RICERCA ITALIANA     

Diagnostic and therapeutic implications of the new clinic and molecular knowledges of medullary thyroid carcinoma del .

Università di Pisa

Abstract

BACKGROUND: Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that arises from C cells. It is a rare neoplasia with a prevalence of 5-10% among all thyroid cancer. Mutations of RET gene are the unique genetic alterations found in MTC. Both somatic and germline RET point mutations are able to constitutively activate the intracellular MAP kinase pathway, which ends up in a uncontrolled cell proliferation. RET point mutations are responsible for the development of virtually all inherited MTCs and of about 40% of sporadic MTC. However 60% of sporadic MTC are still “orphans” of causative oncogene. Since the clinical and pathological features of RET positive and RET negative MTC are very similar, it is conceivable that the same MAP kinase pathway activation can drive the tumoral transformation in the two groups. Other mechanisms of RET activation should be explored as possible alternative causes of MAP kinase pathway activation.
Genetic screening of RET gene is now a powerful diagnostic tool for MTC. Even if this discovery greatly improved the diagnosis of MTC, the definitive cure of the MTC patients can be achieved only in case of an early diagnosis and a total thyroidectomy, performed when the tumor is still intrathyroid. Therefore, the survival rate is 50% at 10 years and decreases to 10% in cases with distant metastases at diagnosis. At present no markers of tumor progression and no specific prognostic factors are used in the clinical practice. >>>

Principal Investigator

Rossella Elisei Università degli Studi di PISA

Research Objectives

The general aim of the present project is to investigate the molecular features of Medullary Thyroid Carcinoma (MTC), to identify alternative mechanisms of tumoral transformation, to find out new prognostic factors and to identify new therapies. Since this thyroid neoplasia is rare (0.05-0.1% of all human tumors) the studies are always performed in small series and with short term follow up. Despite its rarity, it is a killing tumor and the survival rate at 5 years is 50% and decreases up to 10% when the tumoral stage at diagnosis is advanced. Conventional therapies, such as chemotherapy and radiotherapy are ineffective and are only used as palliative therapies. Since the pathogenesis of MTC is related to the activation of RET protooncogene, which encodes for a tyrosine kinase receptor, new tyrosine kinase inhibitors are under development and clinical evaluation. However, while 99% of hereditary MTC are associated to RET germline mutations, only 40-50% of sporadic MTC show a somatic mutation of this gene. It is conceivable that other oncogenes or other mechanisms of RET activation may be responsible for the tumoral transformation of the remaining 50-60% of MTC cases. Thus, the identification of these alternative mechanisms or genes involved in the development of MTC will be of great clinical impact not only for better understand the pathogenesis of the tumor but also for the development of other new therapeutic strategies that are really urgent for these patients.
The >>>

First Results

The main purpose of this proposed project is to investigate some molecular aspects of Medullary Thyroid Carcinoma (MTC) that should allow to identify alternative mechanisms of tumoral transformation and find new markers for the diagnosis and prognosis of this very rare disease. New therapies will be also searched for because, when advanced and metastatic, this tumor is lethal. We feel that the project will end up in very important results with great clinical benefit. The strength of the project is the network of these 5 units that, although with different interests, are all involved in the research on MTC. Furthermore, since the MTC is a very rare disease (0.05-0.1% of all human tumors) only the collaborations of referral centers such those involved in the project may guarantee a relative high number of both tumoral tissues and patients to be included in the different aspects of the research. The results we are planning to obtain can be distinguished according to the 3 different objectives we would like to reach. Here following are the details of the predicted results and the clinical benefits that can derive from them.

OBJECTIVE 1 Analysis of the molecular features of MTC and identification of alternative mechanisms of tumoral transformation. In the framework of this objective we expect to identify the molecular features of MTC and to clarify alternative mechanisms of tumoral transformation. In particular there are 50-60% of sporadic and 1-2% of hereditary >>>

Timescale

24 months

National and international background

Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that arises from parafollicular or calcitonin-producing C cells of the thyroid. It is a rare malignant neoplasia with an unknown incidence and a prevalence of 10% among all thyroid cancers, which are the most frequent endocrine malignancies and represent 1% of all human tumors. The clinical relevance of MTC is its high rate of mortality which is 50% at 10 years and increases up to 90% in cases with distant metastases at the diagnosis. The possibility to definitively cure the MTC affected patient is impaired by the extrathyroidal invasion and/or the presence of metastatic lymphnodes at the time of first surgical treatment.
Calcitonin is the specific and sensitive marker of MTC both at serum and tissue level. Serum CT should be measured in patients with thyroid nodules for the early diagnosis of the tumor. It can be also used for the follow up and the monitoring of the metastatic disease. CT can be also searched for by immunohistochemistry on the tumoral tissue for confirmation of diagnosis. Scanty data are available on the role of serum CT as prognostic factor. No differences in serum CT values have been reported between RET positive and RET negative cases. Since serum CT plays a dominant role in MTC diagnosis, no other biomarkers have been characterized. New tools such as proteomics may be used to discover new MTC biomarkers which might either suggest the presence of the disease or predict >>>