DeCure for Renal Cell Carcinoma Associated with Xp11.2 Translocations/TFE3 Gene Fusions
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Renal Cell Carcinoma Associated with Xp11.2 Translocations/TFE3 Gene Fusions — screening already-approved drugs against its 6-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleRenal Cell Carcinoma Associated with Xp11.2 Translocations/TFE3 Gene Fusions maps to a 6-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedSunitinibApproved drug
Structures already discussed alongside renal cell carcinoma associated with xp11.2 translocations/tfe3 gene fusions in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
KIT kinase domain — Sunitinib has a real, experimentally solved structure in complex with this target (PDB 3G0E, 1.6 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet b49drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3G0E · 1.6 Å · ligand Sunitinib (B49). Experimental structure, not a prediction.
What the evidence adds up to
Four cases of Xp11.2 translocation renal cell carcinoma were identified from 200 patients at Guangdong General Hospital between 2017 and 2020. The median age at diagnosis was 13 years, range 4 to 20 years, with one male and three females. All tumours were unilateral and unifocal, with the largest diameter averaging 5.55 cm (range 2.0 to 10.0 cm). Two patients developed regional lymph node or distant metastasis. Three known fusions were found: ASPCR1–TFE3 in two cases and PRCC–TFE3 in one case. One case carried a previously unreported VCP–TFE3 fusion. Follow-up ranged from 3 to 36 months. Three patients showed no evidence of disease progression, but the patient with the VCP–TFE3 fusion died of disease three months after diagnosis. The authors conclude that the VCP–TFE3 fusion is associated with worse prognosis than other fusion types.
A 2019 study using two tRCC cell lines, UOK109 and UOK120, examined the behaviour of TFE3 fusion proteins. The fusions were overexpressed and showed strong nuclear retention regardless of treatment with an mTORC1 inhibitor. They lost co-localisation with lysosomal proteins and had decreased interaction with 14–3-3 chaperone proteins. The fusion segments alone could not translocate to the nucleus, and inhibition of Gsk3β increased cytoplasmic retention. The fusions could still bind to target gene promoters as wild-type TFE3 does. Knockdown of TFE3 reduced expression of lysosomal biogenesis genes and other targets. ChIP-seq data indicated that TFE3 fusions also regulate genes involved in hypoxic stress response and transcription. The authors propose that the fusions escape mTOR signalling control and accumulate in the nucleus, promoting expression of lysosomal and other genes that may help cancer cells resist extreme environments.
A 2012 review notes that Xp11.2 RCC was classified as a distinct entity in the 2004 WHO classification. It states that increased awareness, positive nuclear TFE3 staining, cytogenetic features, and molecular technology have led to more cases being recognised. The review covers clinical presentation, cytogenetic profile, histopathology, prognosis, and treatment, but provides no new patient-level data.
No drug treatment is tested or recommended in any of these abstracts. The evidence base remains limited to small case series and cell-line experiments. What is missing is prospective collection of larger, multi-centre cohorts with standardised fusion typing, long-term follow-up, and any controlled trial of a targeted agent. Patient stratification by fusion partner is not yet supported by data sufficient to guide clinical decisions.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Frontiers in Oncology · 2021 · 23 citations · open access
Xp11.2 Translocation Renal Cell Carcinoma With TFE3 Rearrangement: Distinct Morphological Features and Prognosis With Different Fusion Partners
AbstractBackground Renal cell carcinoma (RCC) associated with Xp11.2 translocation/ TFE3 gene fusion is a rare and new subtype of RCC and was classified by the WHO in 2004. Since then, multiple 5′ fusion partners for TFE3 have been reported; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11.2 RCCs has not been well defined. Methods Four Xp11.2 translocation RCCs were identified by morphological, immunostaining, and fluorescence in situ hybridization (FISH) assays from 200 patients who attended Guangdong General Hospital between January 2017 and January 2020. All these four cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. The clinicopathologic features, including clinical manifestations, pathological findings, treatment strategies, clinical outcomes, and follow-up information on Xp11.2 translocation RCCs, were recorded and evaluated. Results These four cases affected one male and three females. The median age was 13 years at the time of diagnosis (range = 4–20 years). All the examined tumors were unilateral and unifocal. The largest diameter of these tumors ranged from 2.0 to 10.0 cm, and the average was 5.55 cm. Regional lymph node or distant metastasis developed in two patients. Three cases demonstrated known fusions: ASPCR1 – TFE3 (two cases) and PRCC – TFE3 (one case). However, one case showed an unreported VCP – TFE3 fusion gene in Xp11.2 translocation RCCs. Immunohistochemistry results revealed tumor cells diffusely positive for TFE3 , but have no consistency in other markers. Moreover, there were different clinical prognoses among the different variant TFE3 rearrangements; RCC patients with VCP – TFE3 translocation had worse prognosis compared to those with other fusion types. Follow-up were available for all the patients and ranged from 3 to 36 months. Three patients were without evidence of disease progression, while that with VCP – TFE3 fusion died of the disease 3 months after the diagnosis. Conclusion In conclusion, our data expand the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11.2 RCCs with specific TFE3 gene fusions. We identified a novel VCP – TFE3 fusion in Xp11.2 translocation RCCs for the first time, which has unique morphology and worse prognosis than those with other variant TFE3 rearrangements. Integration of morphological, immunohistochemical, and molecular methods is often necessary for the precise diagnosis and optimal clinical management of malignant tumors.
Cancer Biology & Therapy · 2013 · 14 citations · open access
Establishment of an ASPL-TFE3 renal cell carcinoma cell line (S-TFE)
AbstractXp11 translocation renal cell carcinoma is a rare disease diagnosed in children and adolescents in the advanced stage with an aggressive clinical course. Various gene fusions including the transcription factor E3 (TFE3) gene located on chromosome X cause the tumor. We established an Xp11 translocation renal cell carcinoma cell line from a renal tumor in a 18-y-old Japanese female and named it "S-TFE." The cell line and its xenograft demonstrated definite gene fusion including TFE3. They showed strong nuclear staining for TFE3 in immunohistochemistry, TFE3 gene rearrangement in dual-color, break-apart FISH analysis and ASPL-TFE3 type 1 fusion transcripts detected by RT-PCR and direct DNA sequencing. Although many renal cell carcinoma cell lines have been established and investigated, only a few cell lines are recognized as Xp11.2 translocation carcinoma. S-TFE will be useful to examine the characteristics and drug susceptibility of Xp11 translocation renal cell carcinoma.
North American Journal of Medicine and Science · 2012 · 2 citations
Recent Advances in Renal Cell Carcinoma Associated with Xp11.2 Translocations/TFE Gene Fusions
AbstractRenal cell carcinoma associated with Xp11.2 translocations/ TFE gene fusions (Xp11.2 RCC) has been classified as a distinct entity in the 2004 WHO classification of kidney tumors. Over the past seven years, aided by increased awareness, positive nuclear staining for TFE 3 , unique cytogenetic features, and modern molecular technology, more cases have been recognized as Xp11.2 RCC. This review summarizes the most recent advances in Xp11.2 RCC regarding to its clinical presentation, cytogenetic profile, histopathology , prognosis and treatment.
TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas
AbstractAbstract Background Xp11.2 translocation renal cell carcinoma (tRCC) is mainly caused by translocation of the TFE3 gene located on chromosome Xp11.2 and is characterized by overexpression of the TFE3 fusion gene. Patients are diagnosed with tRCC usually before 45 years of age with poor prognosis. We investigated this disease using two tRCC cell lines, UOK109 and UOK120, in this study. Methods The purpose of this study was to investigate the pathogenic mechanism of TFE3 fusions in tRCC based on its subcellular localization, nuclear translocation and transcriptional activity. The expression of TFE3 fusions and other related genes were analyzed by quantitative reverse transcription PCR (qRT-PCR) and Western blot. The subcellular localization of TFE3 was determined using immunofluorescence. The transcriptional activity of TFE3 fusions was measured using a luciferase reporter assay and ChIP analysis. In some experiments, TFE3 fusions were depleted by RNAi or gene knockdown. The TFE3 fusion segments were cloned into a plasmid expression system for expression in cells. Results Our results demonstrated that TFE3 fusions were overexpressed in tRCC with a strong nuclear retention irrespective of treatment with an mTORC1 inhibitor or not. TFE3 fusions lost its co-localization with lysosomal proteins and decreased its interaction with the chaperone 14–3-3 proteins in UOK109 and UOK120 cells. However, the fusion segments of TFE3 could not translocate to the nucleus and inhibition of Gsk3β could increase the cytoplasmic retention of TFE3 fusions. Both the luciferase reporter assay and ChIP analysis demonstrated that TFE3 fusions could bind to the promoters of the target genes as a wild-type TFE3 protein. Knockdown of TFE3 results in decreased expression of those genes responsible for lysosomal biogenesis and other target genes. The ChIP-seq data further verified that, in addition to lysosomal genes, TFE3 fusions could regulate genes involved in cellular responses to hypoxic stress and transcription. Conclusions Our results indicated that the overexpressed TFE3 fusions were capable of escaping from the control by the mTOR signaling pathway and were accumulated in the nucleus in UOK109 and UOK120 cells. The nuclear retention of TFE3 fusions promoted the expression of lysosomal genes and other target genes, facilitating cancer cell resistance against an extreme environment.
Clinicopathological characteristics of Xp11.2 translocation/TFE3 gene fusion-associated renal cell carcinoma
AbstractObjective To investigate the clinical and pathological characteristics of Xp11.2 translocation/TFE3 gene fusion-associated renal cell carcinoma.Methods Between Jan 2009 and Jul 2013,37 patients with Xp1 1.2 translocation/TFE3 gene fusion-associated renal cell carcinoma,consisting of 17 males and 20 females,were treated in our institution.The median age was 22 years old,which ranged from 3 to 73 years old.The clinical symptoms included painless gross hematuria and (or) flank pain in 18 cases,abdominal mass in 3 cases and no significant clinical presentation in 16 cases.3 patients were diagnosed with distant metastasis,including cervical metastasis in 1 case and hepatic metastasis in 2 cases.All patients were treated with surgical treatment,of which 29 patients received radical nephrectomy,4 patients received nephron sparing surgery and 4 patients received palliative nephrectomy.Of the 37 patients,10 cases received adjuvant sorafenib or sunitinib target therapy after surgery.Results The final pathological diagnosis was Xp11.2 translocation/TFE3 gene fusion-associated renal cell carcinoma in all patients.The maximum diameter of tumor ranged from 1 to 15 cm (mean 6.5 cm).The pathological examination showed the tumor cells contained eosinophilic cytoplasm with psammoma bodies in renal interstitial tissue.Immunohistochemical examination showed that all patients were positive for TFE3,30 patients were positive for CD10,28 patients were positive for P504S and variably positive for CK7,CK8,Vimentin and EMA.The mean follow-up duration was 22 months (range,1-55 months).33 patients survive and 4 patients died due to the tumor recurrence and systemic metastasis.As being treated with adjuvant target therapy,the patient with cervical metastasis has maintained stable,and another 2 patients with hepatic metastases have achieved partial remission.Conclusions Xp11.2 translocation/TFE3 gene fusion-associated renal cell carcinoma is a newly defined rare entity with a high predominance of young patients.The diagnosis mainly depends on patient's age,histopathological characteristics,and TFE3-positive immune markers.Patients with metastatic Xp1 1.2 translocation/TFE3 gene fusion-associated renal cell carcinoma could benefit from the target therapy.
Key words:
Kidney neoplasms; Xp11.2 translocation; TFE3 gene fusion
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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