DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neutropenia — screening already-approved drugs against its 40-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNeutropenia maps to a 40-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 neutropenia 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
inositol monophosphatase 1 (IMPA1) — IMPA1 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 4-oxidanylphenoxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6GIU · 1.39 Å · ligand [1-(4-oxidanylphenoxy)-1-phosphono-ethyl]phosphonic acid (L69). Experimental structure, not a prediction.
What the evidence adds up to
The incidence of drug-induced neutropenia has not changed in the western hemisphere over the last 30 years, though the drugs involved have changed considerably, implying host factors play an intriguing role in this idiosyncratic reaction. It remains remarkably difficult to pinpoint why and how a drug causes this severe adverse event in a given patient, and patient characteristics such as genetics appear to be keys for better understanding, predictions and prevention.
In a study of 15 patients with severe absolute neutropenia of one to 19 years' duration, there was no bone-marrow hypoplasia or splenomegaly, the cause was not apparent, and these patients had no increase in the frequency of infections. Leukemia, lupus erythematosus and other serious disease did not develop, and the neutropenia did not respond to corticosteroids. This benign condition does not require therapy.
Experts agree that patients with acute febrile neutropenia should be treated with antibiotics, and that patients at high risk of severe neutropenia (greater than 20% risk) after myelosuppressive chemotherapy should be treated prophylactically with a myeloid growth factor, usually granulocyte colony-stimulating factor (G-CSF). The administration of myeloid growth factors is the only approved treatment for the prevention of chemotherapy-induced neutropenia and febrile neutropenia, though their specific indications, contraindications and potential side effects limit their application to only a relatively small subset of patients at the highest risk for complications such as infection. There is an abundance of agents undergoing evaluation for the prevention of treatment-induced neutropenia, but the appropriate selection of patients and the optimisation of existing agents remain essential for growth factors to retain their dominant position.
Severe congenital neutropenia comprises several genetically distinct entities, with mutations identified in the neutrophil elastase gene ELA2 (found in cyclic, sporadic and autosomal dominant neutropenia) and homozygous mutations in the antiapoptotic gene HAX1 (found in autosomal recessive severe congenital neutropenia). Ongoing linkage studies suggest more, as yet unidentified, genes may be involved. The underlying causes of neutropenia are extremely heterogeneous and include benign conditions, autoimmune disorders, infections, and malignancies. What is still missing is a reliable way to predict which patients will suffer idiosyncratic drug-induced agranulocytosis, a definitive genetic classification system that can be applied in routine practice, and trial designs that can test novel bone marrow-protective agents against the existing growth factor standard in appropriately stratified patient populations.
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 Hematology · 2009 · 124 citations · open access
Idiosyncratic drug‐induced agranulocytosis: Possible mechanisms and management
AbstractThe incidence of drug-induced neutropenia has not changed in the western hemisphere over the last 30 years. Yet, the drug panorama has changed considerably. This implies that host factors may play an intriguing role for this idiosyncratic reaction. The knowledge as to mechanisms for the reaction has advanced with emerging understanding of neutropoiesis and immune regulation. Nonetheless, it is still remarkably difficult to pinpoint why and how a drug causes this unexpected, severe adverse event in a patient. Patient characteristics, e.g. genetics, appear to be keys for better understanding, predictions and prevention. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.
New England Journal of Medicine · 1968 · 101 citations
Chronic Idiopathic Neutropenia
AbstractIn a study of 15 patients with severe absolute neutropenia of one to 19 years' duration there was no bone-marrow hypoplasia or splenomegaly, and the cause of the neutropenia was not apparent. These patients had no increase in the frequency of infections, and leukemia, lupus erythematosus and other serious disease did not develop. The neutropenia was chronic and did not respond to corticosteroids. This benign condition does not require therapy and should be recognized as such.
Current Opinion in Hematology · 2015 · 81 citations · open access
How I diagnose and treat neutropenia
AbstractPURPOSE OF REVIEW: Neutropenia absolute neutrophil count (ANC) less than 1.5 × 10(9)/l is a common hematological finding, and severe neutropenia, that is, ANC less than 0.5 × 10(9)/l is a well known risk factor for susceptibility to bacterial infections. This review provides a succinct clinical approach to the diagnosis and treatment of neutropenia with specific recommendations on the treatment of severe chronic neutropenia with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF). RECENT FINDINGS: Experts agree that patients with acute febrile neutropenia should be treated with antibiotics and that patients at high risk of severe neutropenia (>20% risk) after myelosuppressive chemotherapy should be treated prophylactically with a myeloid growth factor, usually G-CSF. The diversity of causes and consequences of chronic neutropenia make the diagnosis and management of these patients more complicated. SUMMARY: The review provides a stepwise approach to neutropenia focusing first on reaching a provisional diagnosis and treatment plan then steps to a final diagnosis. It also provides specific recommendations on the treatment of severe chronic neutropenia with G-CSF.
International Journal of Laboratory Hematology · 2020 · 47 citations
How I investigate neutropenia
AbstractNeutropenia is a common laboratory finding in adults and children. Its underlying causes are extremely heterogeneous and include benign conditions, autoimmune disorders, infections, and malignancies. The clinical laboratory plays a central role in the diagnosis of these disorders, including data derived from hematology, microbiology, molecular biology/cytogenetics, and clinical chemistry. The purpose of this review is to (a) highlight the clinical, hematologic, and molecular genetic features of the major entities resulting in neutropenia and (b) outline an algorithm-based approach to permit the classification of neutropenias.
Current Opinion in Rheumatology · 2007 · 29 citations
Severe congenital neutropenia: new genes explain an old disease
AbstractPURPOSE OF REVIEW: This review summarizes the recent advances in the diagnosis and molecular characterization of isolated and syndromal forms of severe congenital neutropenia. RECENT FINDINGS: It has become evident that severe congenital neutropenia comprises several genetically distinct entities. In 1999, mutations were identified in the neutrophil elastase gene ELA2. ELA2 mutations have been found in cyclic, sporadic and autosomal dominant neutropenia. Recently, homozygous mutations in the antiapoptotic gene HAX1 were found in patients with autosomal recessive severe congenital neutropenia. Ongoing linkage studies suggest that more and, as yet unidentified, genes may be involved in the pathophysiology of severe congenital neutropenia. In other patients, congenital neutropenia is not an isolated finding but is associated with other abnormalities, in particular, lymphoid immunodeficiency and pigmentation defects such as Chédiak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2, or deficiency of the endosomal adaptor p14. The molecular identification of these disorders originating from mutations in lysosome (related) proteins has advanced our knowledge of intracellular protein trafficking. SUMMARY: Recent insights into the molecular etiology of severe congenital neutropenia provide the opportunity for a definitive genetic classification system. Based on this knowledge, disease-related risks may be recognized and optimized therapeutic options may become available.
Prostate International · 2019 · 8 citations · open access
Safety and efficacy of cabazitaxel in Japanese patients with castration-resistant prostate cancer
AbstractSeveral studies have reported the efficacy of cabazitaxel in cancer therapy; however, investigations of its safety are few. The aim of this study was to retrospectively analyze the efficacy and safety of cabazitaxel based on treatment outcome data. A questionnaire form on the use of cabazitaxel was mailed to hospitals associated with the Shinshu University. Responses were received from 11 institutions regarding 55 cases. Patients received a median of 4 courses of cabazitaxel treatment. Decreases in prostrate-specific antigen (PSA) were observed in 61.5% of cases with declines of 30%, 50%, and 90% in 36.5%, 23.0%, and 7.6% of cases, respectively. PSA progression-free survival was 5.0 months, and overall survival after the start of cabazitaxel was 13.0 months. Forty-five patients received postcabazitaxel treatment; 17 showed decreased PSA. Safety assessment indicated that white blood cell and neutrophil counts were significantly higher in the second than in the first course of treatment and Grade 3 to 4 leukopenia and neutropenia significantly decreased. Twenty-four subjects were aged ≥75 years; 79% of them had their doses reduced at the first administration. The mean dose was 20 mg/m2. However, there was no significant difference in the PSA progression-free survival between the ≥75-year-old and <75-year-old groups. Patients in the ≥75-year-old group, particularly those whose doses were not reduced, experienced several Grade 3 to 4 adverse effects. Ten patients discontinued treatment owing to adverse effects and systemic worsening. To use cabazitaxel effectively, starting administration as early as possible before disease progression is important, and even if Grade 3 to 4 leukopenia and neutropenia are observed during the first course, it is important to carefully maintain the dose. Even when treating elderly patients, reducing the dose does not reduce therapeutic efficacy. However, because this cohort experienced several ≥ Grade 3 adverse effects, a great deal of caution is required.
Expert Opinion on Emerging Drugs · 2016 · 7 citations
Emerging agents for the prevention of treatment induced neutropenia in adult cancer patients
AbstractINTRODUCTION: The administration of myeloid growth factors is the only approved treatment for the prevention of chemotherapy induced neutropenia and febrile neutropenia. However, their specific indications and contraindications and potential side effects limit their application to only a relatively small subset of patients at the highest risk for complications, such as infection. AREAS COVERED: A computerized systematic literature search was performed through Medline, Google Scholar, Cochrane Library, the Pharmaprojects database and the clinicaltrials.gov website. The shortcomings of the existing treatment approach are reviewed, along with a synopsis of the characteristics of novel agents that protect bone marrow progenitors from the cytotoxic effects of antineoplastic treatment that may be used in the future as a stand-alone preventive strategy or as an adjunct to growth factors. EXPERT OPINION: There is an abundance of agents undergoing evaluation for the prevention of treatment-induced neutropenia. The appropriate selection of patients, the optimization of the use of existing agents and the increasing competition from biosimilars which likely ensure future decreases in healthcare costs are essential for growth factors to retain their dominant position in this setting.
European Urology Oncology · 2023 · 4 citations · open access
Early Identification of Patients at Risk of Cabazitaxel-induced Severe Neutropenia
AbstractBackground Cabazitaxel frequently causes severe neutropenia. A higher cabazitaxel systemic exposure is related to a lower nadir absolute neutrophil count (ANC). Objective To describe the effect of cabazitaxel systemic exposure on ANC by a population pharmacokinetic/pharmacodynamic (POP-PK/PD) model, and to identify patients at risk of severe neutropenia early in their treatment course using a PK threshold. Design, setting, and participants Data from five clinical studies were pooled to develop a POP-PK/PD model using NONMEM, linking both patient characteristics and cabazitaxel systemic exposure directly to ANC. Outcome measurements and statistical analysis A PK threshold, predictive of severe neutropenia (grade ≥3), was determined using a receiver operating characteristic curve. Results and limitations Ninety-six patients were included with a total of 1726 PK samples and 1081 ANCs. The POP-PK/PD model described both cabazitaxel PK and ANC accurately. A cabazitaxel plasma concentration of >4.96 ng/ml at 6 h after the start of infusion was found to be predictive of severe neutropenia, with a sensitivity of 76% and a specificity of 65%. Conclusions Early cabazitaxel plasma levels are predictive of severe neutropenia. Implementation of the proposed PK threshold results in early identification of almost 76% of all severe neutropenias. If prospectively validated, patients at risk could benefit from prophylactic administration of granulocyte colony stimulating factors, preventing severe neutropenia in an early phase of treatment. Implementation of this threshold permits a less restricted use of the 25 mg/m 2 dose, potentially increasing the therapeutic benefit. Patient summary Treatment with cabazitaxel chemotherapy often causes neutropenia, leading to susceptibility to infections, which might be life threatening. We found that a systemic cabazitaxel concentration above 4.96 ng/ml 6 h after the start of infusion is predictive of the occurrence of severe neutropenia. Measurement of systemic cabazitaxel levels provides clinicians with the opportunity to prophylactically stimulate neutrophil growth.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
