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dc.contributor.advisorPetronini, Pier Giorgio-
dc.contributor.authorCaffarra, Cristina-
dc.description.abstractGreat strides have been done in treating cancer. For decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy which targets all dividing cells. In the last ten years the identification of different driver oncogenic mutations has allowed the development of targeted drugs. Targeted cancer therapies are based on the use of drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. The aim of my work was outlining the importance of targeted therapy in treating cancer, especially NSCLC and breast cancer. We focused our attention on these two tumors because of their deep impact in the society; lung cancer is the leading cause of cancer-related mortality for both men and women with more than 1.6 million deaths worldwide, and breast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. In particular, here I studied the molecular mechanisms underneath three targeted drugs: erlotinib and gefitinib in NSCLC, and sorafenib in BC. The research performed during my PhD course was divided in three parts. In the first part, I worked in collaboration with the Oncology Unit of University Hospital of Parma. The aim of the work was to demonstrate the utility of FDG-PET to identify early resistant patients (after 2 days of erlotinib treatment) and to predict the clinical outcome in an unselected population with pretreated advanced NSCLC. In particular, in order to mimic the assessment of tumor glucose utilization, we evaluated, in vitro, the uptake of radio-labeled deoxy-D-Glucose 2-[1,2-3H(N)] (2DG) in a panel of NSCLC cell lines treated with or without erlotinib. In accordance with the clinical data, our preclinical results suggest that conditions where erlotinib treatment increase or fails to reduce glucose uptake can be associated with resistance, whereas a decrease of glucose uptake does not necessarily indicate drug sensitivity. Moreover, the inhibition of AKT signaling pathways seems to play a role in erlotinib-mediated down-regulation of glucose transport activity. Therefore FDG-PET assessment, after 2 days of erlotinib treatment, could be clinically useful to identify early resistant patients and to predict clinical outcome in unselected population with pretreated advanced NSCLC. In the second part of my research, I focused the attention exploring the possible benefits of maintaining gefitinib in a NSCLC cell line become resistant to TKIs. Here, I studied the retained antitumor activity of gefitinib in resistant HCC827 GR5 carrying MET amplification (leading to ERBB3-mediated activation of PI3K/AKT signaling) in order to establish the possible benefits of maintaining gefitinib in patients developing an acquired resistance. In particular, our data demonstrated that despite tumor progression after treatment with gefitinib, NSCLCs with MET amplification are still dependent on EGFR signaling. In these tumors EGFR plays an important role in cell motility and invasiveness and prompts the EMT process possibly via Src signaling. In addition, our preliminary data demonstrated that maintaining gefitinib after acquired resistance in HCC827 GR5 cell line could sensitize cells to chemotherapy increasing cell death after 48 and 72h of treatment. In the last part of my work I investigated the effects and the molecular mechanisms of the multi-kinase inhibitor sorafenib in a panel of BC cell lines of different subtypes with particular attention on the effects on intracellular signaling pathways that control either cell proliferation/survival or energy metabolism. We demonstrated that sorafenib inhibited cell proliferation and induced apoptosis through the mitochondrial pathway. Sorafenib promoted an early perturbation of mitochondrial function, inducing a deep depolarization of mitochondrial membrane, associated with drop of intracellular ATP levels and increase of ROS generation. As a response to this stress condition, the energy sensor AMPK was activated and this activation persisted all along sorafenib treatment. As an early response, in MCF-7 and SKBR3 cells AMPK stimulated glucose metabolism, enhancing glycolysis, and lactate production, and increasing glucose uptake by GLUT-1 upregulation. However, persistence of energy stress during sorafenib treatment in MCF-7 and SKBR3 cells as well as in the highly-glycolytic model MDA-MB-231 resulted in the inhibition of mTORC1 pathway and the consequent decrease of glucose utilization. Our results suggest that sorafenib, being effective in all the BC cell subtypes, may be proposed as a valid support to the current established therapy for ERα-positive or HER-positive BC. Regarding TNBC the use of sorafenib in clinical practice warrants further validations. In conclusion, targeted therapy (here we give three examples of targeted drugs in NSCLC and breast cancer) could be a promising strategy in order to defeat cancer. Genomic and proteomic technologies have generated an enormous amount of information critical to expanding our understanding of cancer biology. New research on the differences between normal and malignant cell biology has paved the way for the development of drugs targeted to specific biological molecules, potentially increasing antitumor efficacy while minimizing the toxicity to the patient that is seen with conventional therapeutics. Thus collaboration among researchers, clinicians, and pharmaceutical companies is vital to conducting clinical trials to translate laboratory findings into clinically applicable therapeutics (Translation Medicine) and then helping to choose “the right therapy for the right patient”.it
dc.publisherUniversità di Parma. Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionaliit
dc.relation.ispartofseriesDottorato di ricerca in biologia e patologia molecolareit
dc.rights© Cristina Caffarra, 2015it
dc.subjectLung cancerit
dc.subjectbreast cancerit
dc.subject18 FDG-PETit
dc.subjectEnergy metabolismit
dc.titleTargeted therapy in lung and breast cancer: a big dealit
dc.title.alternativeTerapia a bersaglio molecolare nel cancro al polmone e alla mammella: una grande opportunitàit
dc.typeDoctoral thesisit
Appears in Collections:Scienze biomediche, biotecnologiche e traslazionali, Tesi di dottorato

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