DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for T-cell acute lymphoblastic leukemia — 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 moduleT-cell acute lymphoblastic leukemia 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
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Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedDasatinibApproved drugapprovedPonatinibApproved drugapprovedRuxolitinibApproved drug
Structures already discussed alongside t-cell acute lymphoblastic leukemia 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 EphA4 kinase domain — Dasatinib has a real, experimentally solved structure in complex with this target (PDB 2Y6O, 1.543 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 1n1drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2Y6O · 1.543 Å · ligand Dasatinib (1N1). Experimental structure, not a prediction.
What the evidence adds up to
T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy derived from early T-cell progenitors, with recognised clinical and biological heterogeneity. In patients aged 21 years and younger treated between 2000 and 2018, 325 of 6,167 (5%) had induction failure, defined as persistent bone marrow lymphoblasts of at least 5% after 4–6 weeks of induction chemotherapy. Among those with induction failure, allogeneic haematopoietic stem cell transplantation in first remission was associated with a disease-free survival benefit, but outcomes still lag considerably behind those who achieve remission at end of induction. The review notes that recognition of heterogeneity has translated into new prognostic biomarkers and emerging targeted therapies, but does not report survival numbers for unselected T-ALL.
Arabinosylguanine (araG) is a nucleoside analog that shows selective in vitro toxicity to T lymphoblastoid cell lines and freshly isolated T-ALL leukaemia cells. In a 1991 report, treatment with 100 microM araG for 18 hours eliminated up to 6 logs of clonogenic T cells from human bone marrow without appreciable toxicity to normal myeloid, erythroid, or megakaryocytoid progenitor cells. The authors discussed its use for ex vivo purging of malignant T cells from marrow before autologous bone marrow rescue. No clinical outcomes from araG treatment in patients are given in that abstract.
A 2020 case report describes a patient with refractory T-ALL and a JAK3 mutation who had a cutaneous relapse after allogeneic blood cell transplantation and was treated with ruxolitinib, a JAK inhibitor. The authors state they were able to show potential benefit, but the abstract provides no quantitative response data such as survival or remission duration. A separate 2023 case report of a 64-year-old man with relapsed JAK3-mutant T-prolymphocytic leukaemia (a related but distinct T-cell malignancy) treated with ruxolitinib and venetoclax reported a partial response: stabilisation of peripheral lymphocyte count, improvement in thrombocytopenia, decrease in splenomegaly, and a numerical reduction in bone marrow involvement. The combination was tolerated except for neutropenic infections. No complete remission or survival data are given for that patient.
A 2021 case report describes a patient with Philadelphia chromosome-positive de novo T-ALL and extramedullary involvement who was treated with the third-generation tyrosine-kinase inhibitor ponatinib, along with chemotherapy intensification, nelarabine, and allogeneic stem cell transplantation. The authors report remarkable effectiveness in obtaining haematological and metabolic remission, but the abstract provides no sample size beyond a single patient and no long-term survival numbers. A 2015 review of dasatinib for Philadelphia-chromosome positive ALL reports haematologic and molecular remission rates of 90% and 35% respectively, disease-free survival at 3 years of 25% to 70%, and rare cardiovascular events; drawbacks include pleural effusions, risk of haemorrhage, and selection of resistant clones. That review covers Ph+ ALL broadly, not specifically T-ALL, and notes the absence of direct comparative studies between tyrosine-kinase inhibitors. A 2019 French experience with tisagenlecleucel (CTL019) in B-cell ALL reports that among 40 evaluable patients, 38 (95%) achieved complete remission or complete remission with incomplete count recovery at one month, with 35 of 38 (92.1%) being MRD negative. Median event-free and overall survival were not reached at a median follow-up of 7.2 months; 18-month overall survival probability was 80% and event-free survival probability 58%. Ten patients relapsed after a median of 3.4 months. That study is in B-ALL, not T-ALL, and no data are provided for CTL019 in T-ALL.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cold Spring Harbor Perspectives in Medicine · 2019 · 67 citations · open access
The Genetics and Mechanisms of T-Cell Acute Lymphoblastic Leukemia
AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T-cell progenitors. The recognition of clinical, genetic, transcriptional, and biological heterogeneity in this disease has already translated into new prognostic biomarkers, improved leukemia animal models, and emerging targeted therapies. This work reviews our current understanding of the molecular mechanisms of T-ALL.
PHARMACOLOGIC PURGING OF MALIGNANT T CELLS FROM HUMAN BONE MARROW USING 9-β-D-ARABINOFURANOSYLGUANINE
AbstractArabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate, resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia. In this report, we demonstrate that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 microM araG for 18 hr, up to 6 logs of clonogenic T cells could be eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We discuss the use of this agent in ex vivo elimination of residual malignant T cells from marrow of patients requiring myeloablative chemotherapy with autologous bone marrow rescue.
Journal of Clinical Oncology · 2023 · 20 citations · open access
Outcome for Children and Young Adults With T-Cell ALL and Induction Failure in Contemporary Trials
AbstractPURPOSE: Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1). METHODS: Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018. RESULTS: = .10, respectively. CONCLUSION: Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.
Safety and Efficacy of Tisagenlecleucel (CTL019) in B-Cell Acute Lymphoblastic Leukemia in Children, Adolescents and Young Adults: The French Experience
AbstractObjectives: Tisagenlecleucel (CTL019) is a chimeric antigen receptor T cell- therapy that reprograms autologous T cells to target CD19+ leukemia cells, approved in the US (2017) and in the EU (2018). This study reports the feasibility, safety and efficacy of CTL019 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated in Robert-Debré and Saint-Louis University Hospitals (Assistance Publique-Hôpitaux de Paris/Université de Paris). Methods: Patients (pts) with an apheresis performed between march 1, 2016 and june 15, 2019, included in sponsored-clinical trials or treated within the French compassionate program or with the commercial product, were analyzed. All infused pts received a fludarabine-cyclophosphamide based lymphodepletion before a single infusion of CAR-T cells (2 to 5 x 106 CTL019/kg if less than 50 kg; a fixed dose of 1 to 2.5 x 108 CTL019/kg if > 50 kg) Results: 55 pts were referred from 25 French centers. Forty-one pts with a median number of relapses of 2 (range, 1-5) were infused with CTL019 at a median age of 18.2 y (range, 1-29.2). Eight pts were not infused due to progressive disease (n=4), screen failure (n=3) or fatal septic shock (n=1). Six pts were waiting to be infused at time of analysis. Out of the 41 infused pts, 26 had a prior history of allogeneic SCT (63%), 11 had received blinatumomab (27%). Among the 40 pts evaluable at one month post-infusion, 38 were in CR/CRi (95%) (one progression at day 5 after infusion and one toxic death at D6), 35/38 (92.1%) being clone-specific Ig-TCR MRD negative. After 3 months 21 out of 26 evaluable pts (81%) had a negative MRD. The 5 remaining MRD positive pts did relapse. No pt underwent allogeneic HSCT while in CR after CTL019 infusion. Median event free survival (EFS) and overall survival (OS) were not reached with a median follow up of 7.2 months (range, 0.2-36.3). The 18-month OS probability was 80% (95%CI, 58%-92%). The 18-month EFS probability was 58 % (95%CI, 37%-74%). Ten pts relapsed after a median time of 3.4 months (range, 1.9-10): 3 relapses were CD19+ and 5 CD19- (4 out of these 5 pts had a preexposure to blinatumomab), 2 being of undetermined status. Loss of B-cell aplasia (BCA) occurred in 9 pts after a median time of 3 months (range, 2-12), followed by relapse for 2 pts (one concomitant with loss of BCA and one 7 months later). Three pts received a second infusion of CTL019 for loss of BCA with no further expansion of CAR-T cells. Prior treatment with blinatumomab was a significant predictive factor for relapse (HR=6.082, 95%CI, 1.2-30, p=0.0005) in a univariate analysis. There was a trend toward increased risk of relapse with increased disease burden (≥ 5%) before lymphodepletion regimen (HR=2.4, 95%CI, 0.7-8, p=0.14). Twenty-two pts experienced a CRS (≥ grade 3: n=13, all ≥ 10 y). ICU was required for 14 pts (34%). One 29 year-old pt died of an uncontrollable CRS at day 6. Ten pts received tocilizumab, 4 pts siltuximab and 9 pts corticosteroids. Age ≥ 10 y (p=0.04) and a high disease burden just before lymphodepletion (marrow blasts ≥ 5%) (p=0.01) were associated with a higher risk of CRS ≥ grade 3. Nine neurological events have been reported, being reversible except in 2 cases (one death in combination with grade 5 CRS-cf supra-, one HHV6-related encephalitis with neurological sequelae). Among the 9 pts who presented neurological events, 8 experienced CRS grade ≥ 3 (RR=17.2, 95%CI, 3.22-100.3, p=0.0001). By day 28, unresolved neutropenia grade ≥ 3 was reported for 13 pts. G-CSF treatment was required in 21 pts overall. Thrombocytopenia grade ≥3 was reported for 14 pts. Conclusion: CTL019 confirms its efficacy with a high response rate after infusion and very encouraging early outcomes in a cohort of pts heavily pretreated for refractory or multiply relapsed B-ALL. Persistent remissions with a potential for cure were observed without additional HSCT, relapses occurring within the first year after infusion of CTL019. Accurate assessment of a potentially deleterious effect of Blinatumomab preexposure notable on CD19 negative relapse will need more pts and a longer follow-up. Toxicity profile was tolerable and manageable thanks to collaboration between intensivists, neurologists and hematologists. The identification of severe CRS predictive risk factors (high disease burden just before lymphodepletion and age ≥ 10 y) points towards the reinforcement of toxicity monitoring and treatment anticipation in these cases. Disclosures Boissel: NOVARTIS: Consultancy. Baruchel:NOVARTIS: Consultancy.
Ruxolitinib is effective in the treatment of a patient with refractory T‐ALL
AbstractAbstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a rare, aggressive T‐cell malignancy. Chemotherapy alone cures only 25‐45% of the cases, thus, novel treatment agents and strategies are urgently needed. We assessed the efficacy of ruxolitinib in a patient with a cutaneous relapse after allogeneic blood cell transplantation of a refractory T‐ALL with a Janus kinase 3 ( JAK3 ) mutation. In this case report, we were able to show the potential benefit of the JAK inhibitor ruxolitinib in JAK3 ‐mutated refractory T‐ALL and emphasize the importance of integrating molecular markers in current treatment decision making for patients with T‐ALL.
Partial response to venetoclax and ruxolitinib combination in a case of refractory T-prolymphocytic leukemia
AbstractBackground: T-prolymphocytic leukemia (T-PLL) is an aggressive hematologic malignancy. A portion of patients can be cured with alemtuzumab induction followed by allogeneic hematopoietic stem cell transplant, but patients who relapse after transplant have a poor prognosis, and there is no standard of care.Methods: We report a case of a 64-year-old man with relapsed JAK3-mutant T-PLL following allogeneic transplant who was treated with ruxolitinib and venetoclax.Results: Treatment with ruxolitinib and venetoclax resulted in a partial response including stabilization of the peripheral lymphocyte count, improvement in thrombocytopenia, decrease in splenomegaly, and a numerical reduction in the percentage of bone marrow involved by T-PLL. The combination was well tolerated with the exception of neutropenic infections.Conclusion: This case adds to the growing body of literature supporting venetoclax and rituximab as a viable treatment option for relapsed/refractory T-PLL with JAK-STAT alterations.
Clinical Efficacy of Ponatinib in Philadelphia-Positive T-Cell Acute Lymphoblastic Leukemia with Extramedullary Involvement
AbstractT-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation.
Expert Opinion on Orphan Drugs · 2015 · 0 citations
Dasatinib for acute lymphoblastic leukemia
AbstractIntroduction: Despite considerable improvement in the prognosis of Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in the era of tyrosine-kinase inhibitors (TKI), less than half of the patients can be cured. Among several TKI now available, dasatinib (SPRYCEL®) displays theoretical advantages and a robust clinical experience.Areas covered: After an overview of Ph+ ALL current and future therapies, this article presents the chemistry, pharmacodynamics and pharmacokinetics of dasatinib, shedding light on mechanisms of action, resistance and toxicity. Clinical efficacy and tolerability of the drug, alone or in combination with chemotherapy and/or hematopoietic stem cell transplantation, are detailed in phase I and II trials, and in one phase III trial dedicated to dose optimization, in the absence of direct comparative studies between various TKI. A potential role for dasatinib in other subsets of ALL is discussed.Expert opinion: Dasatinib displays an interesting tolerance/efficacy profile in ALL; rates of hematologic and molecular remission of 90% and 35% respectively; disease-free survival at 3 years of 25% to 70% and rare cardio-vascular events; its drawbacks include pleural effusions, risk of hemorrhage and the selection of resistant clones. The main competitors are represented by other drugs targeting the BCR-ABL kinase, such as ponatinib and allosteric inhibitors, and by the growing field of immunotherapy.
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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