DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Spindle Cell Melanoma — screening already-approved drugs against its 42-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSpindle Cell Melanoma maps to a 42-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 spindle cell melanoma 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
MDM4 regulator of p53 (MDM4) — MDM4 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 3~{s}drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6Q9Y · 1.2 Å · ligand 7-methoxy-~{N}-[(3~{S})-1-(4-methylphenyl)pyrrolidin-3-yl]-1~{H}-indole-3-carboxamide (HRQ). Experimental structure, not a prediction.
What the evidence adds up to
In a 2001 study of 21 spindle cell and desmoplastic melanomas, only 4 of 21 (19%) were reactive for HMB-45, and only 6 of 21 (29%) were reactive for the anti-Mitf antibody D5. One of those six D5-reactive cases was negative for both S-100 and HMB-45. Among 24 non-melanocytic spindle cell tumors, 8 (33%) were also D5-reactive, including 4 of 6 dermatofibromas. The authors concluded that D5 is not a sensitive or specific marker for spindle cell and desmoplastic melanomas, though they noted it might be diagnostically useful in selected cases when taken in context. A 1998 study of 22 spindle cell melanomas found that 13 of 20 (65%) were focally reactive with HMB-45, while laminin was expressed in 42% and type IV collagen in 77% of tumours; the authors stated that detection of these basement membrane components cannot be used to distinguish spindle cell melanoma from malignant peripheral nerve sheath tumours.
A 2003 analysis of 9 spindle cell melanomas found that the tumour cells expressed S-100, Mel-CAM, and NKIC3, but lacked gp100 and Melan-A; tyrosinase and c-Kit were expressed in 2 of 7 cases. All cases expressed the fibroblastic markers Thy1 (CD90) and aminopeptidase N (CD13), and the authors suggested that lack of CD90 and CD13 staining in other melanocytic lesions indicates specificity of these markers for spindle cell melanoma. A 2014 case report described a single patient with a c-kit-positive and S100A6-positive spindle cell melanoma of the dorsal foot, proposing that these markers might improve diagnosis.
A 2012 sequencing study of 24 spindle cell melanoma patients (including 10 with desmoplastic melanoma) found BRAF mutations in 6 of 20 successfully analysed tumours (30%), of which 5 were V600E and 1 was V600R. No NRAS or KIT mutations were detected in the 18 and 14 patients respectively who had completed sequencing for those genes. The authors concluded that V600 BRAF mutation is the most common mutation among those tested, and that NRAS or KIT mutation appears rare or absent. A 2023 narrative review covering the past decade noted that targeted therapy and immunotherapy have changed the approach to advanced melanoma treatment, but did not provide specific data on spindle cell melanoma outcomes.
What is still missing are prospective trials that stratify spindle cell melanoma as a distinct subgroup, given its rarity and its divergent marker profile from epithelioid melanoma. The genomic data come from only 24 patients, and no study reports response rates to targeted therapy or immunotherapy specifically in this subtype. Funding for multi-centre collection of spindle cell cases, and for trials that test whether the fibroblastic markers CD90 and CD13 identify a biologically distinct tumour, remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Dermatopathology · 2001 · 97 citations
Microphthalmia Transcription Factor
AbstractMicrophthalmia transcription factor (Mitf), a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master lineage regulator and modulates extracellular signals. Recently, Mitf expression was shown to be both a sensitive and specific marker of epithelioid melanoma. Because loss of specific melanocytic markers in melanomas with spindle cell morphology is more common compared with those tumors with epithelioid morphology, we investigated the sensitivity of D5, an anti-Mitf antibody, for diagnosis in this diagnostically problematic subset of melanomas. Twenty of 21 (95%) spindle cell and desmoplastic melanomas examined were reactive for S-100 protein. Only 4 of 21 (19%) spindle cell and desmoplastic melanomas were reactive for HMB-45. Six of 21 tumors (29%) were reactive for D5, including one case that was non-reactive for S-100 and HMB-45. Melan-A reactivity was seen in 2 of 13 cases (15%) studied. Eight of 24 (33%) non-melanocytic spindle cell tumors were reactive for D5, including 4 of 6 dermatofibromas, 1 of 6 schwannomas, 1 of 2 leiomyomas, and 2 of 6 leiomyosarcomas. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study show it is not a sensitive or specific marker of spindle cell and desmoplastic melanomas. Nevertheless, we believe that diffuse positive staining for D5 when taken in clinical, histologic and immunohistochemical context may be diagnostically useful in selected cases of melanoma.
New Phenotypical and Ultrastructural Findings in Spindle Cell (Desmoplastic/Neurotropic) Melanoma
AbstractSpindle cell melanoma is a rare and distinctive variant of malignant melanoma that is composed of spindled neoplastic cells and includes desmoplastic and neurotropic melanoma. The lack of expression of several melanoma markers may result in a delayed or wrong diagnosis. In this study, we have analyzed in detail the phenotype of the tumor cells in 9 spindle cell melanomas on both paraffin-embedded and frozen material, using melanocytic, neural, and mesenchymal markers. The neoplastic cells expressed the melanocytic markers S-100, Mel-CAM, and NKIC3, but lacked gp100 and Melan-A; tyrosinase and c-Kit were expressed in 2 of 7 cases. Most cases expressed the neural markers p75-nerve growth factor receptor, neural cell adhesion molecule, and NSE. All cases expressed vimentin but lacked the mesenchymal markers CD34 and alpha-smooth muscle actin. Remarkably, all spindle cell melanomas strongly and diffusely expressed the fibroblastic markers Thy1 (CD90) and aminopeptidase N (CD13) and variably expressed the enzyme prolyl-4-hydroxylase, involved in procollagen formation. The coexpression of melanocytic, neural, and fibroblastic markers suggests bidirectional differentiation of neoplastic melanocytes toward (myo)fibroblasts and Schwann cells, a feature that was confirmed by electron microscopy. Furthermore, the lack of CD90 and CD13 staining in a wide range of melanocytic lesions suggests specificity of these markers for spindle cell melanoma.
Journal of Cutaneous Pathology · 2012 · 26 citations
<i><scp>BRAF</scp></i>, <i><scp>NRAS</scp></i> and <i><scp>KIT</scp></i> sequencing analysis of spindle cell melanoma
AbstractBACKGROUND: Spindle cell melanoma represents a rare but distinct subset of melanoma, and its genomic spectrum has not been fully defined. METHODS: We searched our institutional database for patients with a diagnosis of pure spindle cell-type melanoma whose tumors had been analyzed for BRAF, NRAS, and KIT mutations using pyrosequencing technique. RESULTS: We identified 24 patients with spindle cell melanoma, including 10 patients with desmoplastic melanoma, whose tumors had been analyzed for at least one of the three genes. The median Breslow thickness was 2.6 mm, and the most common site of the primary melanoma was the trunk, followed by the head and neck region. BRAF, NRAS and KIT genomic sequencing was performed successfully in 20, 18 and 14 patients, respectively. Among the 20 melanomas with completed BRAF-sequencing analysis, 6 (30%) harbored a mutation, of which 5 (83%) had a V600E mutation and 1 (17%) had a V600R mutation. None of the melanomas harbored NRAS or KIT mutations. CONCLUSION: As has been reported in other common types of melanoma, V600 BRAF mutation is the most common mutation of those tested in spindle cell melanoma. NRAS or KIT mutation appears to be rare, if not completely absent.
Journal of Cutaneous Pathology · 1998 · 12 citations
Expression of basement membrane antigens in spindle cell melanoma
AbstractSpindle cell melanoma (SCM) is an uncommon form of melanoma that may be confused histologically with other tumors, including malignant peripheral nerve sheath tumors (MPNST). Tumors with neural differentiation and melanocytic nevi may both show basement membrane immunohistochemically and at the ultrastructural level. However, most ultrastructural studies of melanoma have failed to demonstrate well formed basement membrane around tumor cells. The presence of basement membrane has been used by some authors as evidence favoring MPNST, as opposed to SCM. To evaluate this distinction immunohistochemically, 22 primary and metastatic cutaneous melanomas having a spindle cell component (SCM) were studied using monoclonal antibodies against laminin and Type IV collagen. S100 protein and HMB45 antigen expression were also studied. All but one of the SCM were reactive for S100 protein in at least 25% of the cells. Thirteen of 20 tumors (65%) were focally reactive with HMB45. Laminin was expressed in 42% of the tumors (only membranous pattern in 3; cytoplasmic and membranous in 5). Seventeen tumors (77%) expressed type IV collagen (only membranous pattern in 7; cytoplasmic and membranous pattern in 10). Laminin and type IV collagen, known components of basement membrane, are often found in SCM. Therefore, their detection cannot be used to distinguish SCM from MPNST.
Case Reports in Dermatology · 2014 · 6 citations · open access
S100A6 and c-Kit-Positive Spindle Cell Melanoma of the Dorsal Foot
AbstractSpindle cell melanoma, which is a rare form of melanoma, is clinically and histopathologically difficult to diagnose from a variety of nonmelanocytic spindle cell tumors. We describe a 42-year-old Japanese woman with amelanotic melanoma that comprised spindle cells with positive c-kit and S100A6 staining. The use of c-kit and S100A6 might be useful for improving the diagnosis.
Romanian Journal of Morphology and Embryology · 2023 · 4 citations · open access
Morphological aspects and therapeutic options in melanoma: a narrative review of the past decade
AbstractMelanoma is a malignant cancer of the skin, the incidence of which has been increasing year by year. This neoplasm has high aggressivity as well as the potential for invasion and metastases. Multiple factors related to the proliferation of this type of tumor have been identified, such as exposure to ultraviolet (UV) radiation and specific genetic backgrounds. From a histological and cytological point of view, the most common cells that are found in melanoma are epithelioid or spindle cells. To confirm the diagnosis and the melanocytic origin of the tumor, specific and sensitive markers are used. Also, observation of the behavior of this cancer, including its proliferative properties, has led to the development of multiple therapies, each of which is characteristic of the pathological stage at the time of diagnosis. While surgery is the most important therapeutic and curative option in cases of melanoma in situ, chemotherapy has been the main treatment for advanced stages of melanoma for many years. However, recently, targeted therapy and immunotherapy have changed the approach to treatment. At present, multiple studies are attempting to obtain further data about the tumor microenvironment and investigating how targeting particular molecules can change the prognosis of patients.
OPen Access Repositorium der Universität Ulm (OPARU) (Ulm University) · 2013 · 0 citations · open access
A diagnostic algorithm to distinguish desmoplastic from spindle cell melanoma
AbstractSpindle cell melanoma and desmoplastic melanoma differ clinically in prognosis and therapeutic implications; however, due to partially overlapping histopathological features, diagnostic distinction of spindle cell from desmoplastic melanoma is not always straightforward. A direct comparison of diagnostic and therapeutic biomarkers has not been performed. Meta-review of the literature discloses key clinicopathological differences between spindle cell and desmoplastic melanoma, including immunophenotypes. Using 50 biomarkers available in routine diagnostics we examined 38 archival cases (n = 16 spindle, 18 desmoplastic, 4 mixed spindle/desmoplastic melanoma). S100 remains as the most reliable routine marker to reach the diagnosis of melanoma in spindle cell and desmoplastic melanoma. We identified 9 distinctly labeling markers with spindle cell melanoma showing positivity for laminin, p75, HMB45, c-kit, and MelanA, and desmoplastic melanoma preferentially labeling with collagen IV, trichrome, CD68, and MDM2. Based on comparisons of test performance measures, MelanA and trichrome were used to devise a 94 % sensitive diagnostic algorithm for the distinction of desmoplastic from spindle cell melanoma. Gene amplification and expression status was assessed for a set of potentially drugable targets (HER2, EGFR, MET, MDM2, TP53, ALK, MYC, FLI-1, KIT). Fluorescent in situ hybridizations did not reveal a significant number of gene abberations/rearrangements; however, protein overexpression for at least one of these markers was identified in 35 of 38 cases (92 %). In addition, we found BRAF mutations in 36 % of spindle cell and 5 % of desmoplastic melanoma with an overall mutation frequency of 16 % (n = 6/38). We present the first comprehensive screening study of diagnostic and therapeutic biomarkers in spindle cell and desmoplastic melanoma. The devised algorithm allows diagnostic distinction of desmoplastic from spindle cell melanoma when routine histology is not decisive.
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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