The Laboratory is engaged in the generation of tumor models of ovarian cancer (serous, mucinous, or clear cell) using surgical material obtained directly from patients and implanted into immunodeficient mice. These models, which are fundamental to the molecular biological and pharmacological characterization of these tumors, have characteristics similar to the human tumors from which they originate. Drug resistance is one of the big problems inevitably encountered in the clinic and its reversion/delay is an important clinical need. Starting from these models, we obtained resistant to drugs commonly used in the clinic; these models are under investigation to try to understand the molecular mechanisms related to the onset of resistance and to try to overcome this phenomenon with new combinations and/or new drugs. In addition, drug libraries, siRNA and CRISP-R are being used to find genes in synthetic lethality that are useful in identifying potentially more active and less toxic combinations, and to identify new potentially actionable targets for this cancer. Finally, the laboratory is engaged in the search for biomarkers useful for selecting the best treatment to administer to patients.
Generation of preclinical models that recapitulate human tumor characteristics
The collaboration with the Department of Gynecologic Surgery at San Gerardo Hospital in Monza, Italy, allows us to have tumor material available for transplantation into immune-deficient mice and expand our panel of human carcinoma xenografts (patient-derived xenogarfst-PDXs), which we characterize histologically, molecularly, metabolically and pharmacologically. In addition, during the past years we have obtained sublines of PDXs resistant to cisplatin and olaparib (a PARPi)., two important drugs for the treatment of ovarian cancer, after repeated in vivo treatments of PDX-bearing mice. This way of obtaining resistant sublines is much closer to what happens in the clinic. In fact, ovarian carcinoma patients are very sensitive to chemotherapy treatment, but at relapse the tumor is less and less sensitive to chemotherapy because it acquires resistance. These new models are being used to study the mechanisms underlying resistance, which can give us important information about possible pharmacological approaches that can be used to overcome and/or delay it.
Role of DNA repair in treatment sensitivity/resistance
Cancer cells often have DNA repair systems that make response to drug treatment inefficient. We study these mechanisms with the aim of identifying possible markers of response that can be used in the clinic and at the same time to try to interfere with the repair mechanisms to make the response to treatment more efficient. We are particularly interested in the sensitivity and resistance of platinum-based compounds, very important agents for the treatment of several cancers (such as ovarian and lung) and to poly-ADP-ribosylation inhibitors (PARPi), an emerging class of drugs particularly for the treatment of repair-deficient cancers (such as ovarian and breast). We are looking for biomarkers of response in the area of DNA repair that can distinguish tumors that will respond to platinum- or olaparib (a PARPi) -based therapy. These studies are very important because the identification of such markers would prevent (toxic) treatment in those patients who would most likely not respond based on the presence or absence of the marker.
Tumoral metabolism and resistance to cisplatin
Starting with sensitive and therapy-resistant tumors, we investigated the role of metabolism in causing cisplatin resistance. Recent studies from our laboratory suggest how in fact in resistant tumors there has been an alteration in cellular metabolism, with a different production/utilization of internal energy sources. The identification of this alterated metabolic pathways allowed us to selectively target them with specific drugs that have resulted in a reversion of cisplatin resistance. In addition, we are trying to modulate tumor metabolism with particular dietary interventions (alternate fasting, presence or absence of specific diet components) and test how such modulation may affect the efficacy and toxicity of chemotherapy treatment.
International Consensus on Cardiopulmonary Resuscitation.