Anaplastic astrocytoma

Summary

Anaplastic astrocytoma (MONDO:0016684) is a disease with 8 cohort genes and 140 clinical trials. The dominant Reactome pathway is Pre-NOTCH Transcription and Translation (3 cohort genes). Molecularly, ATRX Underexpression confers sensitivity to Temozolomide + PCV Regimen in Malignant Astrocytoma (CIViC Level B); 3 further subtype–drug associations are mapped below. Top therapeutic interventions include temozolomide, lomustine, and trametinib.

At a glance

• Prevalence: 1-9 / 1 000 000 (United States) [Orphanet-validated]
• Cohort genes: 8
• ClinVar variants: 3
• Clinical trials: 140
• Precision-medicine evidence (CIViC): 4 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.4	United States	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	anaplastic astrocytoma
Mondo ID	MONDO:0016684
EFO	EFO:0002499
Orphanet	251589
DOID	DOID:3078
NCIT	C9477
UMLS	C0334579
MedGen	137784
GARD	0005860
MedDRA	10002224, 10060971
NORD	769
Is cancer (heuristic)	no

Also known as: anaplastic astrocytoma · astrocytoma, anaplastic, malignant · grade III astrocytic neoplasm · grade III astrocytic tumor · grade III astrocytic tumour · grade III astrocytoma · malignant astrocytoma

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record · 46 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › nervous system neoplasm › neuroepithelial neoplasm › glioma › astrocytic tumor › high grade astrocytic tumor › anaplastic astrocytoma

Related subtypes (2): gliomatosis cerebri, glioblastoma

Subtypes (3): IDH-mutant anaplastic astrocytoma, IDH-wildtype anaplastic astrocytoma, high-grade astrocytoma with piloid features

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

3 retrieved; paginated sample, class counts are floors:

1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12364	NM_000546.6(TP53):c.844C>T (p.Arg282Trp)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12365	NM_000546.6(TP53):c.733G>A (p.Gly245Ser)	TP53	Pathogenic	reviewed by expert panel
11724	NM_000489.6(ATRX):c.5579A>G (p.Asn1860Ser)	ATRX	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 54 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BRAF	Limited	Autosomal dominant	anaplastic astrocytoma	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
ATRX	Orphanet:100075	Neuroendocrine tumor of stomach
ATRX	Orphanet:231401	Alpha-thalassemia-myelodysplastic syndrome
ATRX	Orphanet:847	X-linked alpha-thalassemia-intellectual disability syndrome
ATRX	Orphanet:96253	Cushing disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
ACVR1	Orphanet:337	Fibrodysplasia ossificans progressiva
IDH1	Orphanet:163634	Maffucci syndrome
IDH1	Orphanet:251576	Gliosarcoma
IDH1	Orphanet:251579	Giant cell glioblastoma
IDH1	Orphanet:296	Ollier disease
IDH1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
IDH1	Orphanet:99646	Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria
IDH2	Orphanet:163634	Maffucci syndrome
IDH2	Orphanet:251589	Anaplastic astrocytoma
IDH2	Orphanet:251598	Protoplasmic astrocytoma
IDH2	Orphanet:251601	Fibrillary astrocytoma
IDH2	Orphanet:251604	Gemistocytic astrocytoma
IDH2	Orphanet:251627	Oligodendroglioma
IDH2	Orphanet:251630	Anaplastic oligodendroglioma
IDH2	Orphanet:251656	Oligoastrocytoma

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	5
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar,civic_evidence
ATRX	HGNC:886	ENSG00000085224	P46100	Transcriptional regulator ATRX	clinvar,civic_evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gencc
ACVR1	HGNC:171	ENSG00000115170	Q04771	Activin receptor type-1	civic_evidence
H3-3A	HGNC:4764	ENSG00000163041	P84243	Histone H3.3	civic_evidence
H3C2	HGNC:4776	ENSG00000286522	P68431	Histone H3.1	civic_evidence
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	civic_evidence
IDH2	HGNC:5383	ENSG00000182054	P48735	Isocitrate dehydrogenase [NADP], mitochondrial	civic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
ATRX	Transcriptional regulator ATRX	Involved in transcriptional regulation and chromatin remodeling.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
ACVR1	Activin receptor type-1	Bone morphogenetic protein (BMP) type I receptor that is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation.
H3-3A	Histone H3.3	Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes.
H3C2	Histone H3.1	Core component of nucleosome.
IDH1	Isocitrate dehydrogenase [NADP] cytoplasmic	Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase.
IDH2	Isocitrate dehydrogenase [NADP], mitochondrial	Plays a role in intermediary metabolism and energy production.

Protein-family classification

Druggable: 4 · Difficult: 2 · Unknown: 2 · 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
Kinase	2	6.9×	0.126
Enzyme (other)	2	3.0×	0.278
Transcription factor	2	2.1×	0.335
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
ATRX	Transcription factor	no		SNF2_N, Helicase_C-like, Znf_FYVE_PHD
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
ACVR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
H3-3A	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, Histone-fold
H3C2	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, Histone-fold
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
IDH2	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	3
ganglionic eminence	2
ventricular zone	2
calcaneal tendon	2
adrenal tissue	2
tendon of biceps brachii	1
endothelial cell	1
buccal mucosa cell	1
cartilage tissue	1
saphenous vein	1
synovial joint	1
monocyte	1
bone marrow cell	1
corpus epididymis	1
jejunal mucosa	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
ATRX	294	ubiquitous	marker	endothelial cell, calcaneal tendon, colonic epithelium
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
ACVR1	293	ubiquitous	marker	cartilage tissue, synovial joint, saphenous vein
H3-3A	134	ubiquitous	marker	ganglionic eminence, monocyte, ventricular zone
H3C2	94	ubiquitous	marker	adrenal tissue, colonic epithelium, bone marrow cell
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
IDH2	292	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
BRAF	7,394
ATRX	5,796
IDH1	5,464
IDH2	4,912
H3C2	3,550
ACVR1	2,369
H3-3A	1,595

Intra-cohort edges

A	B	Sources
ATRX	H3-3A	intact
ATRX	IDH1	string_interaction
ATRX	TP53	string_interaction
BRAF	TP53	string_interaction
IDH1	IDH2	biogrid_interaction
IDH1	TP53	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H3C2	P68431	548
TP53	P04637	313
BRAF	P15056	131
H3-3A	P84243	103
ACVR1	Q04771	85
IDH1	O75874	61
ATRX	P46100	12
IDH2	P48735	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 150. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Pre-NOTCH Transcription and Translation	3	52.6×	0.003	TP53, H3-3A, H3C2
Oxidative Stress Induced Senescence	3	38.8×	0.003	TP53, H3-3A, H3C2
Factors involved in megakaryocyte development and platelet production	3	28.5×	0.006	TP53, H3-3A, H3C2
Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate	1	1631.4×	0.006	IDH1
Alternative Lengthening of Telomeres (ALT)	1	1631.4×	0.006	ATRX
Defective Inhibition of DNA Recombination at Telomere	1	1631.4×	0.006	ATRX
Diseases of Telomere Maintenance	1	1631.4×	0.006	ATRX
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	1631.4×	0.006	TP53
NADPH regeneration	1	815.7×	0.006	IDH1
Regulation of TP53 Expression	1	815.7×	0.006	TP53
Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations	1	815.7×	0.006	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations	1	815.7×	0.006	ATRX
RNA Polymerase I Promoter Opening	2	52.6×	0.006	H3-3A, H3C2
DNA methylation	2	51.0×	0.006	H3-3A, H3C2
FXIIa activates plasma kallikrein-kinin system	2	49.4×	0.006	H3-3A, H3C2
SIRT1 negatively regulates rRNA expression	2	48.7×	0.006	H3-3A, H3C2
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	2	48.0×	0.006	H3-3A, H3C2
Inhibition of DNA recombination at telomere	2	48.0×	0.006	ATRX, H3-3A
Assembly of the ORC complex at the origin of replication	2	47.3×	0.006	H3-3A, H3C2
Chromatin modifications during the maternal to zygotic transition (MZT)	2	46.6×	0.006	H3-3A, H3C2
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	2	46.6×	0.006	H3-3A, H3C2
Condensation of Prophase Chromosomes	2	44.7×	0.006	H3-3A, H3C2
Defective pyroptosis	2	44.7×	0.006	H3-3A, H3C2
PRC2 methylates histones and DNA	2	43.5×	0.006	H3-3A, H3C2
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	2	43.5×	0.006	H3-3A, H3C2
CHD6, CHD7, CHD8, CHD9 subfamily	2	42.4×	0.006	H3-3A, H3C2
Transcriptional regulation by small RNAs	2	41.3×	0.006	H3-3A, H3C2
NuRD complex assembly	2	40.3×	0.006	H3-3A, H3C2
Meiotic recombination	2	37.1×	0.006	H3-3A, H3C2
Interaction of NuRD complexes with transcription factors	2	36.2×	0.006	H3-3A, H3C2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glyoxylate cycle	2	2106.5×	5e-05	IDH1, IDH2
isocitrate metabolic process	2	842.6×	2e-04	IDH1, IDH2
negative regulation of glial cell proliferation	2	421.3×	5e-04	TP53, IDH2
NADP+ metabolic process	2	383.0×	5e-04	IDH1, IDH2
subtelomeric heterochromatin formation	2	383.0×	5e-04	ATRX, H3-3A
nucleosome assembly	3	52.7×	7e-04	ATRX, H3-3A, H3C2
multicellular organism growth	3	51.4×	7e-04	TP53, ATRX, H3-3A
2-oxoglutarate metabolic process	2	234.1×	9e-04	IDH1, IDH2
telomere organization	2	156.0×	0.002	H3-3A, H3C2
tricarboxylic acid cycle	2	127.7×	0.003	IDH1, IDH2
T cell differentiation in thymus	2	102.8×	0.004	TP53, BRAF
DNA damage response, signal transduction by p53 class mediator	2	89.6×	0.004	TP53, ATRX
negative regulation of helicase activity	1	2106.5×	0.006	TP53
regulation of phospholipid catabolic process	1	2106.5×	0.006	IDH1
endocardial cushion cell fate commitment	1	2106.5×	0.006	ACVR1
cellular response to actinomycin D	1	2106.5×	0.006	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2106.5×	0.006	TP53
negative regulation of G1 to G0 transition	1	2106.5×	0.006	TP53
cellular response to xenobiotic stimulus	2	60.2×	0.006	TP53, BRAF
post-embryonic forelimb morphogenesis	1	1053.2×	0.008	ATRX
positive regulation of mitochondrial membrane permeability	1	1053.2×	0.008	TP53
regulation of phospholipid biosynthetic process	1	1053.2×	0.008	IDH1
oligodendrocyte apoptotic process	1	1053.2×	0.008	TP53
negative regulation of glial cell migration	1	1053.2×	0.008	IDH2
negative regulation of glucose catabolic process to lactate via pyruvate	1	1053.2×	0.008	TP53
negative regulation of matrix metallopeptidase secretion	1	1053.2×	0.008	IDH2
negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric	1	1053.2×	0.008	ATRX
negative regulation of pentose-phosphate shunt	1	1053.2×	0.008	TP53
positive regulation of determination of dorsal identity	1	1053.2×	0.008	ACVR1
transforming growth factor beta receptor signaling pathway	2	39.8×	0.009	TP53, ACVR1

Therapeutics

Drugs indicated for this disease

2 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Carmustine	Approved (phase 4)
Everolimus	Approved (phase 4)
Carboplatin	Phase 3 (in late-stage trials)
Eflornithine	Phase 3 (in late-stage trials)
Lomustine	Phase 3 (in late-stage trials)
Temozolomide	Phase 3 (in late-stage trials)
Trabedersen	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANTINEOPLASTON A10, Aflibercept, Bevacizumab, Cabozantinib, Cilengitide, Doxorubicin, Etirinotecan Pegol, Etoposide, Irinotecan, Nintedanib, Streptozocin, Valacyclovir, Vandetanib, Veliparib, Vincristine, Vorinostat.

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 3

Druggability breadth: 6 of 8 evidence-associated genes (75%) 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
TP53	NITROFURANTOIN
BRAF	VEMURAFENIB
ACVR1	MOMELOTINIB
IDH1	ENASIDENIB
IDH2	ENASIDENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
BRAF	48	4
ACVR1	39	4
IDH1	10	4
IDH2	7	4
ATRX	0	0
H3-3A	0	0
H3C2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
IDH1	488	Binding:475, Functional:12, ADMET:1
ACVR1	299	Binding:293, Functional:4, ADMET:2
IDH2	84	Binding:84
H3-3A	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
ACVR1	2.7.10.2	non-specific protein-tyrosine kinase
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TP53	869
BRAF	1,442
ACVR1	299
IDH1	488

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	TP53, BRAF, ACVR1, IDH1, IDH2
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	3	ATRX, H3-3A, H3C2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATRX	0	—
H3-3A	6	—
H3C2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 140.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	58
PHASE2	31
Not specified	22
PHASE1/PHASE2	15
PHASE3	8
EARLY_PHASE1	3
PHASE2/PHASE3	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT00430911	PHASE3	COMPLETED	Radiotherapy for Malignant Astrocytomas in the Elderly
NCT00717210	PHASE3	COMPLETED	Randomized Phase III Study of Sequential Radiochemotherapy of Anaplastic Glioma With PCV or Temozolomide
NCT00761280	PHASE3	TERMINATED	Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma
NCT01502241	PHASE3	COMPLETED	Phase III Trial of Primary Radio- or Chemotherapy in Malignant Astrocytoma of the Elderly
NCT01656980	PHASE3	UNKNOWN	Safety and Efficacy Study of Intracranially Implanted Carmustine to Treat Newly Diagnosed Malignant Glioma
NCT01765088	PHASE3	UNKNOWN	A Phase III Trial on Adjuvant Temozolomide With or Without Interferon-alpha in Newly Diagnosed High-grade Gliomas
NCT02414165	PHASE2/PHASE3	TERMINATED	The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma
NCT02629757	PHASE3	UNKNOWN	A Study on β-elemene as Maintain Treatment for Newly Diagnosed Malignant Gliomas
NCT02796261	PHASE3	UNKNOWN	Study to Evaluate Eflornithine + Lomustine vs Lomustine in Recurrent Anaplastic Astrocytoma (AA) Patients
NCT04105374	PHASE2/PHASE3	WITHDRAWN	Testing the Addition of an Anti-cancer Viral Gene Therapy, Toca 511/Toca FC, to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed Glioblastoma
NCT01269853	PHASE1/PHASE2	RECRUITING	Repeated Super-selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Relapsed GBM and AA
NCT02800486	PHASE2	RECRUITING	Super Selective Intra-arterial Repeated Infusion of Cetuximab (Erbitux) With Reirradiation for Treatment of Relapsed/Refractory GBM, AA, and AOA
NCT03180502	PHASE2	ACTIVE_NOT_RECRUITING	Proton Beam or Intensity-Modulated Radiation Therapy in Preserving Brain Function in Patients With IDH Mutant Grade II or III Glioma
NCT03581292	PHASE2	ACTIVE_NOT_RECRUITING	Veliparib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600 Mutations
NCT03603405	PHASE1/PHASE2	RECRUITING	HSV-tk and XRT and Chemotherapy for Newly Diagnosed GBM
NCT03919071	PHASE2	ACTIVE_NOT_RECRUITING	Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma
NCT05084430	PHASE1/PHASE2	RECRUITING	Study of Pembrolizumab and M032 (NSC 733972)
NCT05843253	PHASE2	RECRUITING	Study of Ribociclib and Everolimus in HGG and DIPG or Ribociclib and Temozolomide in DHG, H3G34-mutant
NCT05956821	PHASE1/PHASE2	RECRUITING	Treatment of Relapsed/Refractory Intracranial Glioma in Patients Under 22 Years of Age
NCT06264388	PHASE2	RECRUITING	DB107-Retroviral Replicating Vector (RRV) Combined With DB107-Flucytosine (FC) in Patients With Recurrent Glioblastoma or Anaplastic Astrocytoma
NCT00003470	PHASE2	COMPLETED	Antineoplaston Therapy in Treating Patients With Anaplastic Astrocytoma
NCT00004688	PHASE2	COMPLETED	Phase II Study of Carmustine, Streptozocin, and Mercaptopurine for Refractory or Recurrent Brain Neoplasms
NCT00024570	PHASE1/PHASE2	COMPLETED	Interstitial Infusion of IL13-PE38QQR Cytotoxin in Recurrent Malignant Glioma
NCT00041587	PHASE1/PHASE2	COMPLETED	Pre-operative IL13-PE38QQR in Patients With Recurrent or Progressive Malignant Glioma
NCT00062504	PHASE2	TERMINATED	Phase 2 Trial Using Talampanel in Patients With Recurrent High Grade Gliomas
NCT00100802	PHASE2	COMPLETED	Radiation Therapy, Temozolomide, and Lomustine in Treating Young Patients With Newly Diagnosed Gliomas
NCT00114309	PHASE2	UNKNOWN	131-I-TM-601 Study in Adults With Recurrent High-Grade Glioma
NCT00115440	PHASE1/PHASE2	COMPLETED	BNCT to Treat Glioma That Has Progressed Following Radiotherapy
NCT00243490	PHASE2	WITHDRAWN	Photodynamic Therapy in the Treatment of Malignant Intracranial Tumors
NCT00301418	PHASE1/PHASE2	COMPLETED	Oral Tarceva Study for Recurrent/Residual Glioblastoma Multiforme and Anaplastic Astrocytoma
NCT00409214	PHASE2	COMPLETED	Phase IIa Safety and Light Dose-escalation Study in Patients With Primary or Recurrent/High-grade Glioma Using the Litx™ System to Confirm the Zone of Tumor Destruction During the Intraoperative Treatment of Glioma
NCT00431561	PHASE2	COMPLETED	Phase IIb Clinical Trial With TGF-β2 Antisense Compound AP 12009 for Recurrent or Refractory High-grade Glioma
NCT00589875	PHASE2	COMPLETED	Phase 2a Study of CAN-2409 With Standard Radiation Therapy for Malignant Glioma
NCT00606008	PHASE2	COMPLETED	A Phase II Trial of Sutent (Sunitinib; SU011248) for Recurrent Anaplastic Astrocytoma and Glioblastoma
NCT00667394	PHASE2	COMPLETED	Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors
NCT00879437	PHASE2	COMPLETED	Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma
NCT00995007	PHASE2	COMPLETED	A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas
NCT01095094	PHASE2	TERMINATED	Ritonavir and Lopinavir in Treating Patients With Progressive or Recurrent High-Grade Glioma
NCT01189266	PHASE1/PHASE2	COMPLETED	Vorinostat and Radiation Therapy Followed by Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TEMOZOLOMIDE	4	6
LOMUSTINE	4	5
TRAMETINIB	4	4
CARMUSTINE	4	3
DABRAFENIB	4	3
MERCAPTOPURINE ANHYDROUS	4	3
FINGOLIMOD	4	2
MEBENDAZOLE	4	2
PLERIXAFOR	4	2
VALACYCLOVIR	4	2
AMINOLEVULINIC ACID	4	1
BINIMETINIB	4	1
CABOZANTINIB	4	1
EFLORNITHINE	4	1
ENCORAFENIB	4	1
FLUORESCEIN	4	1
GADOTERIDOL	4	1
IMETELSTAT SODIUM	4	1
IMIQUIMOD	4	1
LONAFARNIB	4	1
LORLATINIB	4	1
MANNITOL	4	1
NINTEDANIB	4	1
PALBOCICLIB	4	1
REGADENOSON	4	1
REGADENOSON ANHYDROUS	4	1
RIBOCICLIB	4	1
SONIDEGIB	4	1
SORBITOL	4	1
STREPTOZOCIN	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 4 predictive associations from 4 curated evidence items; also 10 diagnostic, 4 prognostic, 1 oncogenic.

Molecular subtype	Therapy	Effect	Level	CIViC
ATRX Underexpression	Temozolomide + PCV Regimen	Sensitivity/Response	CIViC B	EID1647
ETV6::NTRK3 Fusion	Entrectinib	Sensitivity/Response	CIViC C	EID11853
NF1 Mutation AND Methylation signature PA-NF1	Selumetinib	Sensitivity/Response	CIViC C	EID12270
TP53 R273C	MDM2 Inhibitor AMGMDS3	Resistance	CIViC D	EID10073