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Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.

Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL - PLoS Med. (2008)

Bottom Line: 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.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).Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT

Background: There 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 findings: Based 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).

Conclusions: Rapamycin 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).

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Clinical Trial DesignEnrollment in the Phase I clinical trial was restricted to patients whose initial tumor resection (“surgery 1”) specimen was PTEN-deficient by immunohistochemistry. Patients were enrolled after failing standard therapy with radiation and chemotherapy (i.e., “tumor recurrence”). Prior to the scheduled salvage tumor resection (“surgery 2”), patients received a short course (mean: 7.5 d) of oral rapamycin. Rapamycin was resumed after recovery from surgery until patients developed clinical and/or radiographic evidence of treatment failure. The effects of rapamycin on tumor cell proliferation and mTOR signaling in tumor tissue were determined by comparing the tumor tissue collected during salvage resection (“surgery 2”) with a sample of the same tumor collected during the initial tumor resection (“surgery 1”). Time-to-progression (TTP) was defined as the interval between start of rapamycin therapy and postoperative treatment failure.
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pmed-0050008-g001: Clinical Trial DesignEnrollment in the Phase I clinical trial was restricted to patients whose initial tumor resection (“surgery 1”) specimen was PTEN-deficient by immunohistochemistry. Patients were enrolled after failing standard therapy with radiation and chemotherapy (i.e., “tumor recurrence”). Prior to the scheduled salvage tumor resection (“surgery 2”), patients received a short course (mean: 7.5 d) of oral rapamycin. Rapamycin was resumed after recovery from surgery until patients developed clinical and/or radiographic evidence of treatment failure. The effects of rapamycin on tumor cell proliferation and mTOR signaling in tumor tissue were determined by comparing the tumor tissue collected during salvage resection (“surgery 2”) with a sample of the same tumor collected during the initial tumor resection (“surgery 1”). Time-to-progression (TTP) was defined as the interval between start of rapamycin therapy and postoperative treatment failure.

Mentions: Our primary motive in conducting this single-arm study was to follow up on the compelling preclinical activity of mTOR inhibitors in PTEN- cancer models by designing a small clinical trial focused on measuring antitumor activity using short-term endpoints. To enhance the probability of success based on the preclinical hypothesis, we restricted enrollment to those patients with recurrent glioblastoma whose tumors had evidence of PTEN loss based on an analysis of tissue obtained from the initial resection (S1) (Figure 1). Eligibility was also limited to those patients scheduled to undergo salvage surgical resection (S2) so that tumor tissue would be available for assessing the endpoints of mTOR inhibition and tumor cell proliferation, as well as intratumoral rapamycin concentrations. By mandating access to pre- and posttreatment samples for each patient, this trial design allows intrapatient comparison of molecular endpoints, thereby enhancing the statistical power to detect changes in a small sample size. To provide confidence that any S1-to-S2 changes could be attributed to rapamycin treatment, we conducted an identical set of measurements using S1 and S2 samples from nine glioblastoma patients who did not receive rapamycin (controls).


Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.

Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL - PLoS Med. (2008)

Clinical Trial DesignEnrollment in the Phase I clinical trial was restricted to patients whose initial tumor resection (“surgery 1”) specimen was PTEN-deficient by immunohistochemistry. Patients were enrolled after failing standard therapy with radiation and chemotherapy (i.e., “tumor recurrence”). Prior to the scheduled salvage tumor resection (“surgery 2”), patients received a short course (mean: 7.5 d) of oral rapamycin. Rapamycin was resumed after recovery from surgery until patients developed clinical and/or radiographic evidence of treatment failure. The effects of rapamycin on tumor cell proliferation and mTOR signaling in tumor tissue were determined by comparing the tumor tissue collected during salvage resection (“surgery 2”) with a sample of the same tumor collected during the initial tumor resection (“surgery 1”). Time-to-progression (TTP) was defined as the interval between start of rapamycin therapy and postoperative treatment failure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211560&req=5

pmed-0050008-g001: Clinical Trial DesignEnrollment in the Phase I clinical trial was restricted to patients whose initial tumor resection (“surgery 1”) specimen was PTEN-deficient by immunohistochemistry. Patients were enrolled after failing standard therapy with radiation and chemotherapy (i.e., “tumor recurrence”). Prior to the scheduled salvage tumor resection (“surgery 2”), patients received a short course (mean: 7.5 d) of oral rapamycin. Rapamycin was resumed after recovery from surgery until patients developed clinical and/or radiographic evidence of treatment failure. The effects of rapamycin on tumor cell proliferation and mTOR signaling in tumor tissue were determined by comparing the tumor tissue collected during salvage resection (“surgery 2”) with a sample of the same tumor collected during the initial tumor resection (“surgery 1”). Time-to-progression (TTP) was defined as the interval between start of rapamycin therapy and postoperative treatment failure.
Mentions: Our primary motive in conducting this single-arm study was to follow up on the compelling preclinical activity of mTOR inhibitors in PTEN- cancer models by designing a small clinical trial focused on measuring antitumor activity using short-term endpoints. To enhance the probability of success based on the preclinical hypothesis, we restricted enrollment to those patients with recurrent glioblastoma whose tumors had evidence of PTEN loss based on an analysis of tissue obtained from the initial resection (S1) (Figure 1). Eligibility was also limited to those patients scheduled to undergo salvage surgical resection (S2) so that tumor tissue would be available for assessing the endpoints of mTOR inhibition and tumor cell proliferation, as well as intratumoral rapamycin concentrations. By mandating access to pre- and posttreatment samples for each patient, this trial design allows intrapatient comparison of molecular endpoints, thereby enhancing the statistical power to detect changes in a small sample size. To provide confidence that any S1-to-S2 changes could be attributed to rapamycin treatment, we conducted an identical set of measurements using S1 and S2 samples from nine glioblastoma patients who did not receive rapamycin (controls).

Bottom Line: 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.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).Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT

Background: There 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 findings: Based 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).

Conclusions: Rapamycin 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).

Show MeSH
Related in: MedlinePlus