Inhibition of the Ras/Raf/MEK/ERK and RET Kinase Pathways with the Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Medullary and Differentiated Thyroid Malignancies
| Autor: | David S, Hong, Maria E, Cabanillas, Jennifer, Wheler, Aung, Naing, Apostolia M, Tsimberidou, Lei, Ye, Naifa L, Busaidy, Steven G, Waguespack, Mike, Hernandez, Adel K, El Naggar, Alder K, El Naggar, Savita, Bidyasar, John, Wright, Steven I, Sherman, Razelle, Kurzrock |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
MAPK/ERK pathway endocrine system diseases Pyridines Endocrinology Diabetes and Metabolism Clinical Biochemistry Quinolones Biochemistry Endocrinology Adenocarcinoma Follicular Antineoplastic Combined Chemotherapy Protocols Extracellular Signal-Regulated MAP Kinases Thyroid cancer Aged 80 and over Kinase Farnesyl Transferase Inhibitor Benzenesulfonates Thyroid Farnesyltransferase inhibitor Cell Differentiation Middle Aged Sorafenib MAP Kinase Kinase Kinases female genital diseases and pregnancy complications medicine.anatomical_structure Female raf Kinases Signal Transduction medicine.drug Adult Niacinamide endocrine system medicine.medical_specialty Oncogene Protein p21(ras) Biology Internal medicine medicine Farnesyltranstransferase Humans Thyroid Neoplasms neoplasms Protein Kinase Inhibitors Aged Dose-Response Relationship Drug Endocrine Care Phenylurea Compounds Proto-Oncogene Proteins c-ret Biochemistry (medical) medicine.disease digestive system diseases Carcinoma Neuroendocrine Cancer research Tipifarnib |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 96:997-1005 |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Purpose: Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins. Patients and Methods: We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle. Results: We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1–2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3–4 toxicities were rash, rise in amylase/lipase, and fatigue. Conclusions: Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|