Adrenal gland pheochromocytoma

Summary

Adrenal gland pheochromocytoma (MONDO:0004974) is a disease with 2 cohort genes and 127 clinical trials. Top therapeutic interventions include phenoxybenzamine, doxazosin, and edotreotide gallium ga-68.

At a glance

• Cohort genes: 2
• ClinVar variants: 1
• Clinical trials: 127

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	adrenal gland pheochromocytoma
Mondo ID	MONDO:0004974
EFO	EFO:0000239
DOID	DOID:0050892
NCIT	C3326
UMLS	C4551683
MedGen	1636437
GARD	0024140
Is cancer (heuristic)	no

Also known as: adrenal gland chromaffin paraganglioma · adrenal gland Chromaffinoma · adrenal gland paraganglioma · adrenal gland pheochromocytoma · adrenal medullary paraganglioma · adrenal medullary pheochromocytoma · adrenal pheochromocytoma · chromaffin paraganglioma of the adrenal gland · Intraadrenal paraganglioma · PCC · pheochromocytoma · pheochromocytoma (adrenal)

Data availability: 1 ClinVar variant · 5 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › autonomic nervous system disorder › autonomic nervous system neoplasm › paraganglioma › sympathetic paraganglioma › adrenal gland pheochromocytoma

Related subtypes (1): extra-adrenal sympathetic paraganglioma

Subtypes (3): benign adrenal gland pheochromocytoma, malignant adrenal gland pheochromocytoma, childhood adrenal gland pheochromocytoma

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
523509	NM_001365951.3(KIF1B):c.2680C>T (p.Pro894Ser)	KIF1B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VHL	Orphanet:238557	Chuvash erythrocytosis
VHL	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
VHL	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
VHL	Orphanet:892	Von Hippel-Lindau disease
KIF1B	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
KIF1B	Orphanet:99946	Autosomal dominant Charcot-Marie-Tooth disease type 2A1

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	civic_evidence
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
KIF1B	Kinesin-like protein KIF1B	Has a plus-end-directed microtubule motor activity and functions as a motor for transport of vesicles and organelles along microtubules.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
monocyte	1
mononuclear cell	1
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VHL	3,522
KIF1B	2,257

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
KIF1B	O60333	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Replication of the SARS-CoV-1 genome	1	1427.5×	0.005	VHL
Replication of the SARS-CoV-2 genome	1	1427.5×	0.005	VHL
RHOBTB3 ATPase cycle	1	571.0×	0.009	VHL
SUMOylation of ubiquitinylation proteins	1	146.4×	0.026	VHL
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	1	98.5×	0.028	VHL
Kinesins	1	89.2×	0.028	KIF1B
Golgi-to-ER retrograde transport	1	66.4×	0.032	KIF1B
COPI-dependent Golgi-to-ER retrograde traffic	1	55.4×	0.032	KIF1B
Intra-Golgi and retrograde Golgi-to-ER traffic	1	52.4×	0.032	KIF1B
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.045	KIF1B
Neddylation	1	23.7×	0.057	VHL
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.057	VHL
Membrane Trafficking	1	18.5×	0.057	KIF1B
Hemostasis	1	18.0×	0.057	KIF1B
Vesicle-mediated transport	1	17.4×	0.057	KIF1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retrograde neuronal dense core vesicle transport	1	1685.2×	0.008	KIF1B
regulation of cellular response to hypoxia	1	1404.3×	0.008	VHL
neuron-neuron synaptic transmission	1	842.6×	0.008	KIF1B
apoptotic process involved in development	1	842.6×	0.008	KIF1B
mitochondrion transport along microtubule	1	702.2×	0.008	KIF1B
anterograde synaptic vesicle transport	1	495.6×	0.009	KIF1B
negative regulation of receptor signaling pathway via JAK-STAT	1	443.5×	0.009	VHL
negative regulation of transcription elongation by RNA polymerase II	1	383.0×	0.009	VHL
neuromuscular synaptic transmission	1	300.9×	0.010	KIF1B
amyloid fibril formation	1	300.9×	0.010	VHL
negative regulation of signal transduction	1	187.2×	0.014	VHL
negative regulation of TORC1 signaling	1	162.0×	0.015	VHL
positive regulation of cell differentiation	1	133.8×	0.016	VHL
negative regulation of autophagy	1	129.6×	0.016	VHL
cell morphogenesis	1	78.8×	0.024	VHL
cellular response to hypoxia	1	60.6×	0.030	VHL
vesicle-mediated transport	1	48.1×	0.035	KIF1B
regulation of gene expression	1	41.7×	0.038	VHL
negative regulation of gene expression	1	34.5×	0.043	VHL
protein stabilization	1	33.4×	0.043	VHL
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.052	VHL
negative regulation of cell population proliferation	1	21.1×	0.060	VHL
protein ubiquitination	1	20.7×	0.060	VHL
negative regulation of apoptotic process	1	17.4×	0.067	VHL
proteolysis	1	17.1×	0.067	VHL
regulation of DNA-templated transcription	1	15.8×	0.070	VHL
apoptotic process	1	14.3×	0.073	KIF1B
positive regulation of DNA-templated transcription	1	14.0×	0.073	VHL
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	VHL

Therapeutics

Drugs indicated for this disease

1 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Metyrosine	Approved (phase 4)
Doxazosin	Phase 3 (in late-stage trials)
Filgrastim	Phase 3 (in late-stage trials)
Ifosfamide	Phase 3 (in late-stage trials)
Phenoxybenzamine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Axitinib, Catequentinib, Dexmedetomidine, Dovitinib, Edotreotide, Iobenguane, Lanreotide, Olaparib, Penpulimab, Sunitinib, Talazoparib, Temozolomide.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
VHL	OSIMERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VHL	7	4
KIF1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
DT-2216	1	VHL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
KIF1B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VHL	2.3.2.B13

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
VHL	3,575

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
DT-2216	1	VHL

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VHL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KIF1B

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF1B	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 127.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	62
PHASE2	38
PHASE1	9
PHASE1/PHASE2	7
PHASE3	5
PHASE4	3
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05702944	PHASE4	RECRUITING	The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma
NCT01379898	PHASE4	COMPLETED	Phenoxybenzamine Versus Doxazosin in PCC Patients
NCT01959711	PHASE4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00126412	PHASE3	COMPLETED	Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma
NCT01373736	PHASE3	UNKNOWN	123I-MIBG Scintigraphy in Patients Being Evaluated for Neuroendocrine Tumors
NCT03176693	PHASE3	COMPLETED	Preoperative Alpha Blockade for Pheochromocytoma
NCT00107289	PHASE2	RECRUITING	Iodine I 131 Metaiodobenzylguanidine in Treating Patients With Recurrent, Progressive, or Refractory Neuroblastoma or Malignant Pheochromocytoma or Paraganglioma
NCT02721732	PHASE2	ACTIVE_NOT_RECRUITING	Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic
NCT02834013	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
NCT03206060	PHASE2	RECRUITING	Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma
NCT03839498	PHASE2	ACTIVE_NOT_RECRUITING	Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma
NCT03946527	PHASE2	ACTIVE_NOT_RECRUITING	LAnreotide in Metastatic Pheochromocytoma / PARAganglioma (LAMPARA)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04394858	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy (Temozolomide) for Advanced Neuroendocrine Cancer
NCT04711135	PHASE2	ACTIVE_NOT_RECRUITING	Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs
NCT04924075	PHASE2	RECRUITING	Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
NCT05142241	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Combination of Anti-Cancer Drugs Talazoparib and Temozolomide in Patients With Advanced Stage Rare Cancers, RARE 2 Trial
NCT05636618	PHASE1/PHASE2	RECRUITING	Targeted Alpha-Particle Therapy for Advanced Somatostatin Receptor Type 2 (SSTR2) Positive Tumors
NCT05944237	PHASE1/PHASE2	RECRUITING	HTL0039732 in Participants With Advanced Solid Tumours
NCT06045260	PHASE2	RECRUITING	Receptor Radionuclide Therapy With 177Lu-DOTATOC
NCT06427798	PHASE1/PHASE2	RECRUITING	Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheochromocytoma/Paraganglioma Previously Treated With Systemic Targeted Radioligand Therapy
NCT06429397	PHASE2	NOT_YET_RECRUITING	Anlotinib Combined With Benmelstobart for Advanced Pheochromocytoma
NCT06503146	PHASE2	RECRUITING	18F-Fibroblast Activation Protein Inhibitor ([18F]FAPI-74) PET Imaging for Cancer Detection
NCT06607692	PHASE1/PHASE2	RECRUITING	Study in Children and Adolescents of 177Lu-DOTATATE (Lutathera®) Combined With the PARP Inhibitor Olaparib for the Treatment of Recurrent or Relapsed Solid Tumours Expressing Somatostatin Receptor (SSTR) (LuPARPed).
NCT06683846	PHASE2	RECRUITING	Ivonescimab in the Treatment of Multiple Advanced Tumors
NCT07167329	PHASE2	RECRUITING	Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial
NCT00002608	PHASE2	COMPLETED	Combination Chemotherapy and Tamoxifen in Treating Patients With Solid Tumors
NCT00028106	PHASE2	COMPLETED	131MIBG to Treat Malignant Pheochromocytoma
NCT00458952	PHASE1/PHASE2	COMPLETED	Phase 1 Study of Iobenguane (MIBG) I 131 in Patients With Malignant Pheochromocytoma/Paraganglioma
NCT00466856	PHASE2	TERMINATED	Internal Radiation Therapy in Treating Patients With Liver Metastases From Neuroendocrine Tumors
NCT00843037	PHASE2	COMPLETED	Study Of Sunitinib In Patients With Recurrent Paraganglioma/Pheochromocytoma
NCT00874614	PHASE2	UNKNOWN	A Study Evaluating Ultratrace Iobenguane I131 in Patients With Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma
NCT00923481	PHASE2	COMPLETED	A Broad Multi-histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-small Cell Lung, Head and Neck Hepatocellular and Renal Cell Carcinomas, and Pheochromocytoma and Thyroid Tumors (Multi-H…
NCT01152827	PHASE2	COMPLETED	RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid
NCT01340794	PHASE2	TERMINATED	Pazopanib Hydrochloride in Treating Patients With Advanced or Progressive Malignant Pheochromocytoma or Paraganglioma
NCT01413503	PHASE2	COMPLETED	A Phase II Study of 131I- Metaiodobenzylguanidine (MIBG) for Treatment of Metastatic or Unresectable Pheochromocytoma and Related Tumors
NCT01635907	PHASE2	COMPLETED	Dovitinib in Neuroendocrine Tumors
NCT01967576	PHASE2	COMPLETED	Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENOXYBENZAMINE	4	9
DOXAZOSIN	4	6
EDOTREOTIDE GALLIUM GA-68	4	4
CABOZANTINIB	4	3
LUTETIUM OXODOTREOTIDE LU-177	4	3
AXITINIB	4	2
BELZUTIFAN	4	2
DOXORUBICIN HYDROCHLORIDE	4	2
FILGRASTIM	4	2
IFOSFAMIDE	4	2
IOBENGUANE I 131	4	2
FOSTAMATINIB DISODIUM	4	1
INDIUM IN 111 PENTETREOTIDE	4	1
LANREOTIDE	4	1
LENVATINIB	4	1
OCTREOTIDE ACETATE	4	1
PAZOPANIB HYDROCHLORIDE	4	1
POTASSIUM IODIDE	4	1
FLORBENGUANE F18	3	3
VATALANIB	3	2
VELIPARIB	3	2
BENMELSTOBART	3	1
CATEQUENTINIB HYDROCHLORIDE	3	1
DOVITINIB	3	1
GUADECITABINE	3	1
TIPIFARNIB	3	1
LUTETIUM LU177 EDOTREOTIDE	2	2
EDOTREOTIDE YTTRIUM Y-90	2	1
TIGOZERTINIB	2	1
IOBENGUANE I 123	1	1