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

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          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).

          Abstract

          In a Phase I clinical trial Charles Sawyers and colleagues investigated the role of rapamycin in patients with PTEN-deficient glioblastoma.

          Editors' Summary

          Background.

          Glioblastoma is a highly malignant tumor of the brain. As with other tumors, it can result from a number of different molecular changes. Traditional chemotherapy does little more than contain these tumors, and cannot cure it. An alternative approach to the treatment of such tumors is to target specific molecular changes in the tumor. Obviously such targeted treatment will work only in patients who have the specific molecular defect being targeted. Hence, traditional clinical trials, which include a large variety of different patients and tumors with different genetic changes, may be an inappropriate way to test how effective targeted treatments are.

          One specific change that has been identified in around 40% of patients with glioblastoma is inactivation of a gene known as PTEN, which acts as a tumor suppressor gene. When PTEN is inactivated it has previously been shown to make cells more sensitive to a class of drugs known as mTOR inhibitors—one of which is rapamycin (trade name Sirolimus). mTOR is a protein that is involved in the regulation of a number of cellular processes including growth and proliferation. Drugs active against mTOR are currently being tested for effectiveness against other cancers and as immunosuppressive agents.

          Why Was This Study Done?

          This was a Phase I study—that is, the earliest type of a drug study that is done in humans—which aimed to look at the safety of rapamycin in a selected group of patients who were undergoing surgery after recurrence of glioblastoma, and whose tumors did not express PTEN. In addition, the authors also wanted to assess the feasibility of incorporating detailed molecular studies of the action of this drug into such a Phase I study and whether these molecular studies could predict whether patients were more or less likely to respond to rapamycin.

          What Did the Researchers Do and Find?

          A total of 15 patients were treated with rapamycin at differing doses for one week before surgery and then again after surgery until there was evidence that the tumors were progressing. There was no evidence of very severe toxicity in any of the patients, though there were some adverse effects that required treatment. When samples from the patients were tested after surgery, seven of them showed a reduction in how rapidly the tumor cells divided, and this reduction was associated with how much inhibition there was of mTOR. Two of these patients showed evidence on scans of a reduction in tumor mass. Cells from tumors that appeared resistant to rapamycin in patients were sensitive to rapamycin in tissue culture, suggesting that the lack of response was due to the drug not being able to penetrate the tumor. A second, unfortunate effect of rapamycin was to cause activation of another intracellular protein, Akt, in some patients; when this activation occurred, patients had a shorter time between surgery and a return of their disease.

          What Do These Findings Mean?

          The detailed molecular studies within this Phase I trial allow a better understanding of how this targeted drug works. These findings suggest that the rapamycin can reduce the proliferation rate of glioblastoma cells, and that this reduction appears to be related to how well the drug is able to penetrate the tumor and inhibit mTOR. However, in some patients the activation of a second pathway can speed up the course of the disease, so further trials should incorporate inhibitors of this second pathway.

          Additional Information.

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050008.

          • The US National Cancer Institute provides information on all aspects of cancer (in English and Spanish)

          • The UK charity Cancerbackup provides information on brain tumors

          • Wikipedia has a page on mTOR (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

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          Most cited references35

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          Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.

          Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.
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            The TOR pathway: a target for cancer therapy.

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              mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.

              Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                pmed
                plme
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                January 2008
                22 January 2008
                : 5
                : 1
                : e8
                Affiliations
                [1 ] Department of Neurology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [2 ] Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [3 ] Translational Genomics Research Institute, Phoenix, Arizona, United States of America
                [4 ] Department of Molecular and Medical Pharmacology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [5 ] Taylor Technology, Princeton, New Jersey, United States of America
                [6 ] Department of Neurosurgery, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [7 ] Department of Neurology, Kaiser Permanente; Los Angeles, California, United States of America
                [8 ] Department of Biostatistics and Human Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [9 ] Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
                Brain Tumor Institute, Cleveland Clinic Foundation, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: sawyersc@ 123456mskcc.org
                Article
                07-PLME-RA-0191R3 plme-05-01-12
                10.1371/journal.pmed.0050008
                2211560
                18215105
                bae34f46-2453-4ee3-8da5-e6cdc9cacea8
                Copyright: © 2008 Cloughesy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 22 March 2007
                : 15 November 2007
                Page count
                Pages: 13
                Categories
                Research Article
                Cell Biology
                Genetics and Genomics
                Oncology
                Pathology
                Pharmacology
                Oncology
                Chemotherapy
                Pharmacology and Toxicology
                Genetics
                Custom metadata
                Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, et al. (2008) Antitumor activity of rapamycin in patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5(1): e8. doi: 10.1371/journal.pmed.0050008

                Medicine
                Medicine

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