharmacocinetique La Timone University Hospital Of Marseille, La Timone University Hospital of Marseille and Oncopharmacology Unit
Type: Journal Article | Journal: British journal of clinical pharmacology | Year: 2015

5-FU is the backbone of most regimens in digestive oncology. Administration of standard 5-FU leads to 15-30% of severe side effects, and lethal toxicities are regularly reported with fluoropyrimidine drugs. Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome responsible for most cases of life-threatening toxicities upon 5-FU intake, and pre-treatment checking for DPD status should help to reduce both incidence and severity of side effects through adaptive dosing strategies.We have used a simple method for rapidly establishing the DPD phenotype of patients with cancer and used it prospectively in 59 routine patients treated with 5-FU-based therapy for digestive cancers. No patient with total DPD deficiency was found but 23% of patients exhibited poor metabolizer phenotype, and one patient was phenotyped as profoundly deficient. Consequently, 5-FU doses in poor metabolizer patients were cut by an average 35% as compared with non deficient patients (2390 1225 mg vs. 3653 1371 mg, P < 0.003, t-test).Despite this marked reduction in 5-FU dosing, similar efficacy was achieved in the two subsets (clinical benefit: 40 vs. 43%, stable disease: 40 vs. 37%, progressive disease: 20% in both subsets, P = 0.893, Pearsons chi-square). No difference in toxicities was observed (P = 0.104, Fishers exact test). Overall, only 3% of early severe toxicities were recorded, a value markedly lower than the 15-30% ones usually reported with 5-FU.This feasibility study shows how simplified DPD-based adaptive dosing of 5-FU can reduce sharply the incidence of treatment-related severe toxicities while maintaining efficacy as part of routine clinical practice in digestive oncology.


PubMed | Annaba University, EL OKBI Public Hospital, Mohamed 1st University, Oncopharmacology Unit and 2 more.
Type: | Journal: Biomarker insights | Year: 2016

Shifting from the historical TNM paradigm to the determination of molecular and genetic subtypes of tumors has been a major improvement to better picture cancerous diseases. The sharper the picture is, the better will be the possibility to develop subsequent strategies, thus achieving higher efficacy and prolonged survival eventually. Recent studies suggest that urokinase-type plasminogen activator (uPA), uPA Receptor (uPAR), and plasmino-gen activator inhibitor-1 (PAI-1) may play a critical role in cancer invasion and metastasis. Consistent with their role in cancer dissemination, high levels of uPA, PAI-1, and uPAR in multiple cancer types correlate with dismal prognosis. In this respect, upfront determination of uPA and PAI-1 as invasion markers has further opened up the possibilities for individualized therapy of breast cancer. Indeed, uPA and PAI-1 could help to classify patients on their risk for metastatic spreading and subsequent relapse, thus helping clinicians in their decision-making process to propose, or not propose, adjuvant therapy. This review covers the implications for cancer diagnosis, prognosis, and therapy of uPA and PAI-1, and therefore how they could be major actors in the development of a precision medicine in breast cancer.


PubMed | Oncopharmacology Unit
Type: Journal Article | Journal: Chinese clinical oncology | Year: 2016

The main molecular targeting of lung cancer [non-small cell lung cancer (NSCLC)] concerns mutations of epidermal growth factor receptor (EGFR). The awaited responsiveness of tumors carrying these mutations is high with for instance 60% to 80% with tyrosine kinase inhibitors hitting EGFR mutations. The EGFR T790M as a secondary mutation is responsible for the occurrence of a resistance phenomenon. A multitude of drugs have been produced and tested with the property of a specific binding at the EGFR T790M site. There is currently an evolution oriented to a robust genotyping methods allowing the identification of given molecular anomalies (pyrosequencing for instance) towards the consideration of a much larger set of molecular anomalies under the form of a global genotyping realized with the use of next-generation sequencing (NGS). This phase of whole genome analysis necessitates the introduction of a specialized staff for data treatment. A possible substitution plasma/tumor for the mutation analyses is perceptible in lung cancer, a preference being however given to the intratumoral direct investigation when this is feasible. EGFR mutations as targetable anomalies are illustrative examples, that the management of NSCLC is currently drawing a significant benefit from personalized therapy.

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