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Laboratory of Cancer Pharmacology

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The laboratory investigates the mode of action of anticancer drugs and their pharmacokinetic and pharmacodynamic properties in several preclinical experimental models and in the clinic.

A peculiar interest is directed to the study of “smart combinations” of drugs grounded on detailed knowledge of molecular pharmacology and biological features of each tumor type. The different combinations include those drugs acting against cancer cells and drugs acting on tumor microenvironment. For some tumors such as ovarian cancers, mesotheliomas and sarcomas the biological studies are integrated with preclinical and clinical pharmacological evaluations.


Mode of action of Ecteinascidines and mechanisms of resistance

Our research is focussed on the study of the mode of action and of pharmacokinetic and pharmacodynamic properties of the marine natural product trabectedin and its derivates. These drugs are effective against a variety of tumors but the molecular mechanisms of action is not fully elucidated yet. We have developed in vitro and in vivo preclinical tumor models with a different degree of sensitivity to these drugs. These models are very useful for mechanistic studies. Work is in progress to investigate combinations of drugs that overcome the resistance against trabectedin and its derivatives and thus potentially useful in the clinic.

Mesotheliomas: experimental models and identification of new drugs

The available therapies against the malignant mesothelioma are poorly effective and it is urgent to identify the mechanisms behind the aggressiveness of this tumor. The first step is the development of adequate preclinical models. Our research is focused on development of preclinical models that reproduce the biological features of human tumors by a pathological, pharmacological, and molecular point of view. These models form a preclinical platform that is very useful to test the antitumor efficacy of new therapeutic strategies that include either new compounds or pharmacological combinations selected to inhibit those cellular pathways that cause the malignant behaviour of mesothelioma.

Experimental models of soft tissue sarcomas

Myxoid liposarcomas, leiomiosarcomas and Ewing sarcomas are rare tumors characterized by a poor prognosis if they are diagnosed at advanced stage. To investigate the molecular and cellular mechanisms responsible for the aggressiveness of these tumor we need experimental models suitable to perform preclinical studies. Our research is focused on the development of new cell lines that grow in tissue culture. These cell lines are very useful to investigate molecular mechanisms behind the sensitivity or resistance to drugs. On the other hand the murine in vivo models are important to investigate the effects of drugs on the organism. These experimental models reproduce the biological and clinical features of human tumors both in terms of phenotypic and genotypic characteristics.

Induction of differentiation of liposarcomas

The mechanisms of cellular differentiation that is crucial for the specialized function of normal cells are altered in tumors. Therefore the induction of differentiation can be exploited to achieve an antitumoral effect that is different from those that are obtained using standard cytotoxic therapies. We have observed that combining the antidiabetic drug pioglytazone and the anticancer drug trabectedin we induce the adipocytic differentiation of mixoyd liposarcomas. Our research is currently directly to elucidate the molecular mechanisms behind these pathways in order to set up more effective therapies.

Molecular characterization of epithelial ovarian cancer

The available therapies against epithelial ovarian cancer are not fully satisfactory. The identification of prognostic and predictive biomarkers will make it possible to stratify ovarian cancer patients in order to select the most effective and less toxic therapy to each patient. This approach will be useful for early ovarian cancer as well as for patients at advanced stage. Our research is focused on the integration of mutational profiles of tumor biopsies with gene expression data taking into account also epigenetic mechanisms.

Combinations between marine natural products and other anticancer drugs

A promising research strategy to develop more effective anticancer therapy is the combination of drugs that act on metabolic pathways of neoplastic cells in a synergistic fashion. Our research is particularly focused on the development of combinations between the marine natural product trabectedin and other antineoplastic agents. The in vitro and in vivo studies make it possible the characterization of the pharmacokinetic and pharmacodynamic effects of treatments in order to select those combinations that show the best therapeutic index.

Analysis of cell cycle data: the mechanisms behind the uncontrolled proliferation of tumors

Tumors are characterized by cells that proliferate in an uncontrolled fashion. In normal tissues cell divide reaching mythosis after crossing very well defined cell cycle phases that are regulated according to the physiological needs of each cell type. Tumors loose the balanced regulation between proliferation and cell death with consequent increase in cell numbers. The determination of these phenomena are indirect and our research is directed to decipher them using mathematical models and computers simulation programs that are suitable to provide an overall picture of the processes relevant to tumor growth.

Analysis of the response of tumor cell populations to treatment: towards the optimization of dosage-schedules of anticancer drugs

Within a tumor there is an heterogeneous rate of proliferation and response to anticancer treatments. Some cells are killed, some decrease their rate of proliferation and these effects are dependent on the doses as well as on the duration of treatments, with effects that may change over-time. The response to treatments can be measured by applying a combination of experimental technologies as well as computer simulations that can provide the important information to optimize the doses and the duration of treatments of single drugs and of combinations.

Analysis of response to treatments by means of time-lapse imaging and flow-cytometry

Our research is focused on the evaluation of cellular heterogeneity and cellular response to anticancer drugs by using both multiparametric flow-cytometry analysis and time-lapse imaging. The use of these technologies allow a quantitative evaluation of cell cycle perturbations, of DNA damage and cell death caused by treatment. The comparative analysis of different drugs provide information of the mechanism of action by which they inhibit cell proliferation.

Nanotechnologies applied to identify new therapeutic strategies against cancer

Our research is focused on studies related to polymeric biodegradable nanoparticles used as vehicles of anticancer drugs. The in vitro experiments on cell lines allow the evaluation of the uptake of drugs as well as their intracellular distribution. The in vivo studies are essential to characterize the distribution of drugs vehiculated by nanovectors in neoplastic and normal tissues. The ultimate aim of this work is to improve the efficiency of drug distribution in the tumor with consequent increase in the drug therapeutic index.

Clinical pharmacokinetics of new anticancer drugs

Phase I clinical studies are the first step of investigation of a new drug in man. One of the objectives of phase I studies is to characterize the pharmacokinetic properties of the new drug, i.e. its absorption, distribution, metabolism and elimination. Our research is focused on the development of analytical methods to determine anticancer drugs in biological fluids and tissues that are suitable to characterize the drug pharmacokinetics during phase I clinical studies. Our studies include the evaluation of pharmacological interactions, particularly in relation to the distribution of drugs when given in combination with other drugs.

Pharmacokinetic properties of new drugs and drug combinations

Our research is focused on investigations of anticancer drug distribution both in normal tissues (e.g. liver, kidney, brain, etc.) and in neoplastic tissues, including primary tumors and metastasis. Since a detailed analysis of distribution cannot be made directly in humans we use in vivo animal models that are essential to assess the pharmacokinetic properties of new drugs. An important part of these studies is related to the evaluation of drug distribution according to different dosage-schedules and combinations with other drugs. The ultimate objective is to identify the most appropriate dosage-schedules and combinations that optimize the penetration of active drug concentrations in tumor tissues.

Methods to enhance tumor drug distribution

Our research is focused on the characterization of the heterogeneity of distribution of anticancer drugs in tumors by applying imaging mass-spectrometry methods that allow to detect differences of drug concentrations in the different parts of the tumor. New technologies aimed at enhancing tumor distribution of drugs are under development by i) modifying chemico-phisycal properties of the drug (e.g. incapsulation of nanoparticles); ii) combining the drug with compounds that enhance the distribution modifying the tissue structure (e.g. drugs acting on tumor stroma). The imaging technique are associated with classical analytical quantitative methods that provide a complete picture of the drug distribution in the organism.

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