Gliosarcoma

Summary

Gliosarcoma (MONDO:0016681) is a disease caused by LZTR1 (Orphanet disease-causing). It is a rare histological variant of glioblastoma (WHO grade IV) characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation (WHO) (Mondo). This page aggregates 10 associated genes and 137 registered clinical trials. The dominant Reactome pathway is PIP3 activates AKT signaling (4 associated genes). Molecularly, TPR::NTRK1 Fusion confers sensitivity to Larotrectinib in Gliosarcoma (CIViC Level C). Top therapeutic interventions include bevacizumab, temozolomide, and erlotinib.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: LZTR1 (Orphanet disease-causing)
• Cohort genes: 10
• Clinical trials: 137 (top 3% of diseases corpus-wide)
• Approved drugs (ChEMBL indications): 3 — Bevacizumab, Lomustine, Temozolomide
• Precision-medicine evidence (CIViC): 1 subtype–drug association
• Druggability snapshot: 6 of 10 cohort genes are drug-illuminated (an approved/clinical drug with curated evidence); 4 functionally characterized but not yet drugged (LZTR1, TACC1, TACC3, SEPTIN14). Atlas-derived.

Clinical features

Clinical description

Mondo: A rare histological variant of glioblastoma (WHO grade IV) characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation (WHO).

MeSH: Rare mixed tumors of the brain and rarely the spinal cord which contain malignant neuroectodermal (glial) and mesenchymal components, including spindle-shaped fibrosarcoma cells. These tumors are highly aggressive and present primarily in adults as rapidly expanding mass lesions. They may arise in tissue that has been previously irradiated. (From Br J Neurosurg 1995 Apr;9(2):171-8)

Inheritance: Not applicable · Onset: Adult

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.03	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	gliosarcoma
Mondo ID	MONDO:0016681
EFO	EFO:1001465
MeSH	D018316
Orphanet	251576
DOID	DOID:3071
NCIT	C3796
UMLS	C0206726
MedGen	64638
GARD	0005653
MedDRA	10018340
Is cancer (heuristic)	no

Also known as: glioblastoma with a sarcomatous component · gliosarcoma · sarcomatous glioblastoma

Data availability: 21 cell lines.

Disease family

Classification path: disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › nervous system cancer › central nervous system cancer › brain cancer › brain glioma › brain glioblastoma › gliosarcoma

Sibling subtypes (2): giant cell glioblastoma, … (+1 more under brain glioblastoma)

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Molecular basis

The molecular function of this disease’s causal gene(s), from UniProt. Attributed to the gene/protein — reporting UniProt’s curation, not an assertion about this disease’s clinical phenotype.

LZTR1 — Leucine-zipper-like transcriptional regulator 1 (Q8N653) · Orphanet disease-causing · Belongs to the LZTR1 family. Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras GTPases (M-Ras/MRAS, K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS) and Ras-like protein RIT1. Localization / cofactor: Endomembrane system UniProt gene–disease: Glioma (GLM) [MIM:137800] Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and …

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 72 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

showing 60 of 72 cohort genes:

Gene	Orphanet ID	Rare disease
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules
LZTR1	Orphanet:648	Noonan syndrome
LZTR1	Orphanet:93921	Full schwannomatosis
TACC1	Orphanet:251576	Gliosarcoma
TACC1	Orphanet:251579	Giant cell glioblastoma
TACC3	Orphanet:251576	Gliosarcoma
TACC3	Orphanet:251579	Giant cell glioblastoma
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
EGFR	Orphanet:251576	Gliosarcoma
EGFR	Orphanet:251579	Giant cell glioblastoma
SEPTIN14	Orphanet:251576	Gliosarcoma
SEPTIN14	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:168953	Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1	Orphanet:2117	Hartsfield syndrome
FGFR1	Orphanet:220386	Semilobar holoprosencephaly
FGFR1	Orphanet:2396	Encephalocraniocutaneous lipomatosis
FGFR1	Orphanet:251576	Gliosarcoma
FGFR1	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:251615	Pilomyxoid astrocytoma
FGFR1	Orphanet:2645	Osteoglosphonic dysplasia
FGFR1	Orphanet:280200	Microform holoprosencephaly
FGFR1	Orphanet:314950	Primary hypereosinophilic syndrome
FGFR1	Orphanet:3157	Septo-optic dysplasia spectrum
FGFR1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FGFR1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGFR1	Orphanet:478	Kallmann syndrome
FGFR1	Orphanet:93258	Pfeiffer syndrome type 1
FGFR1	Orphanet:93924	Lobar holoprosencephaly
FGFR1	Orphanet:99798	Oligodontia
FGFR3	Orphanet:15	Achondroplasia
FGFR3	Orphanet:1860	Thanatophoric dysplasia type 1
FGFR3	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR3	Orphanet:251576	Gliosarcoma
FGFR3	Orphanet:251579	Giant cell glioblastoma
FGFR3	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
FGFR3	Orphanet:429	Hypochondroplasia
FGFR3	Orphanet:53271	Muenke syndrome
FGFR3	Orphanet:794	Saethre-Chotzen syndrome
FGFR3	Orphanet:85164	Camptodactyly-tall stature-scoliosis-hearing loss syndrome

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Genes from Orphanet’s curated gene–disease associations — no GWAS / GenCC / ClinVar / CIViC route resolved for this disease.

Evidence partition

Subset	Genes
orphanet	10

Cohort genes

10 cohort genes:

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	orphanet,orphanet_causing
TACC1	HGNC:11522	ENSG00000147526	O75410	Transforming acidic coiled-coil-containing protein 1	orphanet
TACC3	HGNC:11524	ENSG00000013810	Q9Y6A5	Transforming acidic coiled-coil-containing protein 3	orphanet
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	orphanet
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	orphanet
SEPTIN14	HGNC:33280	ENSG00000154997	Q6ZU15	Septin-14	orphanet
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	orphanet
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	orphanet
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	orphanet
MGMT	HGNC:7059	ENSG00000170430	P16455	Methylated-DNA–protein-cysteine methyltransferase	orphanet

Cohort function summary

Lead sentence per gene, UniProt-curated.

10 cohort genes:

Symbol	Protein name	Function (lead sentence)
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras GTPases (M-Ras/MRAS, K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS) and Ras-like protein RIT1.
TACC1	Transforming acidic coiled-coil-containing protein 1	Involved in transcription regulation induced by nuclear receptors, including in T3 thyroid hormone and all-trans retinoic acid pathways.
TACC3	Transforming acidic coiled-coil-containing protein 3	Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
SEPTIN14	Septin-14	Filament-forming cytoskeletal GTPase.
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
FGFR3	Fibroblast growth factor receptor 3	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis.
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.
MGMT	Methylated-DNA–protein-cysteine methyltransferase	Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA.

Protein-family classification

Druggable: 5 · Difficult: 1 · Unknown: 4 · 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	3	8.3×	0.019
Enzyme (other)	2	2.4×	0.401
Transcription factor	1	0.8×	0.907
Other/Unknown	4	0.7×	0.907

Per-gene assignment

10 cohort genes:

Symbol	Family	Druggable?	EC	InterPro (top 3)
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
TACC1	Other/Unknown	no		TACC_C, TACC
TACC3	Other/Unknown	no		TACC_C, TACC, TACC3_Aurora-A_bind
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
SEPTIN14	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
MGMT	Enzyme (other)	yes	2.1.1.63	MethylDNA_cys_MeTrfase_AS, MethylG_MeTrfase_N, MethylDNA_cys_MeTrfase_DNA-bd

Expression context

Cohort genes with no expression data: 0.

10 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)	10
unknown	0

Top tissues across cohort

20 tissues:

Tissue	Cohort genes
calcaneal tendon	2
ventricular zone	2
adenohypophysis	1
pituitary gland	1
sural nerve	1
middle temporal gyrus	1
seminal vesicle	1
oocyte	1
secondary oocyte	1
ganglionic eminence	1
tendon of biceps brachii	1
gingiva	1
gingival epithelium	1
nipple	1
left testis	1
right testis	1
testis	1
buccal mucosa cell	1
stromal cell of endometrium	1
skin of hip	1

Per-gene tissue summary

10 cohort genes:

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
TACC1	295	ubiquitous	marker	middle temporal gyrus, calcaneal tendon, seminal vesicle
TACC3	197	ubiquitous	marker	oocyte, ventricular zone, secondary oocyte
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
EGFR	285	ubiquitous	marker	nipple, gingiva, gingival epithelium
SEPTIN14	132	tissue_specific	marker	right testis, left testis, testis
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon
FGFR3	262	broad	marker	upper leg skin, skin of hip, upper arm skin
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
MGMT	261	ubiquitous	marker	right lobe of liver, liver, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,400
EGFR	17,463
FGFR1	5,223
IDH1	4,810
FGFR3	4,066
MGMT	2,498
TACC3	2,332
TACC1	1,309
LZTR1	1,211
SEPTIN14	592

Intra-cohort edges

15 intra-cohort edges:

A	B	Sources
EGFR	MGMT	string_interaction
EGFR	SEPTIN14	string_interaction
EGFR	TACC3	biogrid_interaction
EGFR	TP53	string_interaction
FGFR1	FGFR3	biogrid_interaction
FGFR1	TACC1	biogrid_interaction, string_interaction
FGFR1	TACC3	string_interaction
FGFR3	SEPTIN14	string_interaction
FGFR3	TACC1	string_interaction
FGFR3	TACC3	string_interaction
IDH1	MGMT	string_interaction
IDH1	TP53	string_interaction
MGMT	TP53	string_interaction
SEPTIN14	TACC1	string_interaction
SEPTIN14	TACC3	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures

9 cohort genes:

Symbol	UniProt	PDB entries
EGFR	P00533	393
TP53	P04637	321
FGFR1	P11362	86
IDH1	O75874	64
MGMT	P16455	23
FGFR3	P22607	16
TACC3	Q9Y6A5	5
LZTR1	Q8N653	3
SEPTIN14	Q6ZU15	1

AlphaFold-only cohort genes (by pLDDT)

1 cohort genes:

Symbol	UniProt	pLDDT
TACC1	O75410	57.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 240. Enrichment computed across 10 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.

30 pathways by enrichment:

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PIP3 activates AKT signaling	4	38.2×	4e-04	TP53, EGFR, FGFR1, FGFR3
Diseases of signal transduction by growth factor receptors and second messengers	4	32.5×	4e-04	TP53, EGFR, FGFR1, FGFR3
Signaling by NOTCH	3	75.3×	5e-04	TACC3, TP53, EGFR
Constitutive Signaling by Aberrant PI3K in Cancer	3	54.4×	9e-04	EGFR, FGFR1, FGFR3
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	3	41.5×	0.002	EGFR, FGFR1, FGFR3
Disease	5	9.3×	0.002	TP53, EGFR, FGFR1, FGFR3, IDH1
Signal transduction by L1	2	148.3×	0.002	EGFR, FGFR1
Signaling by NOTCH3	2	148.3×	0.002	TACC3, EGFR
NOTCH3 Activation and Transmission of Signal to the Nucleus	2	135.9×	0.002	TACC3, EGFR
Signaling by FGFR in disease	2	120.8×	0.003	FGFR1, FGFR3
RAF/MAP kinase cascade	3	26.2×	0.003	EGFR, FGFR1, FGFR3
PI3K Cascade	2	77.7×	0.005	FGFR1, FGFR3
t(4;14) translocations of FGFR3	1	1631.4×	0.008	FGFR3
Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate	1	1631.4×	0.008	IDH1
MGMT-mediated DNA damage reversal	1	1631.4×	0.008	MGMT
Transcriptional activation of p53 responsive genes	1	1631.4×	0.008	TP53
Signaling by FGFR3 fusions in cancer	1	1631.4×	0.008	FGFR3
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	1631.4×	0.008	TP53
Signaling by FGFR1 amplification mutants	1	815.7×	0.014	FGFR1
NADPH regeneration	1	815.7×	0.014	IDH1
Regulation of TP53 Expression	1	815.7×	0.014	TP53
NFE2L2 regulating TCA cycle genes	1	543.8×	0.020	IDH1
PLCG1 events in ERBB2 signaling	1	407.9×	0.020	EGFR
FGFR1c and Klotho ligand binding and activation	1	407.9×	0.020	FGFR1
Signaling by Overexpressed Wild-Type EGFR in Cancer	1	407.9×	0.020	EGFR
Transcriptional activation of cell cycle inhibitor p21	1	407.9×	0.020	TP53
Signaling by plasma membrane FGFR1 fusions	1	407.9×	0.020	FGFR1
DNA Repair	2	28.1×	0.020	TP53, MGMT
Intracellular signaling by second messengers	2	26.1×	0.020	TP53, EGFR
Signaling by ERBB2 in Cancer	1	326.3×	0.023	EGFR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth.

30 GO terms by enrichment:

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of phospholipase activity	2	674.1×	5e-04	FGFR1, FGFR3
astral microtubule organization	2	259.3×	0.002	TACC1, TACC3
nuclear migration	2	146.5×	0.004	TACC1, TACC3
negative regulation of developmental growth	1	1685.2×	0.008	FGFR3
negative regulation of helicase activity	1	1685.2×	0.008	TP53
cellular response to actinomycin D	1	1685.2×	0.008	TP53
negative regulation of G1 to G0 transition	1	1685.2×	0.008	TP53
negative regulation of cardiocyte differentiation	1	1685.2×	0.008	EGFR
positive regulation of miRNA transcription	2	58.1×	0.008	TP53, EGFR
fibroblast growth factor receptor signaling pathway	2	57.1×	0.008	FGFR1, FGFR3
mitotic spindle organization	2	54.4×	0.008	TACC1, TACC3
positive regulation of MAPK cascade	3	24.2×	0.008	EGFR, FGFR1, FGFR3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	3	23.5×	0.008	EGFR, FGFR1, FGFR3
glyoxylate cycle	1	842.6×	0.011	IDH1
oligodendrocyte apoptotic process	1	842.6×	0.011	TP53
fibroblast growth factor receptor apoptotic signaling pathway	1	842.6×	0.011	FGFR3
negative regulation of pentose-phosphate shunt	1	842.6×	0.011	TP53
cerebral cortex development	2	41.1×	0.011	TACC1, TACC3
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	561.7×	0.013	FGFR1
bone maturation	1	561.7×	0.013	FGFR3
signal transduction by p53 class mediator	1	561.7×	0.013	TP53
positive regulation of protein kinase C signaling	1	561.7×	0.013	EGFR
ventricular zone neuroblast division	1	421.3×	0.013	FGFR1
positive regulation of programmed necrotic cell death	1	421.3×	0.013	TP53
response to UV-A	1	421.3×	0.013	EGFR
oxidative stress-induced premature senescence	1	421.3×	0.013	TP53
microtubule cytoskeleton organization involved in mitosis	1	421.3×	0.013	TACC3
isocitrate metabolic process	1	337.0×	0.013	IDH1
NADPH regeneration	1	337.0×	0.013	IDH1
mRNA transcription	1	337.0×	0.013	TP53

Therapeutics

Drugs indicated or in trials for this disease

3 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Bevacizumab	Approved (phase 3)
Lomustine	Approved (phase 3)
Temozolomide	Approved (phase 3)

40 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Depatuxizumab Mafodotin	Phase 3
Rindopepimut	Phase 3
6-O-BENZYLGUANINE	Phase 2
Aflibercept	Phase 2
Bortezomib	Phase 2
Carboplatin	Phase 2
Carboxyamidotriazole	Phase 2
Carmustine	Phase 2
Cilengitide	Phase 2
Dasatinib Anhydrous	Phase 2
Dovitinib	Phase 2
Erlotinib	Phase 2
Etoposide	Phase 2
Fenretinide	Phase 2
Filgrastim	Phase 2
Gefitinib	Phase 2
Hydroxyurea	Phase 2
Incomplete Freund’S Adjuvant	Phase 2
Ipilimumab	Phase 2
Irinotecan	Phase 2
Lenalidomide	Phase 2
Nintedanib	Phase 2
Nivolumab	Phase 2
Oxygen	Phase 2
Pazopanib	Phase 2
Pembrolizumab	Phase 2
Plerixafor	Phase 2
Rilotumumab	Phase 2
Sargramostim	Phase 2
Sirolimus	Phase 2
Sorafenib	Phase 2
Temsirolimus	Phase 2
Tipifarnib	Phase 2
Topotecan	Phase 2
Trebananib	Phase 2
Vandetanib	Phase 2
Veliparib	Phase 2
Vismodegib	Phase 2
Vitespen	Phase 2
Vorinostat	Phase 2

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 6 · Phased (≥1): 6 · Undrugged: 4

Druggability breadth: 7 of 10 evidence-associated genes (70%) 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	Albendazole
EGFR	Afatinib
FGFR1	Pazopanib
FGFR3	Pazopanib
IDH1	Ivosidenib

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
EGFR	175	4
FGFR1	93	4
FGFR3	64	4
IDH1	10	4
MGMT	2	3
LZTR1	0	0
TACC1	0	0
TACC3	0	0
SEPTIN14	0	0

Drugs targeting cohort genes

30 drugs:

Molecule	Max phase	Targets in cohort
Albendazole	4	TP53
Amiodarone	4	TP53
Amiodarone Hydrochloride	4	TP53
Amitriptyline Hydrochloride	4	TP53
Amoxapine	4	TP53
Amsacrine	4	TP53
Anisindione	4	TP53
Apomorphine	4	TP53
Astemizole	4	EGFR, TP53
Azacitidine	4	TP53
Azathioprine	4	TP53
Bifonazole	4	TP53
Bithionolate Sodium	4	TP53
Broxyquinoline	4	TP53
Candesartan Cilexetil	4	TP53
Cantharidin	4	TP53
Chlorhexidine	4	TP53
Chloroxine	4	TP53
Chlorpromazine	4	EGFR, TP53
Cladribine	4	TP53
Clemastine	4	TP53
Clioquinol	4	TP53
Clomiphene Citrate	4	TP53
Clomipramine	4	TP53
Clomipramine Hydrochloride	4	TP53
Clotrimazole	4	EGFR, TP53
Colchicine	4	TP53
Cyclobenzaprine	4	TP53
Cyproheptadine	4	TP53
Daunorubicin	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

Cohort genes with ChEMBL bioactivity

7 cohort genes by assay count:

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
FGFR3	975	Binding:948, Functional:18, ADMET:9
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
IDH1	488	Binding:475, Functional:12, ADMET:1
MGMT	86	Binding:84, ADMET:2
TACC3	3	Binding:3

Cohort enzymes (BRENDA EC)

5 cohort enzymes:

Symbol	EC numbers	Names
EGFR	2.7.10.1	receptor protein-tyrosine kinase
FGFR1	2.7.10.1	receptor protein-tyrosine kinase
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
MGMT	2.1.1.63	methylated-DNA-[protein]-cysteine S-methyltransferase

Cohort genes with high screening signal

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

5 cohort genes:

Symbol	ChEMBL assays
TP53	869
EGFR	6,531
FGFR1	1,465
FGFR3	975
IDH1	488

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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.

30 compounds:

Compound	Max phase	Cohort target (bioactivity)
Albendazole	4	TP53
Amiodarone	4	TP53
Amiodarone Hydrochloride	4	TP53
Amitriptyline Hydrochloride	4	TP53
Amoxapine	4	TP53
Amsacrine	4	TP53
Anisindione	4	TP53
Apomorphine	4	TP53
Astemizole	4	EGFR, TP53
Azacitidine	4	TP53
Azathioprine	4	TP53
Bifonazole	4	TP53
Bithionolate Sodium	4	TP53
Broxyquinoline	4	TP53
Candesartan Cilexetil	4	TP53
Cantharidin	4	TP53
Chlorhexidine	4	TP53
Chloroxine	4	TP53
Chlorpromazine	4	EGFR, TP53
Cladribine	4	TP53
Clemastine	4	TP53
Clioquinol	4	TP53
Clomiphene Citrate	4	TP53
Clomipramine	4	TP53
Clomipramine Hydrochloride	4	TP53
Clotrimazole	4	EGFR, TP53
Colchicine	4	TP53
Cyclobenzaprine	4	TP53
Cyproheptadine	4	TP53
Daunorubicin	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	TP53, EGFR, FGFR1, FGFR3, IDH1
B	Phased (≥1) drug, not yet approved	1	MGMT
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	LZTR1, TACC1, TACC3, SEPTIN14

Undrugged target profiles

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

4 cohort genes:

Symbol	ChEMBL assays	Drugged partners (top 3)
TACC1	0	FGFR1, FGFR3
TACC3	3	FGFR3
LZTR1	0	—
SEPTIN14	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 137.

Phase distribution (across all retrieved trials)

Phase	Trials
Phase 2	55
Phase 1	50
Phase 1/2	15
Early Phase 1	6
Not specified	5
Phase 3	4
Phase 2/3	2

Top trials by phase / activity

showing 40 of 137 trials:

NCT	Phase	Status	Sponsor	Title
NCT02152982	Phase 2/3	ACTIVE_NOT_RECRUITING	National Cancer Institute (NCI)	Temozolomide With or Without Veliparib in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
NCT05095376	Phase 3	ACTIVE_NOT_RECRUITING	NRG Oncology	Testing the Addition of the Chemotherapy Drug Lomustine (Gleostine) to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Methylated Glioblastoma
NCT00884741	Phase 3	COMPLETED	National Cancer Institute (NCI)	Temozolomide and Radiation Therapy With or Without Bevacizumab in Treating Patients With Newly Diagnosed Glioblastoma
NCT01480479	Phase 3	COMPLETED	Celldex Therapeutics	Phase III Study of Rindopepimut/GM-CSF in Patients With Newly Diagnosed Glioblastoma
NCT02573324	Phase 3	COMPLETED	AbbVie	A Study of ABT-414 in Participants With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification
NCT04396860	Phase 2/3	COMPLETED	National Cancer Institute (NCI)	Testing the Use of the Immunotherapy Drugs Ipilimumab and Nivolumab Plus Radiation Therapy Compared to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Unmethylated Glioblastoma
NCT01837862	Phase 1/2	ACTIVE_NOT_RECRUITING	Julie Krystal	A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas
NCT02337686	Phase 2	ACTIVE_NOT_RECRUITING	M.D. Anderson Cancer Center	Pembrolizumab in Treating Patients With Recurrent Glioblastoma
NCT02455557	Phase 2	ACTIVE_NOT_RECRUITING	Roswell Park Cancer Institute	SurVaxM Vaccine Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma
NCT03197506	Phase 2	ACTIVE_NOT_RECRUITING	Mayo Clinic	Pembrolizumab and Standard Therapy in Treating Patients With Glioblastoma
NCT04528680	Phase 1/2	ACTIVE_NOT_RECRUITING	Northwestern University	Ultrasound-based Blood-brain Barrier Opening and Albumin-bound Paclitaxel and Carboplatin for Recurrent Glioblastoma
NCT05039281	Phase 1/2	ACTIVE_NOT_RECRUITING	M.D. Anderson Cancer Center	Atezolizumab and Cabozantinib for the Treatment of Recurrent Glioblastoma
NCT05084430	Phase 1/2	RECRUITING	University of Alabama at Birmingham	Study of Pembrolizumab and M032 (NSC 733972)
NCT05465954	Phase 2	RECRUITING	Mayo Clinic	Efineptakin Alfa and Pembrolizumab for the Treatment of Recurrent Glioblastoma
NCT05864534	Phase 2	RECRUITING	Northwestern University	Phase 2a Immune Modulation With Ultrasound for Newly Diagnosed Glioblastoma
NCT07301268	Phase 2	RECRUITING	Mayo Clinic	GI-102 Alone or With Pembrolizumab Before Surgery for Treatment of Recurrent or Progressive IDH Wildtype Glioblastoma and IDH Mutated Grade 4 Astrocytoma
NCT00100802	Phase 2	COMPLETED	Children’s Oncology Group	Radiation Therapy, Temozolomide, and Lomustine in Treating Young Patients With Newly Diagnosed Gliomas
NCT00107003	Phase 2	COMPLETED	National Cancer Institute (NCI)	GW572016 to Treat Recurrent Malignant Brain Tumors
NCT00114309	Phase 2	UNKNOWN	TransMolecular	131-I-TM-601 Study in Adults With Recurrent High-Grade Glioma
NCT00165477	Phase 2	COMPLETED	Dana-Farber Cancer Institute	Study of Lenalidomide and XRT in Patients With Newly Diagnosed Glioblastoma Multiforme
NCT00187486	Phase 2	COMPLETED	University of California, San Francisco	Safety and Efficacy Study of Tarceva, Temodar, and Radiation Therapy in Patients With Newly Diagnosed Brain Tumors
NCT00354913	Phase 2	COMPLETED	Duke University	Imatinib Mesylate and Hydroxyurea in Treating Patients With Recurrent or Progressive Meningioma
NCT00365222	Phase 2	TERMINATED	H. Lee Moffitt Cancer Center and Research Institute	Phase II Study of Temozolomide in Newly Diagnosed Glioblastoma
NCT00402116	Phase 1/2	COMPLETED	Eli Lilly and Company	Phase 1/2 Study of Enzastaurin in Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma (GS) Patients
NCT00441142	Phase 1/2	COMPLETED	Patrick Y. Wen, MD	Zactima With Temodar During Radiation Treatment for Newly Diagnosed Stage IV Brain Tumors
NCT00525525	Phase 2	COMPLETED	University of California, San Francisco	Study of Bevacizumab Plus Temodar and Tarceva in Patients With Glioblastoma or Gliosarcoma
NCT00597402	Phase 2	COMPLETED	Duke University	Avastin in Combination With Radiation (XRT) & Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma (GBM) and Gliosarcomas
NCT00611325	Phase 2	COMPLETED	Duke University	Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma
NCT00612339	Phase 2	COMPLETED	Duke University	Avastin in Combination With Temozolomide for Unresectable or Multifocal GBMs and Gliosarcomas
NCT00612430	Phase 2	COMPLETED	Duke University	Ph II Bevacizumab + Etoposide for Pts w Recurrent MG
NCT00613028	Phase 2	COMPLETED	Duke University	Ph II Bev + Either Temozolomide/Etoposide for GBM Pts Who Have Failed Bev + Irinotecan
NCT00615927	Phase 2	COMPLETED	Duke University	Phase II Imatinib + Hydroxyurea in Treatment of Patients With Recurrent/Progressive Grade II Low-Grade Glioma (LGG)
NCT00657267	Phase 2	COMPLETED	Patrick Y. Wen, MD	Dose-Intense Temozolomide in Recurrent Glioblastoma
NCT00667394	Phase 2	COMPLETED	National Cancer Institute (NCI)	Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors
NCT00669669	Phase 1/2	TERMINATED	Fred Hutchinson Cancer Center	O6-Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cell in Treating Patients With Malignant Gliomas
NCT00671970	Phase 2	COMPLETED	Duke University	Phase (Ph) II Bevacizumab + Erlotinib for Patients (Pts) With Recurrent Malignant Glioma (MG)
NCT00672243	Phase 2	COMPLETED	Duke University	Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme
NCT00735436	Phase 2	TERMINATED	Duke University	A Study of Gliadel Followed by Avastin + Irinotecan for Glioblastoma Multiforme (GBM)
NCT00879437	Phase 2	COMPLETED	Baylor College of Medicine	Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma
NCT00883298	Phase 2	COMPLETED	Center for Neurosciences, Tucson	Bi-weekly Temozolomide Plus Bevacizumab for Adult Patients With Recurrent Glioblastoma Multiforme

Drugs tested across these trials

30 drugs:

Molecule	Max phase	Trials referencing
Bevacizumab	4	27
Temozolomide	4	6
Erlotinib	4	4
Plerixafor	4	4
Vandetanib	4	4
Lapatinib	4	3
Lomustine	4	3
Hydroxyurea	4	2
Lonafarnib	4	2
Binimetinib	4	1
Cabozantinib S-Malate	4	1
Encorafenib	4	1
Etoposide Phosphate	4	1
Imetelstat Sodium	4	1
Ipilimumab	4	1
Mebendazole	4	1
Mefloquine	4	1
Memantine Hydrochloride	4	1
Metformin Hydrochloride	4	1
Nintedanib	4	1
Palbociclib	4	1
Pazopanib	4	1
Valproic Acid	4	1
Vincristine	4	1
Vorinostat	4	1
Veliparib	3	4
6-O-BENZYLGUANINE	3	2
Rindopepimut	3	2
Balstilimab	3	1
Botensilimab	3	1

Other drugs named in trials

Drugs named in these trials’ interventions but not in the ChEMBL table above — includes investigational drugs not yet in ChEMBL. Linked where an Atlas drug page exists.

30 drugs named in trials:

Drug	Max trial phase
Depatuxizumab mafodotin	Phase 3
Klh	Phase 3
Nivolumab	Phase 2/3
Rindopepimut (CDX-110) with GM-CSF	Phase 3
131-I-TM-601	Phase 2
131I-TM601	Phase 2
Amg 102	Phase 2
AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin)	Phase 2
AXL1717	Phase 1/2
Aldesleukin	Phase 1/2
Atezolizumab	Phase 1/2
Autologous Cytomegalovirus-specific Cytotoxic T-lymphocytes	Phase 1/2
Autologous dendritic cells pulsed with tumor lysate antigen Vaccine	Phase 2
Avastin	Phase 2
Avastin and Temozolomide	Phase 2
Bibf 1120	Phase 2
Bevacizumab and Erlotinib	Phase 2
Bevacizumab and Etoposide	Phase 2
Bevacizumab/Bevacizumab Biosimilar	Phase 2
Bispecific CD80-lgG4Fc-IL-2v Fusion Protein GI-102	Phase 2
Bortezomib	Phase 2
Cabozantinib	Phase 1/2
Carboplatin	Phase 2
Carmustine	Phase 1/2
Cyclophosphamide	Phase 1/2
DNX-2401	Phase 2
ERC1671	Phase 2
Efineptakin alfa	Phase 2
Enzastaurin	Phase 1/2
Epidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL	Phase 1/2

Precision-medicine subtype map (CIViC)

Drug × molecular subtype, from 1 curated evidence items; also 1 oncogenic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

1 predictive associations by evidence level:

Molecular subtype	Therapy	Effect	Level	CIViC
TPR::NTRK1 Fusion	Larotrectinib	Sensitivity/Response	CIViC C	EID11746