Expert Insights  |  Precision Medicine

Precision Medicine in PPGL: Matching Treatment to Tumor Biology

Emerging research is revealing how genetics, tumor biology, biomarkers, and new model systems may help move PPGL care toward more individualized approaches.

The Clinical Challenge

Advanced pheochromocytoma and paraganglioma (PPGL) represents a critical unmet need in neuroendocrine oncology. Effective treatment is still out of reach for most patients due to disease rarity, extensive genetic heterogeneity, and a lack of reliable preclinical models.

To overcome these hurdles, recent translational studies are mapping specific genetic drivers, identifying tumor vulnerabilities, and establishing actionable biomarkers to guide the next generation of targeted therapies. At the forefront of this shift is the SDHB-mutant subtype, which carries an inherently high risk of aggressive and metastatic disease.

Metabolic Dependencies and Genetic Risk

Multi-omic profiling of SDHB-mutant metastatic PPGLs reveals an amplified hypermethylation signature that primes chromaffin cells toward de-differentiation. This epigenetic shift is accompanied by overexpression of the fructose transporter SLC2A5 (GLUT5), displaying a distinct metabolic vulnerability in which tumor cells exploit fructose uptake to sustain growth under pseudohypoxic stress.

These findings reinforce the clinical importance of accurately identifying pathogenic SDHB mutations, because true carriers have a high lifetime risk of aggressive disease. Genetic screening frequently detects ambiguous Variants of Uncertain Significance (VUS) of SDHB, limiting accurate clinical risk assessment. A cellular complementation assay measuring succinate-to-fumarate ratios addresses this diagnostic gap by directly quantifying SDH enzymatic activity, enabling ambiguous SDHB variants to be reclassified as pathogenic or benign and informing lifelong SDHB surveillance in patients.

Complementing these diagnostic advances, recent work also shows that TMEM127-deficient tumors selectively overexpress membrane RET, establishing RET as a promising biomarker for classifying TMEM127 variants.

An Evolving Arsenal of Targeted Therapeutics

Treatment selection for PPGL is beginning to follow the tumor biology of the individual patient, instead of defaulting to one option for everyone. Three classes of therapy illustrate that shift:

Hypoxic Drive

The FDA approval of the oral HIF-2alpha inhibitor belzutifan provided a therapeutic route for pseudohypoxia-driven metastatic PPGL. In the Phase II LITESPARK-015 trial, belzutifan demonstrated a 26% objective response rate alongside catecholamine normalization. However, a recent multistakeholder consensus emphasizes that this aggregate response rate masks significant cluster-specific variability. While direct EPAS1 (Cluster 1B) and SDHB (Cluster 1A) pseudohypoxic mutations achieve response rates of up to 83% (case series) and 38% (trial cohort) respectively, efficacy in non-hypoxic MAPK/WNT subtypes (Clusters 2 and 3) remains elusive, making the immediate release of genotype-stratified clinical trial data essential for precision patient selection.

Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE (Lutathera) achieved an 86% 6-month progression-free survival rate in somatostatin-receptor-positive PPGL. Nuclear medicine is now advancing toward targeted alpha therapy (TAT). A first-in-human Phase I trial evaluated ²¹¹At-MABG, an alpha-emitting radiopharmaceutical that targets the norepinephrine transporter. Unlike the beta-emitter ¹³¹I-MIBG, ²¹¹At-MABG delivers localized, high linear energy transfer radiation that spares surrounding normal tissues. In refractory metastatic PPGL, single-dose ²¹¹At-MABG was well tolerated up to 2.1 MBq/kg with no dose-limiting toxicities, minimal hematologic suppression, and preliminary antitumor activity showing 1 partial response (10%) and 7 cases of stable disease (70%) among 10 patients over a 12-week follow-up.

Advanced Modalities & AI-Guided Care

The therapeutic space is expanding beyond single-agent pathway inhibitors to encompass targeted drug conjugates, combinatorial synthetic lethality, and AI-driven predictive modeling. Overexpression of Delta-like non-canonical Notch ligand 1 (DLK1) in chromaffin cell-derived tumors presents a direct surface target for antibody-drug conjugates (ADCs) such as ADCT-701. Preclinical evidence also indicates SDHB mutations impair homologous recombination DNA repair through oncometabolite accumulation, establishing a biological rationale for synthetic lethality. Ongoing clinical trials are evaluating the combination of temozolomide and a PARP inhibitor. Machine learning models are also being developed to integrate multi-omic and radiomic profiles to predict metastatic risk and inform clinical decision-making.

Modeling PPGL Biology

As these therapeutic strategies evolve, PPGL-specific model systems are beginning to capture clinically relevant tumor biology and lineage plasticity. Patient-derived PPGL organoids retain key features of the parent tumors. Organoids cultured under hypoxic conditions exhibited increased viability, HIF-1alpha activation, and expansion of ASCL1-positive cells, whereas prolonged normoxic culture induced HIF-2alpha activation and a sympathoblast-mesenchymal-like state. A new pilot study characterized human pheochromocytoma organoids that can be established and serially passaged for long-term culture, supporting their use as a renewable PPGL-specific platform for mechanistic and therapeutic studies.

Looking Forward

To our community of patients, patient advocates, clinicians, and industry partners: the narrative of PPGL research is steadily advancing. The mapping of multi-omic signatures, the expansion of clinical trials, and the development of new preclinical models bring us closer to a comprehensive understanding of this complex disease. These collective efforts are opening viable avenues for targeted drug discovery, moving us toward a future where highly effective, personalized therapies become the standard of care.

Educational content only. This article is not a substitute for individualized medical advice.