Pheochromocytoma: A Genetic and Diagnostic Update

Leilani B. Mercado-Asis, MD, PhD, MPH; Katherine I. Wolf; Ivana Jochmanova, MD; David Taïeb, MD


Endocr Pract. 2018;24(1):78-90. 

In This Article

New Therapeutic Perspectives

Targeted Molecular Therapies

Inhibition or alteration of certain metabolic processes involved in tumorigenesis is a very promising therapeutic approach.[31] Moreover, personalized therapy could be designed for each patient based on their genotype-phenotype correlations and metabolomic profile.

In the initial stages of tumorigenesis, (pseudo) hypoxia seems to play an important role in PPGL development, resulting in abnormal metabolic activity. Thus, modifying or interrupting signaling pathways involved in hypoxic responses seem to be an attractive treatment target (reviewed in[31]). Several compounds targeting the HIF signaling pathway are under evaluation (Table 3). Sunitinib, a tyrosine kinase inhibitor targeting the VEGF receptors, was introduced several years ago.[72,73] However, clinical studies showed contradictory results.[74–76] Everolimus, a compound that targets the mTOR pathway, has been used in a limited number of PPGL cases, with unsatisfactory results.[77,78] Nonetheless, co-administration of these compounds with other therapeutic agents may yield anticancer effects. For example, combined treatment with NVP-BEZ235, a dual PI3K/mTORC1/2 inhibitor, and lovastatin, a drug known to reduce ERK signaling, showed a significant additive effect, which supports the use of combination therapies in overcoming compensatory upregulation of other pathways to increase treatment efficacy.[79]

A small molecule inhibitor of HIF-2α (PT2385) is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC). Preclinical data indicates that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors responsible for unrestrained cancer cell growth and proliferation, tumor angiogenesis, and suppression of anti-tumor immune responses characteristic of ccRCC (Peloton Therapeutics Inc, Clinical Trial NCT02293980).

Topoisomerase 1 inhibitors have the ability to interfere with mechanisms that maintain DNA integrity during transcription in both quiescent and dividing cells. In vitro studies showed the efficacy of camptothecin, a prototypical topoisomerase 1 inhibitor, in nondividing PPGL cells. Co-administration of subtoxic concentrations of 5-azacytidine, a DNA methylation inhibitor, increased the efficacy of low concentrations of camptothecin.[80] Schovanek et al demonstrated the effect of another topoisomerase 1 inhibitor LMP-400 in the preclinical mouse model of metastatic PPGL. LMP-400 was shown to decrease HIF-1α levels in tumor cells and reduced tumor growth and metastatic potential. Combination therapy with cyclophosphamide, vincristine, and dacarbazine (CVD) tested in vitro showed a synergistic effect of LMP-400 and CVD.[81]

Restoring the enzymatic activity of nonfunctioning Krebs cycle enzymes, replenishing depleted substrates for the cycle, or inhibiting activity of overexpressed enzymes represent other possible therapeutic schemes. Small-molecule inhibitors of certain proteins or drugs can restore the functionality of mitochondrial enzymes (Table 3) (reviewed in[31,82]).

Different therapeutic approaches focus on altering glucose and/or glutamine uptake and metabolism, since these compounds serve as a primary source of energy for cancer cells. Glucose and glutamine metabolism can be altered by inhibition of uptake (inhibitors of glucose or glutamine transporters) or by inhibition of glycolytic enzymes or glutaminolysis (Table 3) (reviewed in[31]).

Inhibitors of other metabolic pathways, such as lipids and fatty acid synthesis, are also under development (Table 3). Recently, inhibitors of fatty acid synthase were demonstrated to selectively target cancer cells for apoptosis.[83]

Overexpression of HER2 tyrosine kinase receptor was described in metastatic PPGLs; however, the effect of HER2/neu inhibitors on PPGL treatment has not been yet evaluated. Other potential therapy targets include carboxypeptidase E (CPE) and insulin-like growth factor 1 receptor (IGF-1R). High CPE mRNA copy numbers were found in various metastatic tumor cell lines including metastatic PPGL. Use of the IGF-1R antagonist NVP-AEW451 in a mouse model of PPGL significantly reduced tumor cell proliferation and viability (reviewed in[84]).

In PPGLs, DNA methylation is also affected by metabolic changes driven by underlying gene mutations. SDHx-and FH-mutated PPGLs display a hypermethylator phenotype,[41] indicating the therapeutic use of DNA demethylating agents for some PPGLs.[85]

Radionuclide Therapy

Surgical resection remains the best treatment option for PPGL. However, an operative approach is not always viable due to extensive metastatic tumor burden. Therefore, inoperable lesions have been treated with systemic targeted radiotherapies, mainly 131I-MIBG.[86,87] Lack of uptake on 123I-MIBG scintigraphy excludes many patients from therapy, driving researchers to discover alternative treatment options for nonsurgical candidates. SSTR overexpression in PPGL led to their use as therapeutic targets. By attaching radionuclides (177Lu, 90Y,111In) via a linker and vector mechanism to a targeting moiety (DOTATATE, DOTANOC, DOTATOC), PRRT has been studied in well-differentiated, advanced neuroendocrine tumors (NETs).[88–92] While overall results have varied, the majority of studies report the feasibility, effectiveness, and efficacy of PRRT in NETs,[88,91] with increased progression-free survival (PFS), as well as patient-reported pain relief, symptom regression, and increased quality of life.[88] The NETTER-1 Phase III trial compared 177Lu-DOTATATE treatment with the cold analogue Octreotide LAR, and found that the median PFS was not reached in the 177Lu-DOTATATE arm, but it was 8.4 months for Octreotide LAR—while maintaining a safety profile unremarkable for significant findings related to hematological, renal, or hepatic parameters.[92]

Studies are limited regarding PRRT and PPGL, exclusively. Recently, Pinato et al described an overall radiologic disease control rate of 80% in a small cohort of SDHB-related metastatic PPGL patients treated with 177Lu-DOTATATE.[90] With only 1 case of significant toxicity and a median time to progression unreached in their 13-month follow-up timeframe, they concluded that PRRT is a viable, tolerable therapy for PPGL. In 2012, a similar study looked at 4 female SDHD-related nonmetastatic HNPGL patients undergoing 177Lu-DOTATATE treatment, and also reported limited, predictable side effects, with all patients either partially responding or having stable disease.[91] Large-scale studies are needed to confirm the data from these limited patient populations, particularly in metastatic sporadic patients without an underlying genetic mutation.