Iobenguane I-131 (Azedra; Progenics Pharmaceuticals) is a high-specific-activity ¹³¹I-labeled analog of meta-iodobenzylguanidine (MIBG) — a structural guanethidine analog taken up selectively by the norepinephrine transporter (NET, SLC6A2) on chromaffin-lineage cells. NET actively transports iobenguane into the cytoplasm and catecholamine storage vesicles, delivering ¹³¹I-emitting beta particles (β⁻; Emax 606 keV; path length ~2mm in tissue) preferentially to tumor cells expressing NET. FDA approval (July 2018): Azedra was approved for iobenguane-avid, locally advanced or metastatic pheochromocytoma or paraganglioma requiring systemic anti-tumor therapy, becoming the first radiopharmaceutical approved specifically for PPGL. The MACS0010 Phase 2 registration study established overall response rate (ORR) of ~25% and clinical benefit rate (CBR, defined as ≥50% catecholamine reduction sustained for ≥6 months) of ~92%, with acceptable hematologic toxicity in a heavily pre-treated population. SDH-specific rationale — tumor type: SDH-deficient PPGL arise from catecholamine-producing chromaffin cells of the sympathoadrenal lineage, retaining NET/SLC6A2 expression and MIBG avidity. SDHB-mutant tumors often present with the dopaminergic phenotype (elevated dopamine/3-methoxytyramine) but retain NET expression and iobenguane uptake, qualifying them for MIBG-based therapy. While Azedra's approval covers all iobenguane-avid PPGL regardless of genotype, SDH-deficient PPGL constitute a major clinically relevant fraction of the eligible population. SDH-specific rationale — BRCAness radiosensitization: Beyond tumor-type selectivity, the BRCAness phenotype established by Sulkowski et al. (Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005) predicts an SDH-specific layer of radiosensitization: SDH loss → succinate-driven KDM4A/KDM4B inhibition → H3K9me3 persistence at DSB sites → impaired TIP60/ATM → HR repair deficiency. HR-deficient SDH-deficient tumor cells cannot efficiently repair radiation-induced DSBs via HR, potentially amplifying iobenguane I-131 cytotoxicity relative to NET-expressing SDH-intact normal chromaffin cells. This BRCAness-mediated radiosensitization has not been tested in SDH-stratified PPGL cohorts but follows mechanistically from the established HR deficiency. Panobinostat combination — NET upregulation: Martiniova et al. (Endocr Relat Cancer 2011, PMID 21098082) demonstrated panobinostat (pan-HDAC inhibitor, already in this engine) upregulates NET/SLC6A2 expression and significantly increases MIBG uptake in PPGL cells at nanomolar concentrations — a combination strategy to enhance Azedra delivery in tumors with low baseline NET expression. Key limitation: Azedra's MACS0010 registration trial did not report SDH-genotype-stratified outcomes; BRCAness radiosensitization is mechanistically grounded but experimentally unverified in SDH-deficient models. Evidence_score 42 (established): FDA-approved for the exact tumor type; BRCAness radiosensitization rationale is an additional, unexplored mechanistic layer.