DEVELOPMENT AND VALIDATION OF TARGET THERAPIES FOR PATIENTS WITH BRAIN CANCER, THROUGH THE MODULATION OF ANGIOGENESIS, INVASIVENESS, AND PHARMACOLOGICAL SENSITIVITY/RESISTANCE, IN THE ERA OF PRECISION MEDICINE
Tesi di Dottorato
Data di Pubblicazione:
2022
Citazione:
DEVELOPMENT AND VALIDATION OF TARGET THERAPIES FOR PATIENTS WITH BRAIN CANCER, THROUGH THE MODULATION OF ANGIOGENESIS, INVASIVENESS, AND PHARMACOLOGICAL SENSITIVITY/RESISTANCE, IN THE ERA OF PRECISION MEDICINE / L. Guarnaccia ; supervisor: G. Mantovani ; co-supervisor: G. Marfia, S. E. Navone ; PhD coordinator: C. Sforza. Dipartimento di Scienze Cliniche e di Comunità, 2022 Jan 14. 34. ciclo, Anno Accademico 2021.
Abstract:
Brain tumors represent a group of heterogeneous neoplasms which, despite originating in the same
anatomical region, differ in morphology, etiology, molecular biology, and especially in clinical
behavior. It has been estimated that brain tumors affect about 200,000 people worldwide every year,
representing approximately 2% of cancer deaths. Among all primary human brain tumors,
glioblastoma (GBM) is the most malignant and frequent (~70%), with a median survival of about 14
months and a 5-year survival rate at 5%, thus representing an extreme therapeutic challenge. GBM is
characterized by sustained proliferation and survival, immune system escape, intense angiogenesis,
invasion, cell infiltration, rapid progression, resistance to radio- and chemotherapies, with high
frequency of relapse. In cancer pathogenesis, particularly in high grade tumors as GBM, aberrant
neo-angiogenesis is a vital process for the mass growth: it is driven by neoplastic cells in order to
respond to the tumoral hypoxic environment in the necrotic core, which increases the demand for
oxygen and nutrients by neoplastic cells, and is, therefore, essential to carry out the metabolic
functions on which their survival is based. Several observations led to the knowledge that tumoral
neo-angiogenesis gives rise to ultra-structurally abnormal vessels, larger than their normal
counterparts, dilated, convoluted, irregularly branched and exceptionally permeable due to the
presence of fenestrations and the lack of a complete basal membrane. Due to these destructive
features, despite aggressive therapeutic treatment, consisting in surgical resection followed by
chemotherapy with temozolomide (TMZ), most patients experience tumor recurrence in less than one
year, suggesting the urgent need to implement clinical practice with novel prognostic and therapeutic
strategies. To this aim, this research project has been focused on: i) aberrant angiogenesis mediated
by endothelial cells (ECs), which promote tumor infiltration into surrounding tissues, with consequent
compromission of cognitive skills, and ii) genetic instability, which characterize GBM with a high
intra- and intertumoral heterogeneity. In particular, the underlying hypothesis is that a specific
molecular signature characterizes “resistant” and “sensitive” GBM, and it may be responsible for
patient overall survival. Indeed, although GBMs from short- and long-term survivors (STS and LTS)
are histologically the same, their biological and molecular characteristics are remarkably different,
suggesting that factors that contribute to patients’ longevity are important for precise diagnosis and
correct clinical management of the disease. The genetic profiling obtained by array CGH on STS and
LTS revealed a high number of copy number variation (CNVs) across chromosomes 1 to 22, among
which several novel potential prognostic and predictive biomarkers have been described and
discussed. In particular, aCGH highlighted the presence of an altered chromosomic pattern relative
to calpain family genes. Calpains are a conserved family of cysteine proteinases that catalyze the
controlled proteolysis of many specific substrates. Calpain activity is implicated in several
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fundamental physiological processes, including cytoskeletal remodeling, cellular signalling,
apoptosis and cell survival. Alterations of the calpain activity balance has been observed in numerous
cancer types, as they can reduce apoptosis, increase cell proliferation and stimulate cell migration and
invasiveness. The characterization of calpain expression in primary GBM endothelial cells (GECs)
showed an upregulation of calpains and a positive correlation between expression level and patient
survival. The blockade of cal
Tipologia IRIS:
Tesi di dottorato
Keywords:
brain tumors ; glioblastoma; angiogenesis; personalized medicine; array-CGH; calpains
Elenco autori:
L. Guarnaccia
Link alla scheda completa: