DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Sarcomatoid Mesothelioma — screening already-approved drugs against its 21-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSarcomatoid Mesothelioma maps to a 21-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 sarcomatoid mesothelioma 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
SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) — SETDB1 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 unxdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6BHD · 1.25 Å · ligand UNKNOWN ATOM OR ION (UNX). Experimental structure, not a prediction.
What the evidence adds up to
Malignant mesothelioma remains a highly lethal cancer, and the sarcomatoid subtype carries the worst prognosis of the histological variants. A 2021 nationwide Norwegian study of 1509 pleural and peritoneal cases diagnosed between 2000 and 2019 reported a median survival of 5.4 months for pleural sarcomatoid disease, compared with 15.8 months for the epithelioid subtype. Among peritoneal mesotheliomas, the non-epithelioid subtype had a median survival of 5.1 months, while epithelioid cases reached 43.3 months. The same study found that pleural mesothelioma incidence in Norwegian males fell from 1.7 to 1.1 per 100,000 between 2000–2004 and 2015–2019, with female incidence stable below 0.3 per 100,000; median age at pleural diagnosis was 73 years for women and 76 for men in the final five-year period.
The biology of mesothelioma offers some potential targets, but no clinical breakthrough has emerged for sarcomatoid disease. A 2016 laboratory study demonstrated constitutive FAK activation in all 10 mesothelioma cell lines and nine surgical specimens examined, with FAK associated with p53 in five of five cell lines. In four mesotheliomas with wild-type p53, FAK silencing induced p53 expression and phosphorylation. Combining FAK knockdown or inhibition with MDM2 inhibition produced additive anti-proliferative effects, increased apoptosis, and cell-cycle arrest compared with either intervention alone, through coordinated p53 reactivation. However, the authors noted that FAK regulation of proliferation was not restricted to p53-dependent pathways, since effects were also seen in JMN1B cells with mutant or inactivated p53. These are preclinical findings only.
Clinical experience has been sobering. A 2005 review argued that mesothelioma is not inherently resistant to chemotherapy or radiotherapy and that combination therapies offer the best hope, but it explicitly rejected any claim of cure, framing the realistic goal as symptom relief for the longest possible time. A 2008 review described the disease as very difficult to treat, noting that multimodality approaches with neoadjuvant chemotherapy, extrapleural pneumonectomy, and radiation have been studied, and that intrapleural chemotherapy, photodynamic therapy, and hyperthermic perfusion have been used with some success. Novel immunomodulating and targeted treatments were only in phase I/II trials at that time. A 2014 review reiterated that mesothelioma is mostly resistant to conventional therapies and that early diagnosis is very difficult.
What remains missing is any evidence specific to sarcomatoid mesothelioma from prospective trials, which are scarce because the subtype is uncommon and historically grouped with epithelioid cases. No targeted agent has moved from the FAK–MDM2–p53 axis into clinical testing for this population. The Norwegian data predate immunotherapy, so the effect of checkpoint inhibitors on sarcomatoid survival is unknown. Funding for subtype-stratified trials, reliable biomarkers to identify patients most likely to respond, and a trial design that separates sarcomatoid from epithelioid histology are all still needed before any meaningful improvement in this 5.4-month median survival can be expected.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 1980 · 173 citations
Malignant Mesothelioma
AbstractDURING the two decades since the association of asbestos and mesothelioma became established, substantial progress has been made in the under-standing of the biology of this previously rare neoplasm. The causative role of asbestos exposure has been extensively investigated, and populations at increased risk have been identified.1 Observation of the natural history of mesothelioma reveals that in contrast to patients with the other sarcomas, who generally die of hematogenously disseminated metastases, patients with mesothelioma succumb to complications of their primary lesions.2 With more appropriate treatment regimens designed specifically for mesotheliomas, series in single institutions have established that mesotheliomas respond to . . .
Current Opinion in Pulmonary Medicine · 2008 · 58 citations
Malignant mesothelioma 2008
AbstractPURPOSE OF REVIEW: Mesothelioma is an aggressive malignancy of the pleura with poor survival. There will be approximately 3000 cases of mesothelioma in the United States annually. Multimodality treatment including neoadjuvant chemotherapy in selected individuals followed by extrapleural pneumonectomy and radiation has been studied in recent trials for its effects on disease free and overall survival This review provides a general overview of malignant mesothelioma with a summary of the most significant articles from within the past year as well as from the past. RECENT FINDINGS: Areas of recent interest include the evaluation of osteopontin and mesothelin as new tumor markers for mesothelioma. New phase III trials have been performed to evaluate the use of combined chemotherapy regimens. SUMMARY: Malignant mesothelioma is a very difficult malignancy to treat. Patients with the disease usually have an occupational asbestos exposure, and in some, viral exposure with SV40. There have been many historical treatments including combinations of local control with surgery and radiation as well as attempts to prevent systemic failure with chemotherapy. Novel therapies including intrapleural chemotherapy, photodynamic therapy and hyperthermic perfusion have also been used with some success. Finally there are several attempts at immunomodulating and targeted treatments, which are in phase I/II trials.
British Journal of Cancer · 2016 · 33 citations · open access
Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53
AbstractBACKGROUND: Improved mesothelioma patient survival will require development of novel and more effective pharmacological interventions. TP53 genomic mutations are uncommon in mesothelioma, and recent data indicate that p53 remains functional, and therefore is a potential therapeutic target in these cancers. In addition, the tumour suppressor NF2 is inactivated by genomic mechanisms in more than 80% of mesothelioma, causing upregulation of FAK activity. Because FAK is a negative regulator of p53, NF2 regulation of FAK-p53-MDM2 signalling loops were evaluated. METHODS: Interactions of FAK-p53 or NF2-FAK were evaluated by phosphotyrosine-p53 immunoaffinity purification and tandem mass spectrometry, and p53, FAK, and NF2 immunoprecipitations. Activation and/or expression of FAK, p53, and NF2 were also evaluated in mesotheliomas. Effects of combination MDM2 and FAK inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, expression of cell cycle checkpoints, and cell cycle alterations. RESULTS: We observed constitutive activation of FAK, a known negative regulator of p53, in each of 10 mesothelioma cell lines and each of nine mesothelioma surgical specimens, and FAK was associated with p53 in five of five mesothelioma cell lines. In four mesotheliomas with wild-type p53, FAK silencing by RNAi induced expression and phosphorylation of p53. However, FAK regulation of mesothelioma proliferation was not restricted to p53-dependent pathways, as demonstrated by immunoblots after FAK knockdown in JMN1B mesothelioma cells, which have mutant/inactivated p53, compared with four mesothelioma cell lines with nonmutant p53. Additive effects were obtained through a coordinated reactivation of p53, by FAK knockdown/inhibition and MDM2 inhibition, as demonstrated by immunoblots, cell viability, and cell-cycle analyses, showing increased p53 expression, apoptosis, anti-proliferative effects, and cell-cycle arrest, as compared with either intervention alone. Our results also indicate that NF2 regulates the interaction of FAK-p53 and MDM2-p53. CONCLUSIONS: These findings highlight novel therapeutic opportunities in mesothelioma.
Biological Agents Involved in Malignant Mesothelioma: Relevance as Biomarkers or Therapeutic Targets
AbstractMalignant mesothelioma (MM) is a rare, highly aggressive tumor that arises from the surface serosal cells (pleural, peritoneal and pericardial cavities). Epidemiological and clinical data show that there is an association between asbestos exposure and MM development, even if the exact mechanism whereby asbestos induces MM is unknown. The continuing identification and elucidation of the molecular defects involved in mesothelioma pathogenesis and progression should lead to better disease control and greater therapeutic options in the near future. Goal of this article is to summarize the most recent advances in molecular pathogenesis of mesothelioma with particular emphasis on genes that could be considered as biomarkers or therapeutic targets and discuss possible clinical implications of these findings.
Journal of the Royal Society of Medicine · 2005 · 11 citations
Mesothelioma: time to take stock
AbstractMesothelioma is rapidly increasing in frequency, and the perception of this cancer is generally gloomy. It is widely considered to be resistant to chemotherapy and radiotherapy and to be an impossible operative target, so that very little can be done. Taken one at a time each of these beliefs can be challenged. In fact it is sensitive to both chemotherapy and radiotherapy. It is a challenging but not impossible surgical proposition. Combination therapies are the best hope of benefit.
We will describe the best management strategies we know and the evidence for them. 'Cure' would be a big claim. A more modest but realistic objective is to get the best symptom relief we can, for the longest possible time. Sometimes the sum of small things provides a worthwhile whole.
Acta Oncologica · 2021 · 10 citations · open access
Epidemiology and outcome of peritoneal and pleural mesothelioma subtypes in Norway. A 20 year nation-wide study
AbstractBACKGROUND: Mesothelioma of the pleural or peritoneal cavities is one of the deadliest cancer types. The incidence of pleural subtypes has decreased over time due to decrease in asbestos exposure, and the current treatment landscape is changing due to introduction of novel therapies. In this study we have analysed contemporary epidemiological data of mesothelioma on a national level before the advent of immunotherapy. MATERIAL AND METHODS: Complete national data on 1509 pleural and peritoneal malignant mesothelioma from the Cancer Registry of Norway from 2000 to 2019 are presented. Age standardised incidence and median survival were calculated. RESULTS: The age-standardised incidence of pleural mesothelioma among males has decreased from 1.7 per 100 000 in 2000-2004 to 1.1 in 2015-2019, whereas the incidence for females has been stable, lower than 0.3 per 100 000 throughout the period. Incidence of peritoneal mesotheliomas remained low, below 0.08 per 100 000. The female to male ratio among pleural mesotheliomas was 1:7 with no differences among morphological subtypes, whereas this ratio was 1:1.2 in peritoneal mesotheliomas. Median age at diagnosis for pleural mesothelioma was 73 years and 76 years for females and males respectively in the last 5-year period, and 67 years for peritoneal mesotheliomas of both sexes. Median survival among pleural mesotheliomas has been stable, with significantly worse prognosis among sarcomatoid subtype (5.4 months) compared to epithelioid subtype (15.8 months). Peritoneal mesothelioma of the epithelioid subtype, representing 38% of cases, had a median survival of 43.3 months, contrasting the non-epithelioid subtype of 5.1 months. DISCUSSION: Mesothelioma is still a significant disease with a dismal prognosis. Improvement in treatment is warranted.
AbstractThis book brings together the knowledge of eminent experts in the field of malignant mesothelioma, a highly invasive tumor of mesothelium that is the protective lining covering several body cavities. Malignant mesothelioma shows extremely poor progression and is refractory to almost any kind of therapy putting considerable challenges in its treatment. This book covers many important aspects of malignant mesothelioma like epidemiology, immunology, molecular mechanisms and clinical options and will be useful to anybody interested in its history, pathology, and treatment.
Journal of Cancer Science & Therapy · 2014 · 4 citations · open access
Current Therapies for Malignant Mesothelioma
AbstractMalignant mesothelioma (MM) is a deadly cancer caused by asbestos exposure that is increasing worldwide. Early diagnosis for this cancer is very difficult and MM is mostly resistant to conventional therapies. A host of factors may be responsible for development of MM and imparting drug resistance to this cancer. Understanding these processes will be important in designing therapeutic approaches for MM. Some of the conventional as well as current approaches for MM therapy are discussed in this review.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works using Disease Ontology synonyms, resolved on OpenAlex.
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