DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for T-cell non-Hodgkin lymphoma — screening already-approved drugs against its 15-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 non-Hodgkin lymphoma maps to a 15-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
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ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
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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
Structures already discussed alongside t-cell non-hodgkin lymphoma 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 a HDAC-like protein — Vorinostat has a real, experimentally solved structure in complex with this target (PDB 1ZZ1, 1.57 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 shhdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1ZZ1 · 1.57 Å · ligand Vorinostat (SHH). Experimental structure, not a prediction.
What the evidence adds up to
A 2020 multicentre retrospective analysis of 284 patients with mature T-cell lymphoma who received allogeneic stem cell transplantation reported a 2-year overall survival rate of 60.1% and a 2-year progression-free survival rate of 47.8%. Median follow-up for survivors was 49.17 months. At the time of transplant, 60.5% of patients were in complete remission, 33.1% in partial remission, and the remainder had stable or progressive disease. The median progression-free survival for patients in complete remission at transplant was not reached, whereas it was 36.8 months for those in partial remission, 19.2 months for stable disease, and 4.96 months for progressive disease. 88 patients progressed after transplant at a median of 4.65 months. 129 patients died; 56 died of lymphoma, 30 died of transplant complications, and 43 had an unknown or other cause. Transplant-related mortality at 1 year was 13.2%. The study found no significant difference in outcome between the subtypes angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, and anaplastic large cell lymphoma regardless of ALK status.
Earlier reviews from 2009 and 2013 note that peripheral T-cell lymphomas are biologically heterogeneous and that outcomes with standard treatments remain unsatisfactory compared to B-cell lymphomas. The 2009 review highlights that ALK-positive anaplastic large cell lymphoma has a significantly better prognosis than ALK-negative disease, but that ALK-negative anaplastic large cell lymphoma still has an unsatisfactory prognosis. A 2021 review describes targeted therapies including antibody-based treatments, small molecule inhibitors, and immune-based therapies as an expanding area of investigation, but does not report survival data from controlled trials.
The 2020 transplant study is retrospective and lacks a randomised comparator arm. It does not report outcomes for patients who did not receive a transplant, nor does it stratify results by the specific targeted therapies mentioned in the 2021 review. The analysis cannot separate the effect of the transplant from the effect of achieving remission before transplant. No prospective trial has yet established which patients with T-cell lymphoma benefit most from allogeneic transplantation compared to other salvage strategies, and the optimal timing and conditioning regimen remain undefined.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Haematologica · 2010 · 107 citations · open access
Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma
AbstractBACKGROUND: Vorinostat (suberoylanilide hydroxamic acid, SAHA), an inhibitor of class I and II histone deacetylases, has been approved for the treatment of cutaneous T-cell lymphoma. In spite of emerging information on the effect of vorinostat in many types of cancer, little is yet known about this drug's mechanism of action, which is essential for its proper use in combination therapy. We investigated alterations in gene expression profile over time in cutaneous T-cell lymphoma cells treated with vorinostat. Subsequently, we evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of cutaneous T-cell lymphoma. DESIGN AND METHODS: The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, false discovery rate corrected P value<0.05) were selected using the short-time series expression miner. Cell viability was assessed in vitro in cutaneous T-cell lymphoma cells through measuring intracellular ATP content. Drug interactions were analyzed by the combination index method with CalcuSyn software. RESULTS: The functional analysis suggests that vorinostat modifies signaling of T-cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. With regards to effects on cutaneous T-cell lymphoma cells, combining vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when vorinostat was combined with HSP90 inhibitor. CONCLUSIONS: These results demonstrate the potential targets of vorinostat, underlining the importance of T-cell receptor signaling inhibition following vorinostat treatment. Additionally, we showed that combination therapies involving histone deacetylase inhibitors and inhibitors of PI3K are potentially efficacious for the treatment of cutaneous T-cell lymphoma.
Journal of the European Academy of Dermatology and Venereology · 2014 · 26 citations
Treatment of cutaneous T‐cell lymphoma with oral alitretinoin
AbstractBACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a potentially life-limiting malignant disease. Treatment strategies in CTCL aim at disease control and remission with the lowest possible side-effects. OBJECTIVE: Recent reports suggest that the new vitamin A derivative alitretinoin might be a well-tolerated treatment option. METHODS: We analysed the files of 11 CTCL patients with mycosis fungoides (n = 10) or Sézary syndrome (n = 1), who were treated with oral alitretinoin alone or in combination with standard treatment based on individual off-label treatment decisions. Patients had been monitored every 4-8 weeks with skin examination and laboratory analyses. RESULTS: Ten of 11 patients (90.9%) showed a marked improvement of their CTCL skin lesions and no progress of the disease during treatment with alitretinoin, one patient showed no response to the treatment (9.1%). Four of the responding patients (40.0%) had a complete response and 6 (60.0%) had a partial response. Average time to response was 2.5 months. Duration of treatment varied depending on whether patients had reached complete or partial remission. In general, alitretinoin was well tolerated. One of 11 patients developed high non-fasting average serum cholesterol (>300 mg/dL) and 1/11 a mean non-fasting triglyceride value >500 mg/dL. In 3/11 patients, thyroid-stimulating hormone declined without clinical symptoms during treatment, with one of the patients also showing a decreased thyroxin level. CONCLUSION: In our group of CTCL patients we noticed a low rate of side-effects and an overall good clinical response to treatment with alitretinoin. Further studies are required to substantiate this early clinical observation.
Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis
AbstractAbstract Background: Mature T-cell lymphomas (TCL) are an uncommon heterogeneous subset of non-Hodgkin lymphomas for which allogeneic hematopoietic stem cell transplantation (alloHCT) is considered in the relapsed/refractory setting. Outcomes of alloHCT reported through prior registry data has shown that only 31% of patients (pts) with TCL remain disease free 3 years after alloHCT (Smith et al. JCO2013). However, several single institution studies have shown superior outcomes. Methods: We analyzed the baseline characteristics, treatment history, overall (OS) and progression-free survival (PFS) in consecutive patients with mature TCL who received an alloHCT from 1/1/2000- 5/12/2017 at 6 academic institutions. Patients with the following diagnoses were included: peripheral T-cell lymphoma, NOS (PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL); anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) negative; ALCL, ALK positive; ALCL, ALK unknown; adult T-cell leukemia/lymphoma (ATLL); hepatosplenic TCL (HSTCL); extranodal NK/T-cell lymphoma (ENKTL); enteropathy-associated TCL (EATL); cutaneous T-cell lymphoma (CTCL); primary cutaneous ALCL; subcutaneous panniculitis-like TCL (SPTCL); primary cutaneous gamma/delta TCL (GDTCL); blastic plasmacytoid dendritic cell neoplasm (BPDCN). Results: Patient characteristics are shown in Table 1. 284 pts were identified with median age of 50 years (17-74). Of these, 269 had known remission status at the time of transplant. At time of alloHCT, 163 (60.5%) were in complete remission (CR), 89 (33.1%) in partial remission (PR), 10 (3.72%) with stable disease, and 7 (2.60%) with progressive disease. 53 pts received an alloHCT in CR1 and 8 in PR1. 102 pts received an alloHCT in CR2 or beyond and 53 in PR2 or beyond (8 and 28 were in CRx and PRx). 49 pts had a prior autologous transplant. The median hematopoietic cell transplant comorbidity index score was 2 (0-9). The conditioning regimen was myeloablative in 131, reduced intensity/non-myeloablative in 149 and unknown in 4. Donor type was available for 281 patients: 113 matched related, 106 matched unrelated, 24 mismatched, 13 haploidentical donors, 25 cord blood. Following alloHCT, 88 pts have progressed to date at a median of 4.65 months (0.72-88.38). With a median follow-up period for survivors of 49.17 months (0.69-186.51), the OS and PFS rate were 60.1% (95% CI: 53.8-65.7%) and 47.8% (95% CI: 41.7-53.7%) at 2 years. (Figure 1) For the disease specific 2-year PFS please see Table 1. 65.1% of the deaths occurred within 12 months of alloHCT. Of 129 patients who have died, 56 died of lymphoma and 30 died of alloHCT complications (death within 30 days of transplant or due to GvHD). 43 pts had an unknown or other cause of death. In this series, there was no significant difference in outcome for patients with AITL, PTCL-NOS, ALK positive ALCL or ALK negative ALCL which carried a median PFS of 52.2 months (95% CI: 17.9-82.9; p=0.247). The rate of transplant related mortality (TRM) at 1 year was 13.2% (95%CI: 8.3-18.1). Of the 281 pts who had data regarding development of graft-versus-host disease (GvHD), 119 (42.3%) developed acute GvHD and 97 (34.5%) developed chronic GvHD. There were no differences in TRM according to recipient age and HCT-CI, (all p-values NS). Response to prior therapy at the time of alloHCT was associated with PFS (p=0.001). (Figure 2) Median PFS for those with PR, stable disease or progressive disease were 36.8 mo, 19.2 mo, 4.96 mo respectively. In contrast, median PFS was not reached for pts in CR at the time of alloHCT. Degree of donor match was associated with cumulative TRM(p=0.012). For patients who underwent matched related, matched unrelated, or mismatched donor alloHCT, cumulative TRM at 6 months was 2.9% (1.5-7.3%), 7.8%(4.3-14.2%), 14.8%(6.8-32%) respectively. 32 of 88 pts who relapsed survive to date with median survival of 3.55 months post relapse (0.07 -78.6 months). Conclusions: We present the largest series of alloHCT in TCL. This study suggests that alloHCT is a potentially curative treatment option for patients with TCL. Response to prior therapy was associated with PFS. Mismatched alloHCTs were associated with higher TRM. While 64% of relapses occur within 12 months following transplant, 53.5% of the patients in this series remain alive. This data supports the curative potential of alloHCT in a patient group with otherwise poor survival and limited treatment options. Download : Download high-res image (244KB) Download : Download full-size image Disclosures Mehta-Shah: Celgene: Research Funding; Verastem: Research Funding; Bristol Myers-Squibb: Research Funding. Beaven: GlaxoSmithKline: Other: Spouse's employment; Celgene: Honoraria. Porcu: Galderma: Research Funding; Kura: Research Funding; Kiowa: Research Funding; Celgene: Research Funding; Miragen: Research Funding; Cell Medica: Research Funding; Innate Pharma: Research Funding; Tetralogic: Research Funding. Moskowitz: Seattle Genetics: Honoraria, Research Funding; Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding. Horwitz: Celgene: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; BMS: Consultancy; Mundipharma: Consultancy; HUYA: Consultancy. Jacobsen: GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees.
Current Opinion in Hematology · 2009 · 19 citations
The spectrum of peripheral T-cell lymphomas
AbstractPURPOSE OF REVIEW: This review summarizes recent progress that has advanced our understanding of the pathobiology and prognosis of peripheral T-cell lymphomas including the changes introduced to the updated World Health Organization classification of lymphoid neoplasms. RECENT FINDINGS: The International Peripheral T-Cell Lymphoma Project was a large collaborative project, highlighting the clinico-pathologic and geographic differences of this diverse group of diseases. Peripheral T-cell lymphoma, not otherwise specified, is a biologically heterogeneous subtype, and a number of studies including investigations using molecular profiling have explored whether meaningful prognostic or biologic subgroups can be identified. Angioimmunoblastic T-cell lymphoma demonstrates overlapping immunophenotypical and molecular features with normal follicular T-helper cells, giving some insight into the cell of origin. Systemic anaplastic large cell lymphoma is composed of two disease groups based on the presence or absence of anaplastic lymphoma kinase overexpression. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma has a significantly better prognosis than anaplastic lymphoma kinase-negative anaplastic large cell lymphoma and molecular studies have illustrated that each entity has a distinct molecular profile. Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma has been recently shown to have a more favourable, but still unsatisfactory, prognosis than peripheral T-cell lymphoma, not otherwise specified, and biological and molecular distinctions confirm that they are separate entities. SUMMARY: Advances are being made in understanding the unique pathobiology of the peripheral T-cell lymphoma subtypes that will help to refine diagnoses, identify potential prognostic markers, elucidate the molecular mechanisms critical in disease pathogenesis and define new therapeutic targets in the poor-risk population.
AbstractT-cell lymphomas account for 10–15 % of all adult non-Hodgkin lymphomas. Progress in understanding the biology of these lymphomas leads to improvement in their molecular classifications. However, the management of patients with T-cell lymphoma remains challenging, as these patients continue to have worse treatment outcome compared with B-cell lymphomas. In this chapter, we review the recent advances in T-cell lymphoma biology and emerging therapeutic strategies.
Journal of Personalized Medicine · 2021 · 2 citations · open access
Targeted Approaches to T-Cell Lymphoma
AbstractThe T-cell lymphomas are a rare group of Non-Hodgkin's lymphomas derived from mature T-lymphocytes. They are divided broadly into the Peripheral T-cell lymphomas and the Cutaneous T-cell lymphomas. Clinical outcomes vary widely but are generally unsatisfactory with current treatments. The development of an understanding of the various critical pathways in T-cell lymphogenesis and subsequent identification of therapeutic targets has led to a rapid expansion of the previously underwhelming T-cell lymphoma armament. This review aims to provide an up-to-date overview of the current state of targeted therapies in the T-cell lymphomas, including novel antibody-based treatments, small molecule inhibitors and immune-based therapies.
Chemotherapy in aggressive T-cell non-Hodgkin lymphoma
AbstractT-cell non-Hodgkin lymphoma is a group disease with unique clinical and pathological features. It is more aggressive and has lower chemotherapy sensitivity than B-cell lymphoma. In recent years, to search for effective treatment, novel agents such as gemcitabine, targeted therapy combined with chemotherapy and high-dose chemotherapy combined with hematopoietic stem cell transplantation are applied in the treatmentof T-cell non-Hodgkin lymphoma. And some progresses are achieved.
Key words:
Lymphoma,T-cell ; Drug therapy ;
Archives of Clinical and Medical Case Reports · 2024 · 0 citations · open access
Outcomes of Gemcitabine, Vinorelbine, and Doxorubicin in Peripheral T-Cell Lymphoma
AbstractPeripheral T-Cell Lymphoma (PTCL) remains a difficult-to-treat heterogeneous group of Non-Hodgkin Lymphomas. Our current treatment guidelines have been largely based on studies evaluating the treatment of B-cell Lymphomas, in which there were small subsets of T-cell lymphoma patients included. Additionally, there is no clear guideline for sequencing of subsequent salvage regimens. Prior retrospective studies have reported activity with the combination chemotherapy, Gemcitabine, Vinorelbine, and Doxorubicin (GVD) in the treatment of relapsed and refractory PTCL, but these have been international retrospective analyses. Thus, we performed a retrospective analysis within our own institution of the efficacy and safety of GVD in the treatment of relapsed and refractory PTCL. We found an overall response rate of 80%, complete response rate of 50%. Complete response rates were higher in patients receiving GVD as second-line therapy as compared to later lines of therapy. GVD was well tolerated with the most common adverse effects being neutropenia, infection, and peripheral neuropathy. Ultimately, our data supports the use of GVD in relapsed and refractory PTCL, with possible greatest benefit when used as second-line therapy.
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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