DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for mismatch repair cancer syndrome — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMismatch repair cancer syndrome maps to a 3-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 mismatch repair cancer syndrome 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
mutS homolog 2 (MSH2) — MSH2 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8RB1 · 2.085 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
Mismatch repair stabilises the genome by correcting DNA replication errors and blocking recombination between divergent sequences. Inactivation of mismatch repair genes — hMLH1, hMSH2, hPMS1, hPMS2, GTBP/hMSH6 — causes a large increase in spontaneous mutability and, in mice and men, predisposition to tumour development. More than 90% of hereditary nonpolyposis colorectal cancers and 15% of sporadic replication-error-positive colorectal cancers show microsatellite instability due to mismatch repair inactivation. In hereditary cases a germline mutation (usually in hMLH1 or hMSH2) is accompanied by a second event, typically allelic loss. In sporadic cases somatic mutations are not frequent; hypermethylation of the hMLH1 promoter is the predominant cause of inactivation. Inactivation may occur early, before APC gene inactivation, and produce a raised mutation rate, but selection for escape from apoptosis is likely the most important feature in evolution of a replication-error-positive cancer.
In a study of 255 patients with stage III colon cancer, 95 received fluoropyrimidine-based chemotherapy and 160 received oxaliplatin-based chemotherapy. Among those treated with oxaliplatin, patients with positive ERCC1 tumours had lower 5-year disease-free survival (54%) and overall survival (60%) than those with negative ERCC1 tumours (72% and 78% respectively; DFS hazard ratio 1.98, 95% CI 1.19–3.31, P=0.009; OS hazard ratio 2.44, 95% CI 1.37–4.34, P=0.02). ERCC1 status did not impact survival in the fluorouracil-only group. Mismatch repair status had no predictive value for disease-free or overall survival in either treatment group.
A 62-year-old man with mismatch repair deficient metastatic colorectal adenocarcinoma, urothelial carcinoma, and a history of sebaceous carcinomas received compassionate-use pembrolizumab (200 mg every 3 weeks) after second-line treatment failure. His CEA initially responded for four months, then rose for five months before mildly declining again. Treatment was switched to atezolizumab after it was approved for urothelial carcinoma, and his CEA declined again. This single case raises questions about PD-L1 therapy, sequencing of immunotherapy, reliance on CEA trends, and determining future therapies after progression on pembrolizumab, but provides no controlled evidence of efficacy.
What is still missing are prospective trials that stratify patients by mismatch repair status and test specific immune checkpoint sequences or combinations. The predictive value of ERCC1 for oxaliplatin benefit in stage III colon cancer is established, but mismatch repair status itself had no predictive value in that setting. No drug has been shown to restore mismatch repair function. The field lacks randomised data for immunotherapy sequencing in mismatch repair deficient cancers, and the role of CEA as a surrogate endpoint remains uncertain.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annual Review of Biochemistry · 1996 · 1500 citations
MISMATCH REPAIR IN REPLICATION FIDELITY, GENETIC RECOMBINATION, AND CANCER BIOLOGY
AbstractMismatch repair stabilizes the cellular genome by correcting DNA replication errors and by blocking recombination events between divergent DNA sequences. The reaction responsible for strand-specific correction of mispaired bases has been highly conserved during evolution, and homologs of bacterial MutS and MutL, which play key roles in mismatch recognition and initiation of repair, have been identified in yeast and mammalian cells. Inactivation of genes encoding these activities results in a large increase in spontaneous mutability, and in the case of mice and men, predisposition to tumor development.
AbstractPositional cloning and linkage analysis have shown that inactivation of one of the mismatch repair genes (hMLH1, hMSH2, hPMS1, hPMS2, GTBP/hMSH6) is responsible for the microsatellite instability or replication error (RER+) seen in more than 90% of hereditary nonpolyposis colorectal cancers (HNPCC) and 15% of sporadic RER+ colorectal cancers. In HNPCC, a germline mutation (usually in hMLH1 or hMSH2) is accompanied by one further event (usually allelic loss) to inactivate a mismatch repair gene. In contrast, somatic mutations in the mismatch repair genes are not frequently found in sporadic RER+ colorectal cancers. Hypermethylation of the hMLH1 promoter region has recently been described, and this epigenetic change is the predominant cause of inactivation of mismatch repair genes in sporadic RER+ colorectal and other cancers. Inactivation of a mismatch repair gene may occur early (before inactivation of the APC gene) and produce a raised mutation rate in a proportion of HNPCC patients, and these cancers will follow a different pathway to other RER+ cancers. However, it is likely that selection for escape from apoptosis is the most important feature in the evolution of an RER+ cancer.
Annual Review of Biochemistry · 1996 · 81 citations
Mismatch Repair in Replication Fidelity, Genetic Recombination, and Cancer Biology
AbstractMismatch repair stabilizes the cellular genome by correcting DNA replication errors and by blocking recombination events between divergent DNA sequences. The reaction responsible for strand-specific correction of mispaired bases has been highly conserved during evolution, and homologs of bacterial MutS and MutL, which play key roles in mismatch recognition and initiation of repair, have been identified in yeast and mammalian cells. Inactivation of genes encoding these activities results in a large increase in spontaneous mutability, and in the case of mice and men, predisposition to tumor development.
British Journal of Cancer · 2013 · 51 citations · open access
ERCC1, defective mismatch repair status as predictive biomarkers of survival for stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy
AbstractBACKGROUND: Excision repair cross-complementation group 1 (ERCC1) expression status has been identified as a candidate marker for predicting efficacy of oxaliplatin (OX) treatment for metastatic colorectal cancer (CRC) in several trials. Also, an association between expression of mismatch repair (MMR) genes and favourable postoperative survival in stage II CRC receiving 5-FU chemotherapy has been identified. It is unknown if the expression of ERCC1 protein and MMR status are associated with survival of stage III colon cancer receiving OX-based chemotherapy. METHODS: Immunohistochemistry (IHC) analysis of the expression of MMR and ERCC1 was performed on tumour tissue of 255 patients with stage III colon cancer. In all, 95 patients received fluoropyrimidine-based chemotherapy and 160 patients received OX-based chemotherapy. A predictive model for 5-year disease-free survival (DFS) and overall survival (OS) was constructed using Kaplan-Meier analysis, logistic and Cox regression. RESULTS: Patients who were treated with OX-based therapy with positive ERCC1 tumours had lower 5-year DFS (54%) and OS (60%) than those with negative ERCC1 tumours (72% and 78%, respectively; DFS HR: 1.98, 95% confidence interval (CI): 1.19-3.31, P=0.009; OS HR: 2.44, 95% CI: 1.37-4.34, P=0.02). Excision repair cross-complementation group 1 status did not impact DFS or OS in fluorouracil group (DFS HR: 1.16, 95% CI: 0.63-2.14, P=0.62; OS HR: 1.16, 95% CI: 0.63-2.14, P=0.63), whereas MMR status had no impact on DFS or OS in either group. CONCLUSION: Excision repair cross-complementation group 1 status is highly predictive of which patients will benefit from the addition of OX to 5-FU for stage III colon cancer. Mismatch repair status had no predictive value in this setting.
Cancer Biology & Therapy · 2017 · 8 citations · open access
Mismatch repair deficient metastatic colon cancer and urothelial cancer: A case report of sequential immune checkpoint therapy
AbstractA major recent advance in cancer therapy involves the use of immune checkpoint therapy for tumors with mismatch repair deficiency, as they have a high tumor mutation load and neoantigen burden. Approximately 4% of advanced colorectal cancer harbors a mismatch repair deficiency. When mismatch repair deficiency exists in the germline, there is increased susceptibility to a variety of cancers including colorectal cancer, uterine cancer, urothelial carcinoma, and skin cancer. Herein we report the case of a 62-year-old man with mismatch repair deficient metastatic colorectal adenocarcinoma, urothelial carcinoma and a history of sebaceous carcinomas. As the patient in 2016 was ineligible for clinical trials he received immune checkpoint anti-PD-1 therapy with pembrolizumab (200 mg every 3 weeks), on compassionate use basis, after the failure of second-line treatment. The patient's CEA initially responded to pembrolizumab for 4 months and then kept rising for 5 months before mildly declining again. His treatment was then switched to anti-PD-L1 therapy with atezolizumab as it was approved for urothelial carcinoma at that time, and his CEA declined again. This case raises interesting questions about caring for patients with mismatch repair deficient colorectal cancer, including the role of PD-L1 therapy, sequencing of immunotherapy, relying on CEA trends and determining future therapies after progression on pembrolizumab.
AbstractA DNA mismatch repair system exists that repairs mispaired bases formed during DNA replication and genetic recombination. Genetic defects in this mismatch repair system are known to increase the rate of spontaneous mutation in Escherichia coli. Some cases of inherited cancer are associated with inherited defects of mismatch repair genes, showing the importance of the mismatch repair system in maintenance of genetic stability and avoidance of cancer susceptibility. This review focused on what is known about the mechanisms of mismatch repair in human cells and the relationship between defects in mismatch repair and carcinogenesis.
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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