RESEARCH GROUP

Maurizio D'Incalci

  • Maurizio D’Incalci Head of Group of Cancer Pharmacology View More

Group of Cancer Pharmacology

The overall aim of our research is to improve cancer treatments by discovering new drugs and designing new synergistic combinations of drugs and other therapeutic modalities. Our pharmacological approaches are linked to biological investigations aimed at both identification of molecular targets for novel drugs and development of biomarkers potentially useful for the early diagnosis of neoplastic disease and the monitoring of the success of its bespoke therapy.

Integration of biological with preclinical and clinical pharmacology studies drives the discovery and development of new treatments. Genomic and transcriptomic analyses, using robust bioinformatic processes for data integration, and in vitro pharmacological assays are accompanied by analytical techniques for the accurate measurement of drug concentration. Quantifying drugs in samples of biological tissues or fluids by state-of-the-art analytical methods allows the correlation of pharmacodynamic effects with drug levels at the target site. Spatial heterogeneity characterizing the tumor mass is also assessed by taking into account both phenotypic and molecular alterations in cells and visualizing drug distribution within tumor tissue.

Description of the scientific interests of the laboratory

Determination of drug distribution in the preclinical and clinical setting, with a specific focus on drug penetration within neoplastic tissues

Tumor drug concentration is a key determinant for the activity of any drug. Drug plasma levels often fail to predict tumor concentrations because the heterogeneous architecture of the tumor microenvironment prevents reliable extrapolation of circulating to tissue levels. Our research focuses primarily on the development of analytical methods to measure drug concentration in the target tissue after homogenization and to visualize intra-tumoral heterogeneity of drug distribution by mass spectrometry imaging. We also apply these technologies to investigate whether certain compounds which modify tumor structure can act as “distribution enhancers” and improve the ability of drugs to penetrate tumor tissue. A long-term goal is the development of smart drug combinations and therapies against solid tumors that exploit novel nanotechnology approaches.

Evaluation of early molecular alterations in ovarian cancer that improves disease diagnosis and helps identify novel pharmacological targets

The recent development of novel and high sensitivity technologies has engendered a plethora of novel opportunities to identify biomarkers for early disease detection and new targets for selective treatments. We have recently demonstrated in a small cohort of patients that the pathogenic TP53 mutations that characterize the genomic landscape of high grade serous ovarian cancer can be detected in DNA purified from pap test smear as early as 6 years before the diagnosis of ovarian cancer in women who do not present with any clinical evidence of disease. Although these results are preliminary and need validation in a larger cohort of cases, our insights may well pave the way for novel approaches to the early diagnosis of ovarian cancer.

Patients with disease confined to the ovary (stage I) survive longer than patients with advanced disease (stage III/IV). Nevertheless, a proportion of stage I cases do not respond to therapy and relapse with aggressive disease. We investigate whether the variable response to current therapies of stage I ovarian cancer patients correlates with different molecular features of the tumors. Studies are directed to test the hypothesis that relapsing tumors are genomically and/or transcriptionally different from non-relapsing tumors. Identifying these differences could be crucial in the discovery of novel pharmacological approaches.

Predictors of therapeutic response of ovarian cancer patients

We aim to identify biomarkers that are not only predictive of therapeutic response but can also guide the optimisation of each patient’s therapy, consistent with the principle of personalized medicine. We have been part in a European consortium to develop an assay able to select ovarian cancer patients eligible for combined treatment with PARP inhibitors and platinum-based chemotherapy. The assay is based on the detection of alterations in homologous recombination repair, since patients bearing tumors with these defects seem to benefit most from this drug combination. After validating the technical reliability and clinical usefulness of this assay, we plan to apply it to stratify patients, thus optimizing treatments with drugs interfering with DNA repair such as PARP inhibitors or other new compounds currently under development.

Although ovarian cancer patients respond to front-line platinum-based chemotherapy, more than 80% of cases relapse with progressive drug-resistant disease. Current therapeutic strategies for relapsed disease are largely empirical and treatment decisions are based on the time lag between termination of chemotherapy and clinical relapse. Molecular data do not exist on the biology of relapsed disease and the extent to which the molecular portrait of the tumor after chemotherapy mirrors that of the primary disease. To address these issues, we have developed an assay based on the analysis of circulating tumor DNA in the plasma (liquid biopsy), that predicts disease relapse better than do conventional radiological and biochemical diagnostic tools. This assay captures major biological features of relapsed disease.

Identification of molecular features of aggressiveness and development of effective therapies against malignant mesothelioma

Malignant pleural mesothelioma is a rare cancer of the pleural lining with a dismal prognosis and poorly effective treatments. In the recent past only very few new therapies against this disease have been approved. They are immunotherapy, which triggers immune cells to fight tumor cells, and electric fields at low intensity and intermediate frequency (Tumor Treating Fields – TTFields) used in combination with standard chemotherapy. Our research investigates the pathogenesis of mesothelioma and the effects of therapies on tumor cells and their microenvironment through the integration of omics data derived from both clinical cohorts and pre-clinical models. The study of interactions between TTFields, cancer cells and anticancer agents will pave the way for new and hopefully improved therapeutic strategies.

Reactivation of adipocytic differentiation of liposarcomas

For many years our group has played a major role in elucidating the mode of action of the marine natural product trabectedin and in its preclinical and clinical development. This effort has contributed to its routine use in the treatment of soft tissue sarcoma. The ability of trabectedin to modulate tumor-associated macrophages provides a rational for combinations of this drug, or its analog lubinectedin, with immunotherapeutic approaches. We found that the high activity of trabectedin against liposarcoma is related to its ability to induce adipocytic differentiation. We are now exploring if this concept can be translated into the clinic by investigating combinations of trabectedin with drugs that enhance the differentiation effects. Initial data suggest the feasibility of this approach, and a clinical trial of the combination of trabectedin with the PPARg agonist pioglitazone has been started.

    Selected Publications

  • Maurizio D'Incalci Publications

    Selected Publications Belgiovine C, Frapolli R, Liguori M, Digifico E, Colombo FS, Meroni M, Allavena P, D'Incalci M. Inhibition of tumor-associated macrophages by trabectedin improves the antitumor adaptive immunity in ...

  • Sergio Marchini Publications

    Selected publications Paracchini, L., Beltrame, L., Grassi, T., Inglesi, A., Fruscio, R., Landoni, F., Ippolito, D., Marchette, M.D., Paderno, M., Adorni, M., Jaconi, M., Romualdi, C., D'Incalci, M., Siravegna, G., ...

  • Monica Lupi Publications

    Selected publications Restelli V, Lupi M, Chilà R, Vagni M, Tarantelli C, Spriano F, Gaudio E, Bertoni F, Damia G, Carrassa L. DNA damage response inhibitor combinations exert synergistic antitumor ...

  • Lavinia Morosi Publications

    Selected publications Morosi L, Meroni M, Ubezio P, Fuso Nerini I, Minoli L, Porcu L, Panini N, Colombo M, Blouw B, Kang DW, Davoli E, Zucchetti M, D'Incalci M, Frapolli ...

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