Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma

Abstract

BackgroundThere is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.Methods and FindingsBased on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test).ConclusionsRapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development.Trial registration: http://www.ClinicalTrials.gov (#NCT00047073).

The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis

“…We have previously shown that feedback activation of Akt signaling significantly inhibits the clinical efficacy of rapamycin (10). This appears to be mediated through S6K1 inhibition and up-regulation of receptor tyrosine kinases or their substrates (11,15), although the factors that mediate feedback activation in patients have yet to be fully elucidated.…”

“…In glioblastoma, attempts to target mTOR with rapamycin and its analogues have largely failed to show efficacy (7)(8)(9), mediated by difficulty in fully inhibiting mTORC1 signaling and by emergence of a feedback loop, that activates pro-growth, pro-survival Akt signaling (10). Rapamycin analogues also activate MAPK through a PI3K-dependent mechanism in other cancer types, suggesting additional potential mechanisms of clinical resistance and raising the need for alternative strategies to target mTOR signaling in patients (11).…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…Using pre-and post-treatment tissue sampling they showed that treatment with rapamycin could inhibit mTORC1 activity within tumors of a subset of patients and this correlated with reduced proliferation (Cloughesy et al, 2008). However, in half of the patients, rapamycin treatment led to increased levels of phosphorylated AKT and shorter time to tumor progression.…”

Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

“…In addition, inhibition of mTORC1 by rapamycin and its analogues has been shown to result in hyperactivation of AKT through the release of negative feedback loop between S6K1 and IRS-1 (18). Indeed, Cloughesy and colleagues have recently shown that hyperactivation of AKT following rapamycin treatment was associated with shorter time to progression in PTEN-deficient glioblastoma patients, suggesting that TORC1-specific inhibition and associated AKT activation limits anticancer activity (19). Consequently, intense efforts are now underway to develop inhibitors of the PI3K/AKT/mTOR pathway, including ATP-competitive small molecule mTOR kinase inhibitors targeting both mTORC1 and mTORC2 (20).…”