Document Detail


Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: new strategies for overcoming resistance to VEGFR and mTORC1 inhibitors.
MedLine Citation:
PMID:  23319457     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
With the advent of molecularly targeted agents, treatment of metastatic renal cell carcinoma (mRCC) has improved significantly. Agents targeting the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin complex 1 (mTORC1) are more effective and less toxic than previous standards of care involving cytotoxic and cytokine therapies. Unfortunately, many patients relapse following treatment with VEGFR and mTORC1 inhibitors as a result of acquired resistance mechanisms, which are thought to lead to the reestablishment of tumor vasculature. Specifically, the loss of negative feedback loops caused by inhibition of mTORC1 leads to upregulation of downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and subsequent activation of hypoxia-inducible factor, an activator of angiogenesis. De novo resistance involving activated PI3K signaling has also been observed. These observations have led to the development of novel agents targeting PI3K, mTORC1/2 and PI3K/mTORC1/2, which have demonstrated antitumor activity in preclinical models of RCC. Several agents--BKM120, BEZ235 and GDC-0980--are being investigated in clinical trials in patients with metastatic/advanced RCC, and similar agents are being tested in patients with solid tumors. The future success of mRCC treatment will likely involve a combination of agents targeting the multiple pathways involved in angiogenesis, including VEGFR, PI3K and mTORC1/2.
Authors:
Robert A Figlin; Isabelle Kaufmann; Jillian Brechbiel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2013-02-12
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  133     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-06-11     Completed Date:  2013-08-12     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  788-96     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 UICC.
Affiliation:
Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA. robert.figlin@cshs.org
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MeSH Terms
Descriptor/Qualifier:
Carcinoma, Renal Cell / drug therapy*,  pathology
Humans
Kidney Neoplasms / drug therapy*,  pathology
Multiprotein Complexes / antagonists & inhibitors*,  drug effects*
Neoplasm Metastasis
Phosphatidylinositol 3-Kinases / drug effects*
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
TOR Serine-Threonine Kinases / antagonists & inhibitors*,  drug effects*
Chemical
Reg. No./Substance:
0/Multiprotein Complexes; 0/TOR complex 2; 0/mechanistic target of rapamycin complex 1; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.10.1/Receptors, Vascular Endothelial Growth Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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