Magesh, Muthu
(2011)
Protein Kinase inhibitors for the treatment of thyroid cancer: molecular mechanisms of resistance.
[Tesi di dottorato]
(Unpublished)
| Item Type: |
Tesi di dottorato
|
| Lingua: |
English |
| Title: |
Protein Kinase inhibitors for the treatment of thyroid cancer: molecular mechanisms of resistance |
| Creators: |
| Creators | Email |
|---|
| Magesh, Muthu | magesh.research@gmail.com |
|
| Date: |
30 November 2011 |
| Number of Pages: |
100 |
| Institution: |
Università degli Studi di Napoli Federico II |
| Department: |
Biologia e patologia cellullare e molecolare "L. Califano" |
| Scuola di dottorato: |
Medicina molecolare |
| Dottorato: |
Oncologia ed endocrinologia molecolare |
| Ciclo di dottorato: |
24 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Santoro, Massimo | masantor@unina.it |
|
| Tutor: |
| nome | email |
|---|
| Santoro, Massimo | masantor@unina.it |
|
| Date: |
30 November 2011 |
| Number of Pages: |
100 |
| Uncontrolled Keywords: |
Mechanisms of resistance, thyroid cancer, kinase inhibitors |
| Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/04 - Patologia generale |
[error in script]
[error in script]
| Date Deposited: |
09 Dec 2011 10:23 |
| Last Modified: |
17 Jun 2014 06:04 |
| URI: |
http://www.fedoa.unina.it/id/eprint/8777 |
Abstract
Though most types of thyroid cancer are cured by surgery and adjuvant radio-
iodine therapy and TSH suppression, patients with radio-iodine refractory
thyroid carcinoma as well as with medullary thyroid carcinoma, a
neuroendocrine malignancy that does not express iodine transporter, are
difficult to treat because of the lack of effective systemic treatment. Therefore,
there is an urgent need of novel therapeutic measures for these patients.
Thyroid cancer is frequently associated to the oncogenic conversion of protein
kinases such as RET (medullary thyroid cancer) and BRAF (papillary and
undifferentiated thyroid cancer). Therefore, protein kinase small molecule
inhibitors (PKI) have been considered as promising novel agents for the
treatment of thyroid carcinoma. Compounds that revealed good RET and
BRAF activity both in clinical (vandetanib for RET) and in pre-clinical
(vemurafenib for BRAF) settings have been identified. Recently, vandetanib
was approved for patients with medullary thyroid carcinoma and vemurafenib
was approved for patients affected by melanoma. Cancer patients may be
refractory to PKI or develop secondary resistance after an initial response.
Two general mechanisms can explain resistance: i) the presence of mutations
in the kinase that blocks binding to the PKI; ii) the oncogenic switch to
another pathway that rescues cancer cells from kinase blockade. In this
dissertation, we have addressed mechanisms of resistance in the case of RET
PKI (for the treatment of medullary thyroid carcinoma) and BRAF PKI (for
the treatment of radio-iodine refractory thyroid carcinoma). Here we show
that: i) ponatinib is a novel RET PKI and is able to overcome RET resistance
mediated by mutations in RET V804 and Y806; ii) thyroid cancer cells escape
treatment with vemurafenib by switching to another signaling pathway and
that inhibitors of the IGF1R/PI3K/AKT signaling cascade may be exploited to
overcome resistance of thyroid cancer cells lines to BRAF PKI.
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