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Originally published as JCO Early Release 10.1200/JCO.2008.17.9564 on October 14 2008 © 2008 American Society of Clinical Oncology.
Fewer Dollars, More Sense
University of Colorado Comprehensive Cancer Center, Aurora, CO
Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, OH To the Editor: Concern has been expressed, appropriately, regarding the cost of the reportedly active regimen of the antiangiogenesis agent, bevacizumab, plus a cytotoxic agent, irinotecan, in the treatment of recurrent glioblastoma multiforme (GBM)1,2 It is quite timely, then, that in a just-reported-and-presented phase I/II study of patients with recurrent high-grade gliomas—including 19 with GBM—propylthiouracil (PTU), 600 mg/d was administered with concurrent, high-dose tamoxifen, the latter as a putative inhibitor of protein kinase C, overexpressed in some high-grade gliomas.3 Notably, those patients with an early-onset and sustained elevation of thyroid-stimulating hormone (TSH)—defined as occurring within 3 months of entering the study—had a 6-month progression-free survival of 58% as compared with 0% of those who did not (P < .002). In addition, the median survival for the former was 9.7 months as compared with 2.2 months for the latter (P < .01). There were six magnetic resonance imaging responses in hypothyroid patients as compared with zero in the euthyroid individuals (P < .02). The nadir of the free thyroxine decline also correlated positively with survival (P < .003). Interestingly, only one patient developed symptomatic hypothyroidism. It has been demonstrated that the notoriously vascular GBM overexpresses—among a number of factors—vascular endothelial growth factor (VEGF), which is produced by tumor and stromal cells, including inflammatory cells.2 VEGF then acts by paracrine mechanisms on local endothelial cells, resulting in their proliferation, survival, and migration.4 In addition, the insulin-like growth factor-I receptor (IGF-1R) pathway is highly overexpressed in GBM.5 The IGF-1R pathway can, in turn, induce VEGF mRNA expression via the mitogen-activated protein kinase pathway.6 Relative to this, a GBM cell line has been shown to activate phosphophoinositol-3 kinase through IGF-1R, thereby bypassing the effects of epidermal growth factor receptor (EGFR) inhibition on phosphophoinositol-3 kinase.7 The astrocyte (cell of origin of GBM) has been shown to be a focus of thyroid hormone (TH) action.8 In that regard, TH has been shown to modulate expression of IGF-1R. Phosphorylation of IGF-1R by TH in 293T cell lines has been observed, whereas TH deprivation reduced proliferation in glioma cell lines.8
In patients with recurrent GBM, PTU is postulated to exert a therapeutic effect indirectly by decreasing the nongenomic TH signal transduction interaction via the recently identified thyroid hormone plasma membrane receptor (TR) on In addition, there is cross-talk between the plasma membrane TR and EGFR,13 the latter also being an active pathway in GBM.14 Finally, TH availability may be crucial for both nongenomic and genomic synthesis of hypoxia-induced factor-1a,15 which is already overexpressed in recurrent GBM,16 leading to still greater expression of VEGF.
Therefore, based on these preclinical and clinical results, a more rational—yet far less costly—regimen could be bevacizumab, the mechanism of action of which is, as yet, less than fully understood,1,2 plus PTU/tapazole. This could be preferable to somewhat empirically including irinotecan, which, has extremely limited activity as a single agent, with only a 0% to 15% response rate.1,2 Moreover, irinotecan, when added to bevacizumab, can add significant toxicity, including diarrhea; similarly, when bevacizumab is combined with chemotherapy, the risk of arterial thromboembolism is increased.2,17 Though there are scarce data concerning bevacizumab as a single agent in GBM, another antiangiogenic agent—AZD2171—a pan-VEGF receptor tyrosine kinase inhibitor, has shown significant clinical benefit as a single agent in a similar group of patients.18 Therefore, the combination of bevacizumab with PTU/tapazole may be a better choice. Presumably, this regimen would result in pleiotropically inhibiting the VEGF, IGF-1R, and EGFR pathways, their cross-talk, and the functionality of AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print atwww.jco.org on October 13, 2008 REFERENCES
1. Chamberlain MC: Bevacizumab plus irinotecan in recurrent glioblastoma. J Clin Oncol 26:1012-1013, 2008 2. Vredenburgh JJ, Desjardens A, Herndon JE, et al: Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722-4729, 2007 3. Hercbergs AA, Suh J, Reddy C, et al: Early onset propylthiouracil-induced hypothyroidism is associated with improved survival in recurrent high grade glioma. Presented at the American Association of Cancer Research Annual Meeting, San Diego CA, April 12-16, 2008 4. Norden AD, Young GS, Setayesh K, et al: Bevacizumab for recurrent malignant gliomas. Neurology 70:779-787, 2008 5. Trojan J, Cloix JF, Ardourel MY, et al: Insulin-like growth factor type I biology and targeting in malignant gliomas. Neuroscience 145:795-811, 2007[CrossRef][Medline] 6. Miele C, Rochford JJ, Filippa N, et al: Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways. J Biol Chem 275:21695-21702, 2000 7. Chakravarti A, Loeffler JS, Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 62:200-207, 2002 8. Davis FB, Tang H-Y, Shih A, et al: Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells. Cancer Res 66:7270-7275, 2006 9. Davis PJ, Davis FB, Lin H-Y, et al: Cell-surface receptor for thyroid hormone and tumor cell proliferation. Expert Rev Endocrinol Metab 1:753-761, 2006[CrossRef] 10. Davis PJ, Shih A, Lin HY, et al: Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR. J Biol Chem 275:38032-38039, 2000 11. Stupp R, Ruegg C: Integrin inhibitors reaching the clinic. J Clin Oncol 25:1637-1638, 2007 12. Nabors LB, Mikkelsen T, Rosenfeld SS, et al: Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25:1651-1657, 2007 13. Shih A, Zhang S, Cao HJ, et al: Disparate effects of thyroid hormone on actions of epidermal growth factor and transforming growth factor-a are mediated by 3',5'-cyclic adenosine 5'-monophosphate-dependent protein kinase II. Endocrinology 145:1708-1717, 2004 14. Ohgaki H, Kleihues P: Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445-1453, 2007 15. Otto T, Fandry J: Thyroid hormone induces hypoxia-inducible factor 1 gene expression through TRβ/RXR-dependent activation of hepatic leukemia factor. Endocrinology 149:2241-2250, 2008 16. Zagzag D, Lukyanov Y, Lan L, et al: Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: Implications for angiogenesis and glioma cell invasion. Lab Invest 86:1221-1232, 2006[CrossRef][Medline] 17. Scappaticci FA, Skillings JR, Holden SN, et al: Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99:1232-1239, 2007 18. Batchelor TT, Sorensen AG, di Tomaso F, et al: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma multiforme. Cancer Cell 11:83-95, 2007[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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Vβ3 integrin, expressed on both glioma and endothelial cells.
