Strategic Chemotherapy for Pheochromocytoma?

Abstract

During the last several years, research in pheochromocytoma/paraganglioma (PCC/PGL) has undergone a huge renaissance. Today, we have learned that there are at least 19 genes associated with PCC/PGL (1). For the past decade, we have learned that the 10% rule for PCC/PGL has been debunked. Approximately 30%–35% of these tumors are due to genetic causes, 20% are extra adrenal, and 15%–20% are malignant (2, 3). Identification of genes, such as SDHB and FH, have been discovered to be associated with malignant potential (4, 5). However, despite the important strides being made in the genetics of PCC/PGL, the exact treatment for malignant disease is still not known. Presently, the only cure for PCC/PGL is surgery. Treatment options, such as high-dose metaiodobenzylguanidine (MIBG), have been shown to be palliative (6). Tyrosine kinase inhibitors, such as sunitinib, are available for select patients but do not lead to a cure (7). Other efforts, such as mammalian target of rapamycin (mTOR) inhibitors, have not proven to be successful despite the important discovery of the TMEM127 gene associated with mTOR regulation (8, 9). Although targeting both the mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) may be promising, this still warrants further investigation (10). Currently, patients with metastatic disease need to undergo chemotherapy with various combinations, such as cyclophosphamide, vincristine, and dacarbazine (CVD), or other regimens, to control their disease burden (11, 12). Considering this chemotherapy paradigm, Schovanek et al (13), in this issue of Endocrinology, investigated the use of a topoisomerase I inhibitor, LMP-400 (causes DNA damage through formation of double-strand breaks), on PCC tumors using a metastatic mouse PCC model, along with animal and primary culture human cells. The authors found high expression of topoisomerase I in human PCC tumors, providing a basis for the evaluation of a topoisomerase I inhibitor as a therapeutic strategy. Cell metabolic activity was measured by 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT assay) and colorimetric assays, whereas apoptosis was measured by levels of phosphorylated histone, gamma-H2AX. LMP400 distinctly inhibited the growth of sporadic human PCC and animal PCC cells as well as increased apoptosis. Interestingly, the authors also found that topoisomerase I inhibition had an effect on hypoxia-inducible factor 1 (HIF-1) expression in treated cells. This finding is significant, because the HIF proteins are transcription factors that respond to changes in oxygen levels. HIFs are known to play an important role in the pathogenesis of some types of PCC/PGL tumors and may have an effect on invasiveness and metastasis (14). Because the results of targeted therapies have not been completely successful, the authors investigated combination therapy with LMP-400 and other clinically used chemotherapeutic agents (mimicking CVD). The investigators combined LMP-400 with vincristine and cisplatin therapy in PCC tumor cells (13). Results from this study showed that combination treatment led to decreased cell growth in concentrations below and above the respective IC50s, suggesting the possibility of adding LMP-400 to the CVD regimen. At low doses, this synergism might be useful in reducing chemotherapy dosing and resultant toxicity to the patient. Clinical studies will be helpful to validate this prediction. This work by Schovanek et al (13) has taken a different angle on targeted treatment, evaluating “strategic chemotherapy” for PCC/PGL attacking different mechanisms of tumor growth while taking advantage of drugs that are available today. Perhaps the reason why treatment for malignant PCC/PGL has been most challenging is that