TORC1 inhibitors such as rapamycin have been tested in preclinical and clinical trials for cancer. One concern with these compounds is the potential for compensatory up-regulation of PI3K or Akt from TORC1 inhibition which can result from either TORC2 potentiation or relief of IRS1 repression downstream of S6K. Palomid 529 (P529) overcomes these obstacles by inhibiting both TORC1 and TORC2 and thus inhibiting both mTOR downstream signaling and AktS473 in both the tumor cells and vasculature. The cover images show that P529 inhibits the associations of mTOR with raptor (TORC1) and rictor (TORC2) and thus prevents the function of these complexes. Treatment of mice harboring a C6 glioma tumor inhibits overall tumor growth and this is accompanied by decreased vascular density (seen with CD31 staining) and decreased pAktS473 and pS6 staining in tumor cells and prominently tumor glomeruloid–like blood vessels. Thus, P529 represents a novel class of TORC1/2 inhibitor with efficacy in animal models of glioma and tumor angiogenesis. Further preclinical and clinical testing of this and other similar compounds are needed to establish whether TORC1/2 inhibition surpasses TORC1 inhibition in cancer therapy. For details, see the article by Xue and colleagues on page 9551 of this issue.

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