Thyroid cancer (TC) is the most common endocrine malignancy and can be subdivided in differentiated thyroid carcinomas (DTC), follicular and papillary carcinomas, and medullary thyroid carcinoma (MTC), which have distinct cells of origin and biological features. All TCs are surgically removed and DTC patients undergo radioiodine therapy. However, DTCs occasionally progress into more aggressive poorly differentiated (PDTC) and anaplastic (ATC) carcinoma and about half of MTC patients already present metastatic disease at diagnosis.
Patients with in progressive metastatic radioiodine-refractory differentiated thyroid cancer and with MTC undergo protein kinase inhibitors (PKIs) therapies, but the biomarkers currently in use, thyroglobulin for DTC and calcitonin for MTC, can be unreliable in cases of undifferentiated cancer cells, where the expression of these biomarkers can be lost.
The aim of the proposed project is to identify new circulating biomarkers in TC patients who are eligible for PKI therapy. An emerging tool is circulating microRNAs that can be detected from plasma samples. Specifically, they have been used as diagnostic, prognostic and predictive biomarkers in several diseases including cancer while their possible value as biomarker in TC is still poorly defined.
The proposed project will first evaluate microRNAs profile of TC patients at diagnosis, to correlate them with clinico-pathological features; secondly microRNA profiling will be performed on TC patients undergoing PKI treatment and we will correlate detected circulating microRNA with response to therapy.
Finally, selected microRNAs significantly deregulated in TC patients under protein kinase inhibitor treatment will be investigated for their role in TC context through in vitro and in vivo experiments.
The results obtained from this project will prove useful for the classification of TC patients and subsequent treatment plan.
Until now, the use of the serum markers thyroglobulin and calcitonin in DTC and MTC respectively, has proved to be insufficient in poorly differentiated cases, a problem that the scientific community has not yet been able to resolve. The proposed project is a pilot study with the overall purpose of providing predictive molecular biomarkers of response to protein kinase inhibitor treatment in patients with thyroid cancer. We can envisage an important impact due to the possibility of early identification of patients who will not respond to RAI and/or PKI therapy thus avoiding expensive ineffective treatments and toxicity. Since patient mortality and high-risk disease are characterized by the presence of metastatic lesions, there is significant interest in unraveling the role of circulating miRNA profiling in this context. If the efficacy of the PKI could be strictly dependent on the molecular alterations, liquid biopsy represents a non-invasive, and at the same time the most reliable method to obtain tumor-derived molecules. Moreover, liquid biopsies could provide us information superimposable to those obtained with tissue biopsies.
We expect to fulfill the aim of this project and discover a circulating miRNA signature correlated to response to PKI therapy.
We believe that this project can contribute to the advancement of knowledge for the following reasons: Prof. Ferretti has many years of experience and specific expertise in the fields involved in this project. She has concentrated her interest on tumorigenic key events investigating their molecular aspects and focusing on how this information can be used in thyroid cancer (1-16). She also focused on the study of non-coding RNAs, mainly microRNAs, in tumors and metabolic diseases (17-25). On this research field she has established a collaboration with Prof. Giacomelli and Dr. Metere. Prof. Ferretti's laboratory has successfully developed in vitro models of primary cells culture for the study of different types of tumors (26-32). Moreover, in vivo human cancer cell-derived xenograft models have been developed (33). The research unit coordinated by Prof. Ferretti is located in the Department of Experimental Medicine of Sapienza University and provides laboratories of biochemistry, molecular biology, cell culture/cell biology, and animal facility.
Moreover, Prof. Ferretti's laboratory is inserted in an optimal environment, from the translational research point of view, as she has a direct, tight link to the clinical setting. She has recently established a scientific collaboration with the Endocrinology Unit at University of Siena, Prof. Dotta, Dr. Besharat. The external participant of this project have in their possession a biobank of thyroid tumors and there will be ample opportunity to later validate Prof. Ferretti molecular findings in an independent set of tumors and to possibly translate molecular findings into clinical algorithms in the future.
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