DeCure for Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant — screening already-approved drugs against its 12-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleInfiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant maps to a 12-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
No approved-drug candidate for infiltrating bladder urothelial carcinoma sarcomatoid variant is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
ras homolog family member A (RHOA) — RHOA is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet gdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5C4M · 1.3 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
What the evidence adds up to
A 1993 multi-institutional study of 253 patients with T2-T4a transitional cell carcinoma of the bladder reported a cancer-specific 5-year survival rate of 58% for the 227 patients who underwent cystectomy. For patients with histologically proven regional lymph node metastases the 5-year survival was 22%. Neoadjuvant cisplatin-based chemotherapy was correlated with more favourable survival in patients with T3 or greater tumours but did not appear to influence survival in T2 tumours. The authors concluded that chemotherapy seemed to improve survival in deeply infiltrating disease but represented overtreatment in T2 tumours.
Sarcomatoid bladder cancer is a rare and aggressive variant. A single-centre retrospective review of patients treated between 1997 and 2011 found that 85% presented with muscle-invasive disease and 50% with stage IV carcinoma. At a median follow-up of 7 months, 35.7% of patients had died, and the two-year survival was 53.5%. A pooled analysis of 835 patients from two SEER registry studies and thirteen single-institution case series confirmed that these patients present with high-grade, advanced-stage tumours and have a poor prognosis. No clinical trials on sarcomatoid bladder carcinoma were reported in the English literature as of 2015. Tumour stage was identified as the significant predictor of cancer-specific survival in several of the included studies.
A 2023 case report describes a 68-year-old woman with a high-grade infiltrating urothelial carcinoma sarcomatoid variant of the upper tract. After radical nephroureterectomy, a recurrent mass appeared at three months, and gemcitabine-cisplatin chemotherapy was given. The report notes that because the sarcomatoid variant is aggressive, more attention is needed in evaluating this tumour. A 2021 literature review on urothelial carcinoma therapy states that traditional cytotoxic chemotherapy regimens have not produced optimal long-term outcomes and that many patients have comorbidities that disqualify them as chemotherapy candidates. The review discusses immunotherapy, antibody-drug conjugates, kinase inhibitors, and other agents, but does not provide outcome data specific to the sarcomatoid variant.
What is still missing are prospective clinical trials for the sarcomatoid variant specifically, which are absent from the literature. The existing data come from small retrospective series and registry analyses with inconsistent treatment patterns and short follow-up. No randomised evidence exists to guide whether multimodality therapy improves survival over cystectomy alone, and no validated biomarkers exist to stratify patients who might benefit from specific systemic therapies.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cancer · 1993 · 66 citations
A bladder cancer multi-institutional experience with total cystectomy for muscle-invasive bladder cancer
AbstractBACKGROUND: The role of total cystectomy was to be assessed in the curative treatment of muscle-invasive bladder cancer. METHODS: Two hundred and fifty-three patients with T2-T4a transitional cell carcinoma of the urinary bladder were referred to precystectomy radiation therapy (46 Gy, 66 patients; 20 Gy, 187 patients). These patients represented approximately 20% of all patients developing muscle-invasive bladder cancer in Southern Norway from 1980-1990. The clinical T categorization was generally based on palpability and extent of the palpable bladder tumor assessed by the referring urologist. Twenty-six patients (10%) did not have total cystectomy, most often due to peroperatively demonstrated locoregional inoperability. Two or three cycles of cisplatin-based combination chemotherapy were given to 68 patients. RESULTS: For the 227 patients who underwent cystectomy, the cancer-specific 5-year survival rate was 58% (T2 [104 patients], 63%; greater than or equal to T3 [123 patients], 54%) (P = 0.022). The comparable figure for patients with histologically proven regional lymph node metastases was 22%. The 97 stage-reduced cases (less than or equal to pT1) survived significantly longer than the 130 patients without stage reduction (74% versus 46%) (P < 0.0001). Neoadjuvant chemotherapy was correlated with a more favorable survival in patients with greater than or equal to T3 tumors but did not seem to influence survival of patients with T2 bladder cancer. CONCLUSIONS: In a multicenter setting, prognostically relevant T categorization of operable muscle-infiltrating bladder cancer can be based on the palpability of the primary tumor. Approximately 50% of favorably selected patients with operable T2-T4 bladder cancer survived for at least 5 years independent of whether the operation was done at a large uro-oncologic unit or a smaller urologic section. In this retrospective review, chemotherapy seemed to improve the survival in patients with deeply infiltrating (greater than or equal to T3) bladder cancer but appeared to represent an overtreatment in patients with T2 tumors.
Sarcomatoid Urothelial Carcinoma: A Single Cancer Center Experience.
AbstractBACKGROUND: Sarcomatoid bladder cancer is a rare and aggressive variant of urothelial carcinoma. METHODS: A retrospective review of our experience in managing patients with sarcomatoid bladder cancer (SRBC) between 1997 and 2011 was performed to better define the behavior and outcomes of this disease. RESULTS: The median age of the patients was 63 years. All patients presented with high grade histology. Eighty-five percent of the patients presented with muscle invasive disease and fifty percent presented with stage IV carcinoma. Ten of 14 (71%) of patients underwent a cystectomy. Patients with SRBC was younger (P < 0.01), more commonly presented with higher grade histology (P < 0.01) and advanced stage disease (P < 0.01), in comparison with patients with Urothelial carcinoma (UC). At a median follow-up of 7 months (range 1.3 - 112), five (35.7%) patients have died in last follow-up. Two-year survival was 53.5%. Three patients with long term survival were reported. CONCLUSIONS: Sarcomatoid bladder cancer is associated with poor prognosis. Multimodality therapy may improve these patients outcome.
Frontiers in Oncology · 2021 · 10 citations · open access
Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review
AbstractUrothelial carcinoma therapy is a rapidly evolving and expanding field. Traditional cytotoxic chemotherapy regimens have not produced optimal long-term outcomes, and many urothelial cancer patients have comorbidities that disqualify them as chemotherapy candidates. In recent years, a plethora of novel therapeutic agents that target diverse molecular pathways has emerged as alternative treatment modalities for not only metastatic urothelial carcinoma, but also for muscle-invasive bladder cancer and non-muscle invasive bladder cancer in adjuvant and definitive settings. This review paper aims to discuss the various categories of therapeutic agents for these different types of urothelial cancer, discussing immunotherapy, antibody-drug conjugates, kinase inhibitors, CAR-T cell therapy, peptide vaccination, and other drugs targeting pathways such as angiogenesis, DNA synthesis, mTOR/PI3K/AKT, and EGFR/HER-2.
bioRxiv (Cold Spring Harbor Laboratory) · 2023 · 2 citations · open access
Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer
AbstractAbstract Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of the first long-term 3D organoid-like model derived from a SARC patient ( SarBC-01 ). SarBC-01 emulates aggressive morphological and phenotypical features of SARC and harbor somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53, RB1 , and KRAS . High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and organoids derived from a patient with conventional urothelial carcinoma (UroCa), identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, such as agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts, GR was found to be significantly more expressed, at mRNA and protein level, in SARC as compared to UroCa tumor samples. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.
The natural history, treatment pattern, and survival of the patients with sarcomatoid bladder carcinoma: A pooled analysis.
Abstracte15532 Background: Sarcomatoid bladder carcinoma (SRBC) is a rare variant of urothelial cancer. Current data is limited on clinical features, appropriate management and outcomes. Methods: A retrospective review of our experience of managing SRBC was performed in conjunction with a systematic literature search.Literature review was performed on the MEDLINE database using the key words ‘bladder cancer’, ‘sarcomatoid carcinoma’, ‘carcinosarcoma’, ‘diagnosis’, ‘treatment’, and ‘prognosis’. Clinical characteristics, treatment, and survival were compared between the cohorts from SEER and single institutional cohorts. Results: No clinical trials on SRBC were reported in the English literature so far.Two SEER registry and thirteen single institution retrospective studies have been identified. The final cohort for the study included 835 patients: 522 from two registry studies and 313 from 13 case series. Five single institution studies contained adequate clinical follow up information. SRBC usually presented in sixth to seventh decades (age range: 30-91) and was more common in males (M:F 1.3-16:1). Gross hematuria (70-100%) was the most common symptom. Both population and case series showed that these patients present with a high grade tumor, advanced stage and was associated with poor prognosis. Tumor stage was identified as the significant predictor for cancer-specific survival in UNMC, Mayo, Turkey studies and one of the SEER studies (Wang et al). In UNMC series, aggressive multimodality therapy lead to a better cancer control and improved survival. Significant differences existed in the demographic characteristics (age at diagnosis, M:F ratio), tumor stage, treatment pattern (rate of cystectomy, radiation and chemotherapy), and median survival, when comparing single-institution studies to the SEER cohorts, likely reflecting differences in practice patterns. Conclusions: Patients diagnosed with this rare, aggressive malignancy should be referred to a cancer center with an extensive experience in the management of SRBC. The results of this analysis help to increase awareness of this rare malignancy and serve as a baseline for future clinical studies.
INDIGO (University of Illinois at Chicago) · 2023 · 0 citations · open access
Supplementary Material for: Complete Response of Rare Sarcomatoid Upper Tract Urothelial Carcinoma Variant : Case Report and Literature Review
AbstractInfiltrating urothelial carcinoma sarcomatoid variant is a rare variant of urothelial carcinoma. We report a case of a 68-year-old female with a history of hematuria. CT Scan with contrast showed a mass in the 1/3 distal of the right ureter. The biopsy result showed a high-grade infiltrating urothelial carcinoma. A radical nephroureterectomy (RNU) was performed but at the follow-up after 3 months, there was a recurrent mass and Gemcitabine-Cisplatin chemotherapy was given. Since a high-grade infiltrating urothelial carcinoma sarcomatoid variant was an aggressive tumor, we need to give more attention to evaluating this tumor.
Supplementary Material for: Complete Response of Rare Sarcomatoid Upper Tract Urothelial Carcinoma Variant : Case Report and Literature Review
AbstractInfiltrating urothelial carcinoma sarcomatoid variant is a rare variant of urothelial carcinoma. We report a case of a 68-year-old female with a history of hematuria. CT Scan with contrast showed a mass in the 1/3 distal of the right ureter. The biopsy result showed a high-grade infiltrating urothelial carcinoma. A radical nephroureterectomy (RNU) was performed but at the follow-up after 3 months, there was a recurrent mass and Gemcitabine-Cisplatin chemotherapy was given. Since a high-grade infiltrating urothelial carcinoma sarcomatoid variant was an aggressive tumor, we need to give more attention to evaluating this tumor.
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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