Missing content? – Request curation!
Request curation for specific Genes, variants, or PubMed publications.
Have questions, comments or suggestions? - Let us know!
Email us at : email@example.com
|Ref Type||Journal Article|
|Authors||Liu Y, Pandeswara S, Dao V, Padrón Á, Drerup JM, Lao S, Liu A, Hurez V, Curiel TJ|
|Title||Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment.|
|Date||2017 01 15|
|Abstract Text||mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T-cell lymphoma. Typical pharmacologic rapamycin (1-8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of antitumor immunity. Denileukin diftitox (DD)-mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T-cell-dependent fashion. However, typical rapamycin inhibited T-cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low-dose (LD) rapamycin (75 μg/kg) increased potentially beneficial CD44hiCD62L+ CD8+ central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of antitumor immunity. Instead, rapamycin upregulated EL4 IL2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B-cell lymphoma, but not against human Jurkat T-cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T-cell lymphomas. Cancer Res; 77(2); 520-31. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Denileukin diftitox||Ontak||DAB389IL2|DAB389-IL2|LY335348|DAB389 interleukin-2||Ontak (denileukin diftitox) is an interleukin-2 (IL-2) recombinant fusion protein comprised of the IL-2 protein and the diptheria toxin, and may potentially inhibit the growth and survival of tumor cells expressing the IL-2 receptor (PMID: 11707818, PMID: 27737881).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||B-cell lymphoma||not applicable||Denileukin diftitox + Sirolimus||Preclinical - Cell culture||Actionable||In a preclinical study, Rapamune (sirolimus) enhanced the efficacy of Ontak (denileukin diftitox) in human B-cell lymphoma cells, resulting in decreased cell viability in culture (PMID: 27737881).||27737881|
|Unknown unknown||ovarian carcinoma||no benefit||Denileukin diftitox + Sirolimus||Preclinical||Actionable||In a preclinical study, an ovarian carcinoma mouse model did not respond to the combination of Ontak (denileukin diftitox) and Rapamune (sirolimus), demonstrating no decrease in tumor burden (PMID: 27737881).||27737881|
|Unknown unknown||B-cell lymphoma||not applicable||Denileukin diftitox + Temsirolimus||Preclinical - Cell culture||Actionable||In a preclinical study, Torisel (temsirolimus) enhanced the efficacy of Ontak (denileukin diftitox) in human B-cell lymphoma cells, resulting in decreased cell viability in culture (PMID: 27737881).||27737881|
|Unknown unknown||lymphoma||not applicable||Denileukin diftitox + Sirolimus||Preclinical||Actionable||In a preclinical study, a low dose of Rapamune (sirolimus) enhanced the efficacy of Ontak (denileukin diftitox) treatment in lymphoma mouse models, resulting in greater inhibition of tumor growth and higher survival compared to either agent alone (PMID: 27737881).||27737881|
|Unknown unknown||melanoma||not applicable||Denileukin diftitox + Sirolimus||Preclinical||Actionable||In a preclinical study, the combination of Ontak (denileukin diftitox) and Rapamune (sirolimus) resulted in a greater decrease in tumor volume compared to treatment with either agent alone in a melanoma mouse model (PMID: 27737881).||27737881|