The laboratory is involved in the evaluation of the prognostic and predictive effect of molecular alterations (gene mutations, amplifications, translocations, DNA methylation), investigated in different genes of lung cancer patients; furthermore, it is working in the generation of cellular models expressing the main molecular alterations found in the clinic, in order to identify new drugs with selective action.
The generation of tumor models of ovarian cancer, thymomas and mesotheliomas using surgical specimens obtained directly from patients and implanted in immunodeficient mice is another focus of the laboratory. The use of these models allows a better biological, molecular and pharmacological characterization of these tumors. In particular, in these models siRNA and CRISP-R libraries are employed in order to find genes in synthetic lethality useful in the identification of potentially more active and less toxic drugs combinations as well as in the identification of those genes responsible for drug resistance, unfortunately events inevitably in the clinic.
Characterization of thoracic (lung, thymus and mesothelioma) and ovarian carcinoma tumor models
In collaboration with many surgery departments in Lombardy, during the last years many different animal models were generated, by transplanting fragments of surgical material into immunodeficient mice. In this manner, Patient Derived Xenograft (PDX) are obtained, in order to study human tumors that grow in the animal. Furthermore, we are producing also Patients Derived Organoids (PDO) or simple cell lines, after enzymatic digestion of the surgical specimen. All these models, different in complexity and composition, represent a priceless source that allows the investigation of tumor biology and the research of compounds able to contrast tumor growth and its metastasis generation, by identifying targets and drugs that can inhibit them. In particular, the ovarian PDX biobank, generated during these years, permits the identification of markers of response to platinum-compounds, first-line therapy in the treatment of ovarian cancer.
DNA repair pathway role in the onset of sensitivity/resistance to treatments
Frequently, the DNA repair pathway of cancer cells contrasts and weakens the response to drug treatment. The study of these mechanisms is done with the aim of identifying potential response markers, that can be used in clinic; moreover, the understanding of these mechanisms could help in interfering with the DNA repair pathway, so that treatments can become more efficient. We are particularly interested in the study of drug-sensitivity and of resistance development to platinum-based compounds, very effective drugs in the treatment of different tumors (including ovary and lung). We also focus our research on poly-ADP-ribosylation inhibitors (PARPi), an emerging class of drugs used for the treatment of tumors with repair deficits (such as ovary and breast).
Cellular metabolism, and cisplatin and active drugs versus signaling pathway resistance
Starting from sensitive and therapy-resistant tumors, we evaluate whether cellular metabolism alterations could help to explain the onset of resistance. Cancer cells could use endogenous cell energy in a different manner: thus, this represents a good point to be targeted in tumor metabolism with selective drugs.
Development of drugs able to improve immunotherapy response
The discovery and the use of drugs able to activate the immune response shake up the chemotherapy of lung cancer. In a good percentage of cases, indeed, a high response, which translates in a strong increase in survival, is observed. Unfortunately, treatments response is not always the same in all patients. For this reason, through the screening of drug libraries, we are trying to identify molecules able to increase the immune-response in those patients that are unresponsive.
New combination studies by screening of siRNA, drugs and CRISP-R libraries
Using chemical libraries of small interference RNA and of CRISP-R (a new efficient kind of genetic engineering method), we try to identify new druggable targets in our studied tumors, and we are also trying to find combinations of two drugs, whose effect should be more effective than that obtained from the sum of single drugs effect. This would offer an advantage in terms of reduced toxicity.
Identification of tumor critical issues, targets of new therapeutic strategies
The most common lung cancer (that is the Non Small Cell Lung Cancer) is often characterized by alterations in genes that make it more aggressive and metastatic. We have recently highlighted that alterations in the STK11/LKB1 gene, one of the most frequently mutated in lung cancer, could promote tumor growth and dissemination. We have demonstrated that these alterations could represent a vulnerability that could be targeted by specific drugs, such as ERK inhibitors that are indeed active in this tumor only if the STK11/LKB1 gene is altered.
International Consensus on Cardiopulmonary Resuscitation.