DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Central Nervous System Lymphoma — 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 moduleCentral Nervous System Lymphoma 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
Current lead
No approved-drug candidate for central nervous system lymphoma 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
dihydrofolate reductase (DHFR) — DHFR 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 ndpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4M6J · 1.201 Å · ligand NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NDP). Experimental structure, not a prediction.
What the evidence adds up to
Primary central nervous system lymphoma is an aggressive non-Hodgkin lymphoma confined to the brain, eyes, and leptomeninges, accounting for less than 5% of primary brain tumours. At least 95% of cases are large B-cell histology. Its incidence has risen over three decades in both immunocompromised and immunocompetent patients. The disease carries a worse prognosis than comparable extranodal lymphomas, and as of 2005 the optimal treatment remained undefined. A 1999 molecular analysis of five AIDS-associated cases found that four were monoclonal, there was no preferential use of any VH gene family, and an antigen-driven process had occurred in at least two patients before the oncogenic event, but no intraclonal variability was seen, suggesting the hypermutation mechanism was no longer active in the lymphoma B cells.
High-dose methotrexate-based chemotherapy improved outcome over radiation alone, and by 2009 nonrandomised data suggested further gains in progression-free survival and long-term disease-free survival were achievable. However, withholding or deferring whole-brain radiotherapy became a priority because neuropsychological testing of patients who received chemoradiation showed significant cognitive deficits attributable to irradiation. A 2016 randomised trial of 58 patients compared rituximab plus methotrexate against methotrexate plus whole-brain radiotherapy. The rituximab-methotrexate group had a total effective rate of 82.76% versus 58.62% in the control group, and 1-year and 3-year survival rates of 86.21% and 62.07% versus 58.62% and 31.03%, respectively. Incidences of anaemia, liver damage, gastrointestinal side effects, and oral ulcer were lower in the rituximab-methotrexate group. A 2018 review noted that high-dose methotrexate-based polychemotherapy followed by maintenance offered one of the best chances to control the disease, but the definition of optimal consolidation treatment and a shared management for elderly patients and intraocular localisation remained unresolved.
The International Primary Central Nervous System Lymphoma Collaborative Group proposed standardised baseline evaluation and response criteria for clinical trials, but as of 2005 no standard salvage therapy existed for progressive or recurrent disease. The 2018 review emphasised that treatment-related neurologic toxicities were frequently as disabling as the disease itself. What is still missing are adequately powered randomised trials to define the role of intrathecal chemotherapy, the optimum consolidation strategy, and the management of elderly and intraocular subgroups, as well as a clearer biological understanding of why the lymphoma localises to the CNS and how it recurs.
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 · 1980 · 127 citations
Successful treatment of recurrent primary central nervous system lymphoma with high-dose methotrexate
AbstractPrimary central nervous system (CNS) lymphoma is a rare disease, usually resistant to therapy. In the case presented, a 51-year-old woman with documented primary cerebellar CNS lymphoma, lymphoplasmacytoid type, underwent surgical resection and whole brain irradiation and then recurred within the CNS. Treatment with 17 courses of high-dose methotrexate resulted in complete disappearance of the tumor and clearing of all neurologic signs and symptoms. She is now free of disease 12 months after beginning chemotherapy. The potential usefulness of systemic anti-metabolites for treatment of CNS lymphoma, primary or disseminated, is discussed.
Neurosurgical FOCUS · 2006 · 45 citations · open access
Molecular pathogenesis of primary central nervous system lymphoma
AbstractPrimary central nervous system lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma (NHL) typically associated with a worse prognosis than other localized extranodal lymphomas with similar histological characteristics. The defining feature of PCNSL is its confinement to the central nervous system (CNS), with proclivity for growth within the leptomeningeal as well as intraocular compartments. Primary CNS lymphoma rarely disseminates outside the CNS and accounts for less than 5% of all primary brain neoplasms. At least 95% of PCNSLs are of large B-cell histology, the most common subtype of NHL. Consistent with the trend seen in systemic NHLs, the incidence of PCNSL has markedly increased over the past three decades, both in immunocompromised and immunocompetent patients. Because PCNSL is relatively rare, the identification of molecular prognostic biomarkers and the definition of a standard therapeutic strategy have been challenging. The authors discuss the current knowledge of the molecular pathogenesis of CNS lymphomas and review the recent advances in gene expression profile analysis and identification of novel prognostic biomarkers.
AIDS Primary Central Nervous System Lymphoma: Molecular Analysis of the Expressed VH Genes and Possible Implications for Lymphomagenesis
AbstractAIDS-associated primary central nervous system lymphomas are late events that have an extremely poor prognosis. Despite different hypotheses, the brain localization of these B cell lymphomas remains an enigma. To better define the cell origin of the lymphomas and the possible role of the B cell receptor (BCR) in the brain localization and/or in the oncogenic transformation, we analyzed the V region genes of the Ig heavy chain expressed by lymphoma cells in five randomly selected patients. After amplifying the rearranged VHDJH DNA by PCR, cloning, and sequencing of the amplified products, we observed that: 1) of the five lymphomas analyzed, four were clearly monoclonal; 2) there was no preferential use of one peculiar VH family or one peculiar segment of gene; 3) the mutation analysis showed that an Ag-driven process occurred in at least two cases, probably before the oncogenic event; and 4) there was no intraclonal variability, suggesting that the hypermutation mechanism is no longer efficient in these lymphoma B cells. Taken together, our results suggest that distinct Ags could be recognized by the BCR of the lymphoma cells in different patients and that, if the Ags are responsible for the brain localization of these B cells bearing mutated BCR, other factors must be involved in B cell transformations in primary central nervous system lymphoma.
Current Opinion in Neurology · 2005 · 10 citations
Update on primary central nervous system lymphoma
AbstractPURPOSE OF REVIEW: Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin's lymphoma that is confined to the central nervous system and eye. Numerous studies examining this disorder have been published in the past 2 years. This review will discuss recent advances in the understanding of the pathology, radiographic appearance, and treatment of this disorder. RECENT FINDINGS: Novel treatment regimens continue to be studied for newly diagnosed and recurrent primary central nervous system lymphoma. As overall survival improves, the burden of late neurotoxicity has become more apparent. Neuropsychological testing of patients treated with chemoradiation shows significant cognitive deficits that can be attributed to whole brain irradiation. Standardization of phase II clinical trials across individual institutions remains an important goal within the oncology community. The International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) has proposed guidelines for the baseline evaluation and response criteria for clinical trials of the disorder. In addition, series of patients with uncommon histological variants of primary central nervous system lymphoma have been published. SUMMARY: In 2005, the optimal treatment for primary central nervous system lymphoma remains undefined. Treatment of newly diagnosed disease should include methotrexate-based chemotherapy but the role of irradiation and intrathecal chemotherapy remain unclear. Salvage therapy for progressive or recurrent primary central nervous system lymphoma is an area of active interest but no standard recommendations exist at the present time. Future studies on the biology of recurrent primary central nervous system lymphoma should help to clarify treatment options for these patients.
Expert Review of Neurotherapeutics · 2018 · 9 citations
Challenges and prospects in the diagnosis and treatment of primary central nervous system lymphoma
AbstractIntroduction: Primary central nervous system lymphoma (PCNSL) retains peculiar biological and clinical characteristics and a worse prognosis with respect to other comparable lymphomas. The need for high doses of chemotherapy to achieve valid drug concentrations in cerebral tissues and/or radiotherapy results in severe treatment-related toxicities, mainly neurologic, which are frequently as disabling as the disease itself.Areas covered: Several emerging combined therapies are addressed that focus on treating PCNSL. The prognosis has improved in the last years but several questions remain unanswered and the research of more effective therapies goes on. Information and data were obtained from direct authors’ experience and a PubMed search of recent peer-reviewed original articles, review articles, and clinical guidelines.Expert commentary: The substantial progress observed in PCNSL has to be ascribed to a carefully combination of standard chemotherapeutic drugs. High-dose methotrexate-based polychemotherapy followed by mainteinance therapy offers one of the best chances to control the disease. Major issues that deserve many efforts by researchers are the definition of optimal consolidation treatment and a shared management of specific conditions such as elderly population and intra-ocular localization.
Primary central nervous system lymphoma: recent progress, many remaining questions
AbstractPURPOSE OF REVIEW: To review what progress has been made in the treatment of primary central nervous system lymphoma since the time when it was first recognized that high-dose methotrexate based chemotherapy improved outcome over radiation therapy alone. RECENT FINDINGS: Recent work has explored the use of high-dose methotrexate alone; the optimum dose of methotrexate; the need for intrathecal therapy; combinations of other drugs with high-dose methotrexate, most notably alkylators, high-dose cytarabine, and rituximab; and the use of myeloablative chemotherapy and autologous stem-cell rescue. Recent progress has also been made in the identification of clinical prognostic factors, and in identifying underlying biologic properties that may account for this tumor's distinctive clinical behavior. SUMMARY: Further improvement in progression-free survival and in the proportion of patients achieving long-term disease-free survival does seem to be achievable, based on the results of nonrandomized data. Reduction in the risk of severe neurotoxicity by withholding or deferring radiation therapy also appears feasible. Existing treatment options can be individualized to the patient's circumstances. However, the optimal management of primary central nervous system lymphoma remains to be defined, and participation in a suitable clinical trial is highly appropriate.
Hematology/Oncology and Stem Cell Therapy · 2020 · 6 citations · open access
Promising effect of PDL1 inhibitors in the front-line management of primary aggressive central nervous system lymphoma: A case report
AbstractPrimary central nervous system lymphoma (PCNSL) is a rare lymphoma that involves the central nervous system. The standard treatment involves chemotherapy with high-dose methotrexate. To the best of our knowledge, this is the first reported case of employing checkpoint inhibitor, nivolumab, alone to treat a patient with PCNSL who could not tolerate the induction therapy. In aggressive cases of PCNSL where chemotherapy may become futile, stand-alone checkpoint inhibitors should be considered as the front-line treatment protocol.
[Clinical Therapeutic Efficacy of Rituximab Combined with Methotrexate on Primary Central Nervous System Lymphoma].
AbstractOBJECTIVE: To investigate the therapeutic efficacy of rituximab combined with methotrexate on patients with primary central nervous system lymphoma. METHODS: Fifty eight patients with central nervous system lymphoma treated in our hospital from February 2008 to September 2011 years were randomly divided into the observation group and the control group. The control group was treated with methotrexate combined with whole brain radiotherapy; the observation group was treated by rituximab combined with methotrexate. The curative efficacy, adverse effects, life quality, and the 1 and 3 year survival rate after 2 cycles of treatment were compared between 2 groups. RESULTS: The total effective rate of observation group was 82.76%, which significantly higher than 58.62% of the control group (P < 0.05). In observation group, the incidences of anemia, liver damage, gastrointestinal side effect and oral ulcer were significantly lower than that in control group, respectively (P < 0.05). The physiological function, physical function, health status, social and emotional function in the observation group were significantly higher than those in the control group (P < 0.05), 1 and 3 years survival rates in the observation group were 86.21% and 62.07%, significantly higher than 58.62% and 31.03% in the control group (P < 0.05). CONCLUSION: Targeted therapy combined with chemotherapy for the primary central nervous system lymphoma can improve the patients' outcomes, reduce adverse effects, and improve the quality of life and survival rate.
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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