Wednesday, May 23, 2012

VEGF and mTOR


Several recent clinical trials indicate that agents targeting VEGF signaling, including sunitinib and sorafenib, and mTOR (mammalian target of rapamycin) pathway signaling, including temsirolimus and everolimus, demonstrate substantial tumor responses or significant improvement in progression-free survival.
Agents targeting mTOR prolong survival in patients with poor-risk RCC (temsirolimus) and demonstrate responses in patients failing prior targeted molecular therapies (everolimus).
                                                     
Aberrant activation of additional signal transduction pathways in RCC may also contribute to altered cell cycle kinetics and represent excellent targets for therapeutic intervention. One such regulatory pathway in RCC is the mammalian target of rapamycin (mTOR) pathway, which interfaces with Akt (protein kinase B) and the PTEN tumor suppressor gene (Klatte and Pantuck, 2008). Expression of mTOR is upregulated by various growth factors or by mutation or loss of PTEN (Kim et al, 2009). Through complex pathways involving a variety of intermediaries, the mTOR pathway leads to increased expression of HIF-1 and other growth-promoting and potentially tumorigenic sequelae (Klatte and Pantuck, 2008; Kim et al, 2009).

Inhibition of mTOR with temsirolimus (Torisel), now also FDA approved, has yielded prolonged survival in patients with poor-risk, metastatic RCC, confirming the clinical relevance of this pathway (Hudes et al, 2007; Hudes, 2009b).

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