Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer
Abstract
:Simple Summary
Abstract
1. Introduction to Radioligand Therapy
2. Overview of Regulation and Signaling of mTORC1 in Cancer
3. Inhibitors of mTOR for Cancer Therapy
4. Targeting mTORC1 for Improved RLT
Inhibitor | RLT | Cancer | Results | Ref. |
---|---|---|---|---|
Preclinical in vivo studies | ||||
Rapamycin | [177Lu]Lu-RM2 | Human prostate cancer PC-3 xenograft mouse model | Significantly longer survival as compared with the monotherapies without treatment-related toxicity | [79] |
Everolimus | [177Lu]Lu-DOTA-PP-F11N | Human epidermoid carcinoma A431/CCKBR xenograft mouse model | Everolimus significantly enhanced tumor-specific uptake of radiolabeled minigastrin without adverse effects | [81] |
Metformin | [177Lu]Lu-DOTA-PP-F11N | Human epidermoid carcinoma A431/CCKBR xenograft mouse model | Metformin did not increase tumor uptake of radiolabeled minigastrin | [81] |
Everolimus | [177Lu]Lu-DOTA-PP-F11N | Human epidermoid carcinoma A431/CCKBR xenograft mouse model | Increased tumor growth inhibition and extended survival as compared with the monotherapies without adverse effects | [82] |
Everolimus | [177Lu]Lu-DOTA-TATE | Rat pancreatic cancer model with CA20948 tumors | Lack of therapeutic benefit. Metastases were found in combination and everolimus-treated groups | [83] |
Everolimus | [177Lu]Lu-DOTA-TATE | Rat pancreatic cancer model with CA20948 tumors | Metastases were not dose-dependent or related to the duration of everolimus treatment | [84] |
Everolimus | [177Lu]Lu-DOTA-TATE | Lewis rats: non-tumor bearing | Everolimus did not increase renal and hematological toxicity of the RLT | [85] |
Clinical studies | ||||
Everolimus | [177Lu]Lu-DOTA-TATE | Retrospective study; 24 patients with well- and moderately differentiated GEP-NETs (grades 1, 2) | The safety profile of everolimus was not influenced by the previous RLT. Partial responses (16.7%), stable disease (62.5%), and progressive disease (12.5%). | [86] |
Everolimus | [177Lu]Lu-DOTA-TATE | Single-center retrospective study; 41 patients with NETs (80% with primary GEP-NETs) | No statistically significant differences in severe subacute hematotoxicity of RLT were seen in the everolimus pretreated group as compared with the untreated group | [87] |
Everolimus | [177Lu]Lu-DOTA-TATE | Case study of a patient with grade II, well-differentiated rectal NET | Everolimus-induced SSTR overexpression, making the patient eligible for a second course of RLT | [88] |
Everolimus | [177Lu]Lu-DOTA-TATE | Clinical phase I; 16 patients with advanced unresectable progressive well-differentiated GEP-NETs | The maximum tolerated dose of everolimus was 7.5 mg daily. Overall response (44%) and no progression during 6-month treatment. Partial response (80%) in pancreatic NET patients | [89] |
Everolimus | [177Lu]Lu-DOTA-TATE | Clinical phase I/II; 11 patients with grade 1–2 NET of different origin | Everolimus at a dose of 10 mg daily with RLT was terminated due to toxicity and progression. One patient achieved partial response, and nine had stable disease. One patient developed disease progression. | [90] |
5. Conclusions and Outlook
Author Contributions
Funding
Conflicts of Interest
References
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Grzmil, M.; Wiesmann, F.; Schibli, R.; Behe, M. Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer. Cancers 2023, 15, 17. https://doi.org/10.3390/cancers15010017
Grzmil M, Wiesmann F, Schibli R, Behe M. Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer. Cancers. 2023; 15(1):17. https://doi.org/10.3390/cancers15010017
Chicago/Turabian StyleGrzmil, Michal, Fabius Wiesmann, Roger Schibli, and Martin Behe. 2023. "Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer" Cancers 15, no. 1: 17. https://doi.org/10.3390/cancers15010017
APA StyleGrzmil, M., Wiesmann, F., Schibli, R., & Behe, M. (2023). Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer. Cancers, 15(1), 17. https://doi.org/10.3390/cancers15010017