Valutazione dell'attivita' antitumorale di farmaci a target osseo-chemioterapici convenzionali e identificazione di biomarcatori per la selezione di pazienti con carcinoma della mammella per la terapia a target osseo in fase adiuvante

Mercatali, Laura (2014) Valutazione dell'attivita' antitumorale di farmaci a target osseo-chemioterapici convenzionali e identificazione di biomarcatori per la selezione di pazienti con carcinoma della mammella per la terapia a target osseo in fase adiuvante, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze farmacologiche e tossicologiche, dello sviluppo e del movimento umano, 26 Ciclo. DOI 10.6092/unibo/amsdottorato/6394.
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Abstract

Bone metastases are responsible for different clinical complications defined as skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, hypercalcaemia, bone marrow infiltration and severe bone pain requiring palliative radiotherapy. The general aim of these three years research period was to improve the management of patients with bone metastases through two different approaches of translational research. Firstly in vitro preclinical tests were conducted on breast cancer cells and on indirect co-colture of cancer cells and osteoclasts to evaluate bone targeted therapy singly and in combination with conventional chemotherapy. The study suggests that zoledronic acid has an antitumor activity in breast cancer cell lines. Its mechanism of action involves the decrease of RAS and RHO, as in osteoclasts. Repeated treatment enhances antitumor activity compared to non-repeated treatment. Furthermore the combination Zoledronic Acid + Cisplatin induced a high antitumoral activity in the two triple-negative lines MDA-MB-231 and BRC-230. The p21, pMAPK and m-TOR pathways were regulated by this combined treatment, particularly at lower Cisplatin doses. A co-colture system to test the activity of bone-targeted molecules on monocytes-breast conditioned by breast cancer cells was also developed. Another important criticism of the treatment of breast cancer patients, is the selection of patients who will benefit of bone targeted therapy in the adjuvant setting. A retrospective case-control study on breast cancer patients to find new predictive markers of bone metastases in the primary tumors was performed. Eight markers were evaluated and TFF1 and CXCR4 were found to discriminate between patients with relapse to bone respect to patients with no evidence of disease. In particular TFF1 was the most accurate marker reaching a sensitivity of 63% and a specificity of 79%. This marker could be a useful tool for clinicians to select patients who could benefit for bone targeted therapy in adjuvant setting.

Abstract
Tipologia del documento
Tesi di dottorato
Autore
Mercatali, Laura
Supervisore
Co-supervisore
Dottorato di ricerca
Scuola di dottorato
Scienze biologiche, biomediche e biotecnologiche
Ciclo
26
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
Bone metastases, breast cancer, Zoledronic acid, Denosumab,cell lines, Translational research
URN:NBN
DOI
10.6092/unibo/amsdottorato/6394
Data di discussione
7 Aprile 2014
URI

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