Inhibition of the Mechanistic Targets of Rapamycin Beyond Transplant Immunosuppression: A Mini-Review
Main Article Content
Abstract
It has been about thirty years since identifying the target of rapamycin and using mTOR inhibitors in organ transplantation. There was a promise that they would replace calcineurin inhibitors with fewer nephrotoxic effects and better graft survival. Unfortunately, with time, the enthusiasm for using them in transplantation decreased due to the unpleasant profile of adverse events and limited evidence of tangible clinical benefit.
With more understanding of physiology and judicious clinical application, new venues for mTOR inhibitors emerged. The mTOR pathway regulates primary cellular functions, including cell growth, metabolism, proliferation, and survival, and is critical for autophagy induction. Thus, as a master regulator, mTOR inhibitors emerged as anticancer therapies. In addition, such action proved beneficial for native or post-transplant malignancies.
Signaling through components of the mTOR pathway is an essential regulator of normal cardiac growth and pathological hypertrophy. mTOR inhibitors are effective in reducing left ventricular thickness and mass. It could be an add-on benefit in kidney transplant recipients with high cardiovascular risk or attenuate cardiac allograft vasculopathy in heart transplant recipients.
The mTOR inhibitors may help manage viral infections like cytomegalovirus, human herpesvirus 8-related Kaposi sarcoma, and possibly the BK virus. Furthermore, the mTOR pathway is modulated in many RNA viruses. Based on these facts, the idea of using mTOR inhibitors to treat COVID-19 infection has been evaluated. Accordingly, a new therapeutic role for mTOR inhibitors for treating COVID-19 infection t has emerged through reducing viral replication, and autophagocytosis, improving T cells function and preventing cytokine storm.
This paper will review these applications of mTOR inhibitors beyond the horizon of transplant immunosuppression.
Keywords:
Autophagy, Cancer, mTOR inhibitors, Transplant, Viral infection
Article Details
How to Cite
AL-TAEE, Huda; ALI, Ala.
Inhibition of the Mechanistic Targets of Rapamycin Beyond Transplant Immunosuppression: A Mini-Review.
Medical Research Archives, [S.l.], v. 11, n. 2, feb. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3660>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i2.3660.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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4. Gitto SB, Altomare DA. Recent insights into the pathophysiology of mTOR pathway dysregulation. Res Rep Biol. 2015:6 1–16
5. Mohamed MA, Elkhateeb WA, Daba GM. Rapamycin golden jubilee and still the miraculous drug: a potent immunosuppressant, antitumor, rejuvenative agent, and potential contributor in COVID-19 treatment.
Bioresour Bioprocess. 2022;9:65.
6. Bhaoighill MN, Dunlop EA. Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics. Cancer drug Resist. 2019;2:1069-85.
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8. Becker MA, Hou X, Tienchaianada P, et al. Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. BMC Cancer. 2016;16:814.
9. Chresta CM, Davies BR, Hickson I, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70:288–298.
10. Knechtle SJ, Marson LP, Morris PJ. Kidney Transplantation Principles and Practice. Eighth Edition. Elsevier;2020.261p.
11. Furian L, Baldan N, Margani G, et al. Calcineurin inhibitor-free immunosuppression in dual kidney transplantation from elderly donors. Clin Transplant. 2007;21:57–62.
12. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562-2575. doi:10.1056/NEJMoa067411.
13. Berger SP, Sommerer C, Witzke O, et al. Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study. Am J Transplant. 2019;19(11):3018-3034. doi:10.1111/ajt.15480.
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28. Rad E, Murray JT, Tee AR. Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression. Cancers. 2018, 10, 5.
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30. Reungwetwattana T, Molina JR, Mandrekar SJ, Allen-Ziegler K, Rowland KM, Reuter NF, et al. Brief report: A phase II "window-of-opportunity" frontline study of the mTOR inhibitor, temsirolimus given as a single agent in patients with advanced NSCLC, an NCCTG study. J. Thorac. Oncol. 2012, 7, 919–922.
31. Cejka D, Preusser M, Woehrer A, Sieghart W, Strommer S, Werzowa J, et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol. Ther. 2008, 7, 1377–1385.
32. Fuereder T, Jaeger-Lansky A, Hoeflmayer D, Preusser M, Strommer S, Cejka D, et al. mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves antitumor activity against gastric cancer in vivo. Cancer Lett. 2010, 296, 249–256.
33. Liao Y, Hou H, Han Z, Liu Y. Systemic therapies for metastatic renal cell carcinoma in the second-line setting: A systematic review and network meta-analysis. Medicine (Baltimore). 2022;101(37):e30333. doi:10.1097/MD.0000000000030333.
34. Massari F, Mollica V. Personalizing immunotherapy for renal cell carcinoma: how far have we come?. Expert Opin Biol Ther. 2022;22(10):1221-1225. doi:10.1080/14712598.2022.2122809.
35. Milowsky MI, Iyer G, Regazzi AM, Al-Ahmadie H, Gerst SR, Ostrovnaya I, et al. Phase II study of everolimus in metastatic urothelial cancer. BJU Int. 2013, 112, 462–470.
36. Seront E, Rottey S, Sautois B, Kerger J, D'Hondt LA, Verschaeve V, et al. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: Clinical activity, molecular response, and biomarkers. Ann. Oncol. 2012, 23, 2663–2670.
37. Bouyahya A, El Allam A, Aboulaghras S, et al. Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy. Cancers (Basel). 2022;14(22):5520. Published 2022 Nov 10. doi:10.3390/cancers14225520.
38. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012, 366, 520–529.
39. Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): A phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015, 16, 816–829.
40. Wang Z, Valera JC, Zhao X, Chen Q, Silvio Gutkind J. mTOR co-targeting strategies for head and neck cancer therapy. Cancer Metast. Rev. 2017, 36, 491–502.
41. Luo C, Ye WR, Shi W, Yin P, Chen Ch, He YB,et al. Perfect match: mTOR inhibitors and tuberous sclerosis complex. Orphanet J Rare Dis. 2022,17:106.
42. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358(2):140–51.
43. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9869):817–24.
44. De Fijter JW. Cancer and mTOR Inhibitors in Transplant Recipients. Transplantation 2018;102: S60–S70.
45. Alberu J, Pascoe MD, Campistol JM, et al. Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation. 2011;92:303–310.
46. Evrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348:1681–91.
47. Salgo R, Gossmann J, Schofer H, et al. Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial. Am J Transplant 2010;10:1385–93.
48. Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013;31:1317–1323.
49. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 352:1317-1323.
50. Majewski M, Korecka M, Joergensen J, et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 2003;75:1710–7.
51. Sang AX, McPherson MC, Ivison GT, et al. Dual blockade of the PI3K/Akt/mTOR pathway inhibits posttransplant Epstein-Barr virus B cell lymphomas and promotes allograft survival. Am J Transplant. 2019;19(5):1305-1314. doi:10.1111/ajt.15216.
52. Novalic Z, van der Wal AM, Leonhard WN, Koehl G, Breuning MH, Geissler EK, et al. Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease. J Am Soc Nephrol. 2012;23:842–53.
53. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):820-829. doi:10.1056/NEJMoa0907419.
54. Walz G, Budde K, Mannaa M, et al. everolimus in patients with autosomal dominant polycystic kidney disease [published correction appears in N Engl J Med. 2010 Nov 11;363(20):1977] [published correction appears in N Engl J Med. 2010 Sep 16;363(12):1190]. N Engl J Med. 2010;363(9):830-840. doi:10.1056/NEJMoa1003491.
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2. Kurdi A, Martinet W, De Meyer GRY. mTOR Inhibition and Cardiovascular Diseases: Dyslipidemia and Atherosclerosis. Transplantation. 2018 February;102:2S-1.
3. Mishra S, Charan M, Verma AK, Ramaswamy B, Ahirwar DK, Ganju RK. Racially Disparate Expression of mTOR/ERK-1/2 Allied Proteins in Cancer. Front Cell Dev Biol. 2021;9:601929.
4. Gitto SB, Altomare DA. Recent insights into the pathophysiology of mTOR pathway dysregulation. Res Rep Biol. 2015:6 1–16
5. Mohamed MA, Elkhateeb WA, Daba GM. Rapamycin golden jubilee and still the miraculous drug: a potent immunosuppressant, antitumor, rejuvenative agent, and potential contributor in COVID-19 treatment.
Bioresour Bioprocess. 2022;9:65.
6. Bhaoighill MN, Dunlop EA. Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics. Cancer drug Resist. 2019;2:1069-85.
7. Kwitkowski VE, Prowell TM, Ibrahim A, et al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist. 2010;15:428–435.
8. Becker MA, Hou X, Tienchaianada P, et al. Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. BMC Cancer. 2016;16:814.
9. Chresta CM, Davies BR, Hickson I, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70:288–298.
10. Knechtle SJ, Marson LP, Morris PJ. Kidney Transplantation Principles and Practice. Eighth Edition. Elsevier;2020.261p.
11. Furian L, Baldan N, Margani G, et al. Calcineurin inhibitor-free immunosuppression in dual kidney transplantation from elderly donors. Clin Transplant. 2007;21:57–62.
12. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562-2575. doi:10.1056/NEJMoa067411.
13. Berger SP, Sommerer C, Witzke O, et al. Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study. Am J Transplant. 2019;19(11):3018-3034. doi:10.1111/ajt.15480.
14. Zaza G, Tomei P, Ria P, Granata S, Boschiero L, Lupo A. Systemic and nonrenal adverse effects occurring in renal transplant patients treated with mTOR inhibitors. Clin Dev Immunol. 2013;2013:403280. doi:10.1155/2013/403280.
15. Diekmann F, Andrés A, Oppenheimer F. mTOR inhibitor-associated proteinuria in kidney transplant recipients. Transplant Rev (Orlando). 2012;26(1):27-29. doi:10.1016/j.trre.2011.10.003.
16. Diekmann F. Proteinuria and Mammalian Target of Rapamycin Inhibitors in Renal Transplantation. Trends in Transplant. 2011;5:139-43.
17. Galluzzi L, Bravo-San Pedro JM, Blomgren K, Kroemer G. Autophagy in acute brain injury. Nat. Rev. Neurosci. 2016;17: 467–484.
18. Levy JMM, Towers ChG, Thorburn A. Targeting autophagy in cancer. Nat. Rev. Cancer. 2017;17: 528–542.
19. Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 2015; 16: 461–472.
20. Ballesteros-Álvarez J, Andersen JK. mTORC2: The other mTOR in autophagy regulation. Aging Cell. 2021;20:e13431.
21. Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR: Pathophysiology of cardiac hypertrophy and heart failure: Signaling pathways and novel therapeutic targets. Arch Toxicol. 2015;89: 1401-1438.
22. Gao G, Chen W, Yan M, Liu J, Luo H, Wang Ch, et al. rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling Int J Mol Med. 2020;45: 195-209.
23. Bennett MR. IN-STENT STENOSIS: Pathology and Implications for the Development of Drug Eluting Stents. Heart. 2003;89:218–224.
24. Elezaby A, Dexheimer R, Sallam K. Cardiovascular effects of immunosuppression agents. Front Cardiovasc Med. 2022;9:981838. Published 2022 Sep 21. doi:10.3389/fcvm.2022.981838.
25. Vitiello D, Neagoe PE, Sirois MG, White M. Effect of everolimus on the immunomodulation of human neutrophils inflammatory response and activation. Cell Mol Immunol 2014; in press.
26. Zhu Z, Yang Ch, Iyaswamy A, Krishnamoorthi S, Sreenivasmurthy SG, Liu J, et al. Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson's Disease. Int. J. Mol. Sci. 2019;20, 728.
27. Villa-González M, Martín-López G, Pérez-Álvarez MJ. Dysregulation of mTOR Signaling after Brain Ischemia. Int J Mol Sci. 2022;23(5):2814. Published 2022 Mar 4. doi:10.3390/ijms23052814.
28. Rad E, Murray JT, Tee AR. Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression. Cancers. 2018, 10, 5.
29. Tian T, Li X, Zhang J. mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. Int J Mol Sci. 2019 Feb 11;20(3):755. doi: 10.3390/ijms20030755. PMID: 30754640; PMCID: PMC6387042.
30. Reungwetwattana T, Molina JR, Mandrekar SJ, Allen-Ziegler K, Rowland KM, Reuter NF, et al. Brief report: A phase II "window-of-opportunity" frontline study of the mTOR inhibitor, temsirolimus given as a single agent in patients with advanced NSCLC, an NCCTG study. J. Thorac. Oncol. 2012, 7, 919–922.
31. Cejka D, Preusser M, Woehrer A, Sieghart W, Strommer S, Werzowa J, et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol. Ther. 2008, 7, 1377–1385.
32. Fuereder T, Jaeger-Lansky A, Hoeflmayer D, Preusser M, Strommer S, Cejka D, et al. mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves antitumor activity against gastric cancer in vivo. Cancer Lett. 2010, 296, 249–256.
33. Liao Y, Hou H, Han Z, Liu Y. Systemic therapies for metastatic renal cell carcinoma in the second-line setting: A systematic review and network meta-analysis. Medicine (Baltimore). 2022;101(37):e30333. doi:10.1097/MD.0000000000030333.
34. Massari F, Mollica V. Personalizing immunotherapy for renal cell carcinoma: how far have we come?. Expert Opin Biol Ther. 2022;22(10):1221-1225. doi:10.1080/14712598.2022.2122809.
35. Milowsky MI, Iyer G, Regazzi AM, Al-Ahmadie H, Gerst SR, Ostrovnaya I, et al. Phase II study of everolimus in metastatic urothelial cancer. BJU Int. 2013, 112, 462–470.
36. Seront E, Rottey S, Sautois B, Kerger J, D'Hondt LA, Verschaeve V, et al. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: Clinical activity, molecular response, and biomarkers. Ann. Oncol. 2012, 23, 2663–2670.
37. Bouyahya A, El Allam A, Aboulaghras S, et al. Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy. Cancers (Basel). 2022;14(22):5520. Published 2022 Nov 10. doi:10.3390/cancers14225520.
38. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012, 366, 520–529.
39. Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): A phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015, 16, 816–829.
40. Wang Z, Valera JC, Zhao X, Chen Q, Silvio Gutkind J. mTOR co-targeting strategies for head and neck cancer therapy. Cancer Metast. Rev. 2017, 36, 491–502.
41. Luo C, Ye WR, Shi W, Yin P, Chen Ch, He YB,et al. Perfect match: mTOR inhibitors and tuberous sclerosis complex. Orphanet J Rare Dis. 2022,17:106.
42. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358(2):140–51.
43. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9869):817–24.
44. De Fijter JW. Cancer and mTOR Inhibitors in Transplant Recipients. Transplantation 2018;102: S60–S70.
45. Alberu J, Pascoe MD, Campistol JM, et al. Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation. 2011;92:303–310.
46. Evrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348:1681–91.
47. Salgo R, Gossmann J, Schofer H, et al. Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial. Am J Transplant 2010;10:1385–93.
48. Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013;31:1317–1323.
49. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 352:1317-1323.
50. Majewski M, Korecka M, Joergensen J, et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 2003;75:1710–7.
51. Sang AX, McPherson MC, Ivison GT, et al. Dual blockade of the PI3K/Akt/mTOR pathway inhibits posttransplant Epstein-Barr virus B cell lymphomas and promotes allograft survival. Am J Transplant. 2019;19(5):1305-1314. doi:10.1111/ajt.15216.
52. Novalic Z, van der Wal AM, Leonhard WN, Koehl G, Breuning MH, Geissler EK, et al. Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease. J Am Soc Nephrol. 2012;23:842–53.
53. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363(9):820-829. doi:10.1056/NEJMoa0907419.
54. Walz G, Budde K, Mannaa M, et al. everolimus in patients with autosomal dominant polycystic kidney disease [published correction appears in N Engl J Med. 2010 Nov 11;363(20):1977] [published correction appears in N Engl J Med. 2010 Sep 16;363(12):1190]. N Engl J Med. 2010;363(9):830-840. doi:10.1056/NEJMoa1003491.
55. Qian Q, Du H, King BF, Kumar S, Dean PG, Cosio FG, et al. sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol. 2008;19:631–8.
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