[18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy - PubMed (original) (raw)

Clinical Trial

[18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy

Wen Wee Ma et al. J Clin Oncol. 2009.

Abstract

Purpose: Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models.

Patients and methods: Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1.

Results: Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression.

Conclusion: FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Fig 1.

[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) response was not predictive of clinical tumor response and time to progression (TTP) to rapamycin therapy in patients. Tumor response was defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and FDG-PET response was defined by European Organisation for Research and Treatment of Cancer (EORTC; 1999) criteria. TTP was defined as time interval from study registration to disease progression. (A) Waterfall plot of mean change in maximum standardized uptake value (mδSUVmax) in 34 patients with assessable FDG-PET scans showing that changes in mSUVmax did not correlate with tumor response. Patients with pancreatic cancer are marked with an asterisk (*). Deidentified patient numbers are listed on the _x_-axis for reference to patients discussed in B. (B) FDG-PET/computed tomography images of selected patients at baseline and after one cycle of rapamycin therapy. White circles denote the target lesions. Patient 4 had desmoplastic small round cell tumor, and patient 5 had pancreatic adenocarcinoma. Both had progressive disease (PD) but partial metabolic response (PMR) on FDG-PET. Patient 12 had neuroendocrine tumor of the pancreas, and had stable disease (SD), but PMR (C) Scatter plot of mδSUVmax in patients from A treated with rapamycin ≥ 5 mg daily dose (n = 28). The changes in mSUVmax did not correlate with TTP (r = −0.274 for all patients; r = 0.072 for pancreatic cancer patients). Patients with pancreatic cancer are marked with an asterisk (*). The table shows the TTP and mδSUVmax of corresponding patients.

Fig 2.

Fig 2.

[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) response was not predictive of tumor growth response in nude mice xenograft models. (A) Growth of tumor xenografts after 2 weeks of therapy (n = 8 tumors in each treatment group). Tumor volume was measured by caliper for 2 weeks and reported as mean ± SEM. Growths of the temsirolimus-treated tumors (blue bars) are normalized to vehicle-treated tumors (yellow bars) for each xenograft model. The tumor models resistant to temsirolimus (growth resistant [GR]) were Panc420, Panc194, Panc294, and Panc1, and the sensitive models (growth sensitive [GS]) were Panc140 and BxPC3. (B) Quantitative changes in FDG-PET signal of the vehicle-treated (yellow bars) and temsirolimus-treated (blue bars) groups for each xenograft models (n = 6 tumors in each group). Change in maximum standardized uptake value (δSUVmax) was determined, and δSUVmax(av) for each treatment group was derived by averaging the δSUVmax of all the tumors within the group (reported with SEM). δSUVmax(av) of temsirolimus-treated group was normalized to the vehicle-treated group for comparison between xenograft models. δSUVmax(av) values of two of the temsirolimus-resistant xenograft models (Panc420 and Panc194) increased but were not statistically significant compared with controls. Compared with respective controls, the δSUVmax(av) values of the other two temsirolimus-resistant xenograft models (Panc 294 and Panc1) and the two temsirolimus-sensitive xenograft models (Panc140 and BxPC3) decreased after 1 week of temsirolimus treatment compared with controls (P < .05). (C) Representative FDG-PET images of the xenograft models. Small animal FDG-PET images were obtained at baseline and after 1 week of vehicle or temsirolimus treatment. The size of temsirolimus-treated Panc194 and Panc294 tumors continued to grow (GR), whereas the size of Panc140 tumors decreased (GS) after 2 weeks of therapy. The FDG-PET signal in the temsirolimus-treated Panc194 tumors continued to increase (FDG-PET nonresponders), whereas that for Panc294 and Panc140 decreased (FDG-PET responders) after 1 week of therapy.

Fig 3.

Fig 3.

Changes in tumor biomarkers in response to temsirolimus and vehicle treatment. Subcutaneous tumor xenografts were harvested after 2 weeks of therapy and stored as fresh frozen and paraffin-embedded specimens. (A) Western blots of the tumors for the expression of pAktser473, total Akt, and actin. The experiment was performed in triplicate. pAktser473 expression correlated with changes in [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) signal for the tested tumors. Compared with controls, pAktser473 expression was stable (Panc420) and increased (Panc194) in all xenografts with increased change in maximum standardized uptake value (δSUVmax) during therapy; whereas pAktser473 expression decreased in all xenografts with decreased δSUVmax during therapy (Panc1, Panc 294, BxPC3, and Panc140). (B) Quantitative assessment of the proportion of cell membrane that stained positive for GLUT1 (n = 3 in each treatment group). GLUT1 percent membrane score is higher in temsirolimus-treated than vehicle-treated tumors in the xenograft models with positive δSUVmax(av) (Panc420 and Panc194), whereas the score is lower in the xenograft models with negative δSUVmax(av) (Panc294, Panc1, Panc140, and BxPC3). (C) Immunohistochemical staining for GLUT1 of paraffin-embedded tumor specimens. In the models with positive δSUVmax during therapy (Panc420 and Panc194), the percentage of cell membrane that stained positive for GLUT1 was higher in temsirolimus-treated tumors than controls. In the models with negative δSUVmax during therapy (Panc294, Panc1, Panc140, and BxPC3), the percentage of cell membrane that stained positive for GLUT1 was lower in temsirolimus-treated tumors than controls. To note, cytosolic GLUT1 staining in temsirolimus-treated Panc140 and BxPC3 was higher than in controls, although the percentage of cell membrane that stained positive for GLUT1 was less than in controls.

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