mTOR is a rational target in
renal cell carcinoma (RCC) because of its role in
disease progression. However, the effects of
temsirolimus, the only first-generation mTOR inhibitor approved by the FDA for first-line treatment of metastatic RCC, on
tumor reduction and progression-free survival are minimal. Second-generation
mTOR inhibitors have not been evaluated on RCC. We compared the effects of
temsirolimus and
MLN0128, a potent second-generation mTOR inhibitor, on RCC growth and
metastasis using a realistic patient-derived tissue slice graft (TSG) model. TSGs were derived from three fresh primary RCC specimens by subrenal implantation of precision-cut tissue slices into immunodeficient mice that were randomized and treated with
MLN0128,
temsirolimus, or placebo.
MLN0128 consistently suppressed primary RCC growth, monitored by magnetic resonance imaging (MRI), in three TSG cohorts for up to 2 months.
Temsirolimus, in contrast, only transiently inhibited the growth of TSGs in one of two cohorts before resistance developed. In addition,
MLN0128 reduced liver
metastases, determined by human-specific quantitative polymerase chain reaction, in two TSG cohorts, whereas
temsirolimus failed to have any significant impact. Moreover,
MLN0128 decreased levels of key components of the two mTOR subpathways including
TORC1 targets 4EBP1, p-S6K1, HIF1α and MTA1 and the
TORC2 target c-Myc, consistent with dual inhibition. Our results demonstrated that
MLN0128 is superior to
temsirolimus in inhibiting primary RCC growth as well as
metastases, lending strong support for further clinical development of dual
mTOR inhibitors for RCC treatment.