Reference Detail

Ref Type Journal Article
PMID (27737881)
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.
Journal Cancer research
Vol 77
Issue 2
Date 2017 Jan 15
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Denileukin diftitox Denileukin diftitox 0 1
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).
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 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 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 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
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