The Role of PI3K/AKT/mTOR Inhibitors in the Treatment of Hematological Malignancies

The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases—either alone or in combination with other treatment regimens. This review highlights experimental evidence underlying the molecular mechanisms of mTOR inhibitors and summarizes their evolving role in the treatment of hematologic disease, including leukemia, lymphoma, myeloma, immune hemocytopenia, and graft-versus-host disease (GVHD). Based on data presented in this review, we believe that mTOR inhibitors are becoming a trusted therapeutic in the clinical hematologist’s toolbelt and should be considered more routinely in combination therapy for the management of hematologic disease.

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Potential role of vitamin D in restoring sensitivity to mTOR inhibitors in hepatocellular carcinoma (HCC): 1,25(OH)vitamin D (VitD) reverts everolimus (EVE) resistance in a hcc cell line

Endocrine Abstracts ◽

10.1530/endoabs.49.ep786 ◽

2017 ◽

Author(s):

Claudia Pivonello ◽

Donatella Paola Provvisiero ◽

Mariarosaria Negri ◽

Gilda Di Gennaro ◽

Angelis Cristina de ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Vitamin D ◽

Cell Line ◽

Potential Role ◽

Mtor Inhibitors

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Bifunctional Role of Kruppel-Like Factor 4 in Hematological Malignancies

Forum on Immunopathological Diseases and Therapeutics ◽

10.1615/forumimmundisther.2016017234 ◽

2016 ◽

Vol 7 (1-2) ◽

pp. 141-151

Author(s):

Mario Morales-Martinez ◽

Luz A. Franco-Cea ◽

Liliana Moreno Vargas ◽

Otoniel Martinez-Maza ◽

Sara Huerta-Yepez ◽

...

Keyword(s):

Hematological Malignancies

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Defining the Role of Autophagy Kinase ULK1 Signaling in Therapeutic Response of Tuberous Sclerosis Complex to mTOR Inhibitors

10.21236/ada604191 ◽

2014 ◽

Author(s):

Reuben J. Shaw

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Therapeutic Response ◽

Mtor Inhibitors

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Should the BCRA1/2-mutations healthy carriers be valid candidates for hematopoietic stem cell donation?

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00179-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Alberto Fresa ◽

Simona Sica

Keyword(s):

Hematological Malignancies ◽

Conditioning Regimen ◽

Stress Factors ◽

Brca Mutations ◽

Hematopoietic Stem ◽

Mutational Status ◽

Stem Cell Donation ◽

Radiation Treatments ◽

Healthy Carriers

AbstractIt’s still not clear whether the mutational status of BRCA-mutated healthy hematopoietic stem cells (HSCs) donors could have an impact on the engraftment. Comparing the studies present in literature, we focused on the correlation between BRCA mutations and the development of hematological malignancies and Fanconi anemia (FA); then, we explored HSCs types, frequencies, and functions in the presence of BRCA mutations, as well as the reconstitution of hematopoiesis after chemotherapy and radiation treatments. The role of BRCA mutations in the FA showed a possible involvement in the onset of the disease; the mutation carriers, indeed, did not show any sign of the typical phenotype of the FA. BRCA mutational status can be considered as a risk factor for hematological malignancies, but only for secondary malignancies and/or in the presence of bone marrow stress factors. Currently we don’t know if a conditioning regimen could be compensated by BRCA mutated HSCs, even if murine models tried to show the possible differences between fully mutated, haploinsufficient and normal HSCs. Thus, given the downregulating effect of the mutations on hematopoiesis, it could be questionable to use the HSCs of a BRCA-mutated donor in the presence of another available donor with the same compatibility.

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The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures

Scientific Reports ◽

10.1038/s41598-021-87930-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Elieser Hitoshi Watanabe ◽

Fernando Morbeck Almeida Coelho ◽

Hilton Leão Filho ◽

Bruno Eduardo Pedroso Balbo ◽

Precil Diego Miranda de Menezes Neves ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Blood Vessels ◽

Tuberous Sclerosis Complex ◽

Hounsfield Unit ◽

Mtor Inhibitors ◽

Volume Reduction ◽

Tumor Reduction ◽

Vascular Structures ◽

Remarkable Reduction

AbstractRenal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

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Maximizing the clinical outcome with mTOR inhibitors in the renal transplant recipient: defining the role of calcineurin inhibitors

Transplant International ◽

10.1007/s00147-004-0716-5 ◽

2004 ◽

Vol 17 (6) ◽

Author(s):

Bj�rn Nashan

Keyword(s):

Renal Transplant ◽

Clinical Outcome ◽

Transplant Recipient ◽

Renal Transplant Recipient ◽

Calcineurin Inhibitors ◽

Mtor Inhibitors

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The role of MOZ/KAT6A in hematological malignancies and advances in MOZ/KAT6A inhibitors

Pharmacological Research ◽

10.1016/j.phrs.2021.105930 ◽

2021 ◽

pp. 105930

Author(s):

Jingtian Su ◽

Xuan Wang ◽

Yuwei Bai ◽

Moran Sun ◽

Yongfang Yao ◽

...

Keyword(s):

Hematological Malignancies

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OVERVIEW ON ASSOCIATION OF DIFFERENT TYPES OF LEUKEMIAS WITH RADIATION EXPOSURE

Experimental Oncology ◽

10.31768/2312-8852.2015.37(2):89-93 ◽

2015 ◽

Vol 37 (2) ◽

pp. 89-93 ◽

Cited By ~ 5

Author(s):

D F Gluzman ◽

L M Sklyarenko ◽

M Zavelevich ◽

S V Koval ◽

T Ivanivskaya ◽

...

Keyword(s):

Radiation Exposure ◽

Hematological Malignancies ◽

Causative Factor ◽

World Health ◽

Lymphoid Tissues ◽

Different Types ◽

Large Populations ◽

Precise Diagnosis ◽

Health Organization

Exposure to ionizing radiation is associated with increasing risk of various types of hematological malignancies. The results of major studies on association of leukemias and radiation exposure of large populations in Japan and in Ukraine are analyzed. The patterns of different types of leukemia in 295 Chernobyl clean-up workers diagnosed according to the criteria of up-to-date World Health Organization classification within 10–25 years following Chernobyl catastrophe are summarized. In fact, a broad spectrum of radiation-related hematological malignancies has been revealed both in Life Span Study in Japan and in study of Chernobyl clean-up workers in Ukraine. The importance of the precise diagnosis of tumors of hematopoietic and lymphoid tissues according to up-to-date classifications for elucidating the role of radiation as a causative factor of leukemias is emphasized. Such studies are of high importance since according to the recent findings, radiation-associated excess risks of several types of leukemias seem to persist throughout the follow-up period up to 55 years after the radiation exposure.

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