DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for combined small cell lung carcinoma — screening already-approved drugs against its 48-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCombined small cell lung carcinoma maps to a 48-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
Structures already discussed alongside combined small cell lung carcinoma in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of the syk tyrosine kinase domain — Imatinib has a real, experimentally solved structure in complex with this target (PDB 1XBB, 1.57 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 stidrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1XBB · 1.57 Å · ligand Imatinib (STI). Experimental structure, not a prediction.
What the evidence adds up to
Combined small cell lung carcinoma is a highly malignant tumour. Initial chemotherapy and radiotherapy produce high remission rates, but the disease almost always relapses with drug resistance. A 2001 review notes that progress over the prior 20 years had been painfully slow: despite dramatic initial responses, most patients relapse quickly and overall 5-year survival is about 5%. Combining standard regimens with newer agents had doubled median survival in some cases, but the review offers no specific survival numbers from those trials. A 2017 review confirms that treatment for relapsed disease remains a difficult problem, with research focused on new drug development, optimisation of chemotherapy regimens, and targeted drugs. A 2021 review states that the 5-year survival rate for small cell lung cancer is less than 10% and that, despite decades of research, little progress has been made, calling it one of the most intractable diseases in clinical practice.
A 2023 observational study of 125 patients with extensive stage small cell lung cancer reports a median follow-up of 12 months, during which 98 patients (78.4%) died. For the whole group, median overall survival was 13 months. Among the 73 patients (58.4%) who had a complete response to initial platinum-etoposide chemotherapy, progression-free survival was 8 months. Twenty patients (16%) received thoracic radiotherapy to the primary site after that complete response. Those who received radiotherapy had better overall survival (19 months versus 12 months, p=0.002) and better progression-free survival (11 months versus 8 months, p=0.01). The authors conclude that thoracic radiotherapy may improve survival in this subgroup.
What is still missing are prospective randomised trials large enough to confirm the radiotherapy benefit seen in this single-centre observational study, and any reliable strategy for treating patients who relapse after initial chemotherapy. No targeted agent or combination regimen has yet changed the overall 5% survival figure in a phase III trial. The field lacks both funding for adequately powered trials and a method to stratify patients by molecular subtype or resistance mechanism before treatment.
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 · 2013 · 3411 citations · open access
Crizotinib versus Chemotherapy in Advanced <i>ALK</i> -Positive Lung Cancer
AbstractBACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).
Clinical Cancer Research · 2004 · 10 citations · open access
Imatinib for Small Cell Lung Cancer, Aiming for a Target <b> <i>in Vivo</i> </b>
AbstractThere are an estimated 25,000 patients who develop small cell lung cancer per year in the United States. The currently available therapy is inadequate because >95% of patients die from their small cell lung cancer (1, 2). The work with conventional chemotherapy has not dramatically altered the relatively poor outcome for patients with small cell lung cancer in the past 20 years (1, 2). There is an ongoing effort to identify effective therapeutic agents developed against molecular targets in patients with lung cancer. Perhaps equally as important is the ongoing effort to determine why drugs aimed at a specific target do not have the anticipated efficacy.This article provides important in vivo information about attempting to use imatinib as a therapeutic agent for patients with small cell lung cancer. The data presented in the article add important information to the recently reported clinical trial of imatinib for patients with small cell lung cancer (3). The clinical trial of 19 patients with small cell lung cancer showed that only 4 of the 19 patients studied had immunohistochemical evidence of the c-kit receptor, and there were no objective tumor responses in any of these patients. The study of the patients with small cell lung cancer documented that the mean maximal plasma concentration of imatinib reached 7.4 μm but did not assess drug levels in the tumors, phosphorylation status of the c-kit receptor in the tumors, or study the tumors for the presence of mutations in KIT gene coding for the receptor. Therefore, information has not been available to determine whether the drug did not have evidence of clinical activity because the tumor was not sensitive to the drug, whether adequate amounts of drug reached the tumor, or whether the drug was able to inhibit the signaling through the c-kit receptor as assessed by the phosphorylation status of the receptor.Wolff et al. (4) provide important in vitro and in vivo data that add to our knowledge about attempts to therapeutically exploit the c-kit receptor in small cell lung cancer. They studied small cell lung cancer cell lines in common use that have been extensively characterized. The cell lines NCI-H209, H526, and H1607 have in vitro evidence of functional c-kit receptors because the receptors are phosphorylated. They show that the c-kit receptors increase their phosphorylation status upon stimulation with the agonist, stem cell factor, and that stimulation in some of the cell lines can be inhibited by concentrations of imatinib as low as 0.1 μm, but concentrations of 1–3 μm are required to completely block the phosphorylation of the c-kit receptor after stimulation with its agonist, stem cell factor, concentrations that can be achieved in human plasma (3).The cell lines NCI-H209, H526, and H1607 were studied in vivo. The investigators show that peak concentrations of imatinib were an average of 3.8 μm in the tumor but declined to 0.6 μm 8 h after the oral dose, a concentration where imatinib does not have its maximal effect on the phosphorylation status of the receptor in the in vitro studies. There was no significant inhibition of growth in the murine model. Therefore, the treatment of small cell lung cancer with imatinib in humans and in murine models does not yet show any evidence of efficacy despite achieving plasma concentrations that are associated with inhibition of growth of small cell lung cancer in vitro.Oral imatinib mesylate therapy is effective therapy for patients with one of the solid tumors, gastrointestinal stromal tumors. Wolff et al. (4) point out that c-kit is overexpressed and constitutively activated by mutations in the gastrointestinal stromal tumors. Additional work has shown that 88% of 112 gastrointestinal tumors have activating mutations of the KIT gene (5). The in vitro growth of gastrointestinal stromal tumor cells with KIT mutations is inhibited by concentrations as low as 0.1 μm of imatinib (5, 6). Furthermore, patients whose gastrointestinal stromal tumors have KIT mutations are more likely to respond to treatment with imatinib and live longer than patients without mutations. Therefore, the activating mutations of KIT play an important role in the sensitivity and efficacy of imatinib in both in vitro and in clinical studies.The preclinical information has shown that stem cell factor is produced by small cell lung cancer, c-kit receptors were present on the surface of the small cell lung cancer cells, and the phosphorylation can be blocked in vitro by incubating the cells with imatinib. The new information presented by Wolff et al. (4) shows the in vivo growth of small cell lung cancer is not inhibited by the oral administration of imatinib. There are a number of potential explanations for these findings. Perhaps the most important is that 68 small cell lung cancer cell lines and tumors studied thus far do not have activating mutations in the KIT gene and are therefore not very sensitive to imatinib (7, 8). The concentrations that inhibit the in vitro growth of small cell lung cancer cells are approximately 10–50-fold higher than the concentrations that inhibit the in vitro growth of gastrointestinal stromal tumors (5, 6, 9, 10). Therefore, the concentrations achieved by oral administration in mice and humans may not be adequate to inhibit the growth of small cell lung cancer. The authors show that the concentrations of imatinib reach 0.6 μm 8 h after dosing and may not be consistently high enough to cause growth inhibition of the small cell lung cancer in the mice.The use of molecularly targeted agents directed against solid tumors with mutations in the appropriate receptor have been clinically successful in gastrointestinal stromal tumors. A more widely applicable therapeutic use is when the receptor is present and active but has not undergone an activating mutation. The initial clinical data has shown that there is no obvious evidence of antitumor activity in a small Phase II trial with imatinib for patients with small cell lung cancer. The studies by Wolff et al. (4) have provided supporting evidence that there is no evidence of antitumor activity in a murine model. This provides additional evidence that further testing with in vivo studies of targeted agents directed against receptors without activating mutations may be helpful in developing the rationale before embarking on an expensive, time consuming, and potentially ineffective clinical trials.Requests for reprints: Bruce E. Johnson, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-4790; Fax: (617) 632-5786; E-mail: [email protected]
[Advances in the Treatment of Relapsed Small Cell Lung Cancer].
AbstractSmall cell lung cancer (SCLC) is a highly malignant tumor. The initial treatment of radiotherapy and chemotherapy are more sensitive, high remission rate, but susceptible to drug resistance and relapse after treatment. Although the treatment of lung cancer has undergone enormous changes in recent years, treatment for relapsed SCLC is still a difficult problem in clinical field. In view of the serious resistance of recurrent SCLC to the existing chemotherapeutic drugs, the research on recurrent SCLC around the world is focused on the clinical trial of new drug development, optimization of chemotherapy regimen and target drug development. This paper summarize and estimate studies and literature reports of chemotherapy and precision therapy for relapsed SCLC, hopefully it could help clinicians treat relapsed SCLC and give us clinical research direction for relapsed SCLC in the future.
Expert Review of Anticancer Therapy · 2001 · 4 citations
Advances in systemic therapy of small cell cancer of the lung
AbstractOver the last 20 years, progress in the therapy of small cell lung cancer has been painfully slow. Despite dramatic initial responses to chemotherapy, most patients relapse quickly with an overall 5-year survival of about 5%. Recent trials however offer some hope at changing this picture. Combining standard regimens with newer agents has doubled median survival in some cases. The use of novel targeted agents holds the promise of significantly increasing the survival in this disease, with manageable toxicity. This review outlines current treatment strategies, summarizes recent clinical trials and offers a view of what the next 5 years may hold for the treatment of small cell lung cancer.
AbstractSmall cell lung cancer (SCLC) accounts for approximately 15 % of all lung cancer cases. The prognosis for patients with MRL is unfavorable: the 5-year survival rate is less than 10 %. Due to the limited and low effectiveness of treatment options for SCLC, the search for more effective therapeutic approaches does not weaken. However, despite decades of basic and clinical research, little progress has been made in the treatment of MRL SCLC, leading to one of the most intractable diseases in clinical practice. In this regard, in recent years, the question arises of the need to consider the possibilities and options for combined treatment in small cell lung cancer.
Journal of College of Physicians And Surgeons Pakistan · 2023 · 0 citations · open access
Thoracic Radiotherapy Effect on the Outcome in Extensive Stage Small Cell Lung Cancer
AbstractOBJECTIVE: To evaluate the efficacy of thoracic radiotherapy to primary site in patients with extensive stage small cell lung cancer (SCLC) who had responded completely to systemic chemotherapy. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Departments of Radiation and Medical Oncology, Baskent University and Dr. Ersin Arslan Research and Training Hospital in Turkey, between the years of 2011 and 2020. METHODOLOGY: The study included 125 patients with extensive stage SCLC. Demographic data and outcomes of chemotherapy and radiotherapy were collected. The efficacy of thoracic radiotherapy to primary site was evaluated in patients who had responded completely to systemic chemotherapy, in terms of progression-free survival and overall survival (OS). RESULTS: The median follow-up time was 12 months and 98 (78.4%) patients died during follow-up. Seventy-three (58.4%) patients had complete response. Progression-free survival (PFS) for complete responder patients was 8 months, and OS for the whole group was found 13 months. Twenty (16%) patients received thoracic radiotherapy to primary site after complete response to platinum etoposide combination treatment. Patients receiving thoracic radiotherapy had better OS than those who did not (19 versus 12 months respectively and p=0.002). Patients receiving thoracic radiotherapy had better PFS than those who did not (11 versus 8 months, respectively, and p=0.01). CONCLUSION: Thoracic radiotherapy to primary site may improve the survival outcomes in extensive stage SCLC patients who had complete response to initial systemic chemotherapy. KEY WORDS: Small cell lung cancer, Thoracic radiotherapy, Complete response, Outcomes, Lung cancer.
Combination Chemotherapy With or Without Maintenance Sunitinib Malate (NSC 736511) for Untreated Extensive Stage Small Cell Lung Cancer: A Phase IB/Randomized Phase II Study
AbstractThis partially randomized phase I/II trial studies the side effects and best dose of sunitinib malate and to see how well it works when given together with cisplatin or carboplatin and etoposide in treating patients with extensive-stage small cell lung cancer. Drugs used in chemotherapy, such as cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether cisplatin or carboplatin and etoposide are more effective when given with or without sunitinib malate in treating small cell lung cancer.
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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