Cancer Lab · DeCure for X
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for leptomeningeal melanoma — screening already-approved drugs against its 6-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Structures already discussed alongside leptomeningeal melanoma in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Crystal structure of hPXR — Dabrafenib has a real, experimentally solved structure in complex with this target (PDB 6HJ2, 2.28 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.
RCSB Protein Data Bank · entry 6HJ2 · 2.28 Å · ligand Dabrafenib (P06). Experimental structure, not a prediction.
A 2024 case report describes a young man with stage IV BRAF V600E mutant melanoma who developed leptomeningeal disease after initial treatment with ipilimumab and nivolumab. When switched to dabrafenib, trametinib, and nivolumab together, he achieved a durable complete response that remained ongoing, off treatment, seven years from diagnosis. The authors call this the first published case of that triplet regimen and the first durable response with therapy discontinuation in melanoma leptomeningeal disease. They caution that this is an exceptional case and that management of symptomatic leptomeningeal disease remains a critical unmet clinical challenge with limited trial data.
A 2021 report of a primary leptomeningeal melanoma of the cerebellopontine angle found a GNA11 p.Q209L mutation and a KIT p.M541L missense variant, with losses of chromosomes 1p and 3p. Complete surgical resection was not possible, and leptomeningeal metastatic disease rapidly ensued despite immunotherapy. The authors note that primary leptomeningeal melanomas are aggressive, radioresistant tumours with poor prognosis, and that the mainstay of treatment — complete surgical resection and chemotherapy — has limited success.
A 2019 series of four children with neurocutaneous melanocytosis and leptomeningeal melanoma states that the prognosis is poor with no known effective treatment options. The majority of neurocutaneous melanocytosis results from a single postzygotic mutation in codon 61 of NRAS. A 2009 case of neurocutaneous melanosis with malignant leptomeningeal melanoma in a 50-year-old woman is described as exceptional for the late onset of symptoms and death. A 1969 report of leptomeningeal melanoma in a Ugandan African child of seven years notes a direct relationship between depth of pigment in the leptomeninges and the skin, suggesting similar factors control melanocytes in both sites.
What is missing are prospective clinical trials that include patients with leptomeningeal disease, which the 2024 authors explicitly call for. No trial has defined the best treatment strategy. Patient stratification by molecular signature — NRAS, GNAQ, GNA11, BRAF, KIT — remains largely speculative because the numbers are too small to test targeted therapies systematically. Funding for multi-centre registries and trials in this rare, rapidly fatal condition is absent.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractA case of neurocutaneous melanosis with malignant leptomeningeal melanoma is reported in a 50-year-old white woman. The case is exceptional as regards the late onset of symptoms and death. Although the association of extracutaneous melanomas with cutaneous pigmented lesions is rare, dermatologists must be aware of their presence.
https://doi.org/10.1159/000247089AbstractNeurocutaneous melanocytosis (NCM) is a disorder characterized by multiple or large congenital nevi and excessive proliferation of melanocytes in the leptomeninges and brain parenchyma. The majority of NCM is a result of somatic mosaicism due to a single postzygotic mutation in codon 61 of NRAS. Patients with NCM are at high risk of developing leptomeningeal melanoma. The prognosis for leptomeningeal melanoma is poor with no known effective treatment options. We describe the clinical features, treatment, and outcome of 4 children with NCM and leptomeningeal melanoma and discuss the latest molecular findings and treatment options for this rare condition.
https://doi.org/10.1097/mph.0000000000001680AbstractA case of leptomeningeal melanoma in an African child of 7 years is presented together with a survey of pigmentation in the normal African brain. There is a direct relationship between the depth of pigment of the leptomeninges and the skin in Ugandan Africans, suggesting that similar factors operate in the control of melanocytes in these two sites.
https://doi.org/10.1136/jcp.22.2.183AbstractPrimary leptomeningeal melanomas are rare, comprising less than one percent of all brain tumours. They are aggressive and radioresistant tumours, with a poor prognosis. The mainstay of treatment is complete surgical resection and chemotherapy with limited success. Distinguishing a primary leptomeningeal melanoma from the more common metastatic disease can be difficult, and often requires the use of ancillary molecular testing. Primary central nervous system melanomas, including uveal melanomas, frequently exhibit mutations in GNAQ and GNA11, rare in the cutaneous and mucosal counterparts.A case of a primary leptomeningeal melanoma of the cerebellopontine angle is described. Molecular studies identified a GNA11 p.Q209L and a KIT p.M541L missense variant, with losses of chromosomes 1p and 3p demonstrated with cytogenetic studies. Complete surgical resection was not possible and leptomeningeal metastatic disease rapidly ensued despite immunotherapy. Further understanding of the molecular signature may translate to improved diagnosis, prognostication and development of targeted therapies.
https://doi.org/10.1136/bcr-2020-239496AbstractLeptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple-drug regimen may be considered a viable option in fit patients. This case highlights the potential for long-term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies.
https://doi.org/10.1111/pcmr.13179Disease 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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