Edition 74 - July 2019 / Subject Review

Subject Review – Ed. 74

Marco A. Rivarola y Alicia Belgorosky. Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina. 

For this issue of Endocrinología Pediátrica On Line, we have selected to comment on the following publication:

 

J Clin Endocrinol Metab. 2019 Jun 1; 104(6):1929-1936.

Effect of Everolimus in Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas. Zhang D1Way JS1Zhang X2Sergey M2Bergsneider M3Wang MB4Yong WH2Heaney AP1,3.

1 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 2 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 3 Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 4 Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Abstract

CONTEXT: Aggressive prolactin (PRL)-secreting pituitary adenomas that are resistant to conventional therapy with dopamine agonists, surgery, and radiation pose a therapeutic challenge. The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved to treat neuroendocrine tumors (NETs), and co-treatment with the somatostatin receptor ligand octreotide improved median progression-free survival in patients with metastatic pancreatic NETs.

PATIENT, INTERVENTION, AND RESULTS: Authors describe off-label everolimus treatment of a prolactinoma (PRLoma) refractory to cabergoline, repeat surgical resection, and radiation therapy in a 68-year-old patient. Addition of everolimus to cabergoline led to decreased PRL levels and tumor regression after 5 months. Tumor size remained stable for 12 months, and although PRL levels rose, they remained below pretreatment levels. Immuno-histochemical (IHC) evaluation of expression of key mTOR pathway drivers of cell proliferation revealed elevated phosphorylated (p-) AKT, p-4EBP1, and p-S6 in the index patient’s tumor. IHC analysis of seven additional PRLomas demonstrated increased expression of nuclear p-AKT, cytoplasmic p-S6, and globally increased p-4EBP1 in the PRLomas compared with 11 autopsy-derived normal pituitary tissues. In in vitro studies in murine mammo-somatotroph tumor GH3 cells, they observed that both the dopamine agonist cabergoline and the mTOR inhibitor everolimus inhibited GH3 cell proliferation and PRL secretion as single agents, and the synergistic effect was noted with combination treatment only on inhibition of PRL secretion but not proliferation.

CONCLUSIONS: In summary, these findings demonstrate that the mTOR pathway is activated in PRLomas and that everolimus exhibits anti-proliferative actions in vitro. Authors suggest that everolimus may be a novel therapeutic option for some aggressive PRL-secreting tumors unresponsive to conventional treatments.

 

Comments extracted from the publication:

Most PRLomas are slow-growing benign tumors. They respond well to medical management with dopamine agonists (DAs) such as cabergoline or bromocriptine with symptom (galactorrhea, menstrual irregularity) control, normalization of prolactin (PRL) levels, and reduction in tumor volume in 80% of cases. A minority of tumors are resistant to DA therapy, defined as the failure to achieve a normal serum PRL level and, 50% tumor shrinkage with maximally tolerated doses of medication.

However, normalization of PRL is achievable in only 8% to 50% of these patients, recurrence rates are high; although radiation therapy can be offered, only one third of patients achieve normalization of serum PRL; the long-term side-effects include hypopituitarism and cognitive impairment.

Activation of the mammalian target of rapamycin (mTOR) pathway and in vitro antiproliferative responses to mTOR inhibitors have been previously reported in pituitary tumors.

In this publication, authors describe a dramatic tumor response in association with a fall in serum PRL to everolimus in a 68-year-old patient, who was refractory to high-dose DA, prior multiple surgical resections, and maximal radiation therapy. So far, his tumor has remained stable, and serum PRL levels have stayed below pretreatment levels across 12 months of everolimus therapy.

 

For better understanding of this report, we have transcribed a brief description of the mTOR pathway.

 

The mTOR Pathway.

Oncol Lett. 2014 Dec; 8(6):2367-2370. mTOR pathway: A current, up-to-date mini-review (Review).

Zarogoulidis P1Lampaki S1Turner JF2Huang H3Kakolyris S4Syrigos K5Zarogoulidis K1.

1, Pulmonary Department-Oncology Unit, G. Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece. 2, Interventional Pulmonary and Critical Care Medicine, Western Regional Medical Center, Goodyear, Arizona 85338, USA. 3, Department of Respiratory Diseases Shanghai Hospital, Second Military University Hospital, Shanghai 210000, P.R. China. 4, Oncology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis 68100, Greece. 5, Oncology Department, Sotiria General Hospital, University of Athens, Athens 11527, Greece.

 

Abstract.

Mechanistic target of rapamycin (mTOR) is a protein serine/threonine kinase that was initially identified as the cellular target of rapamycin. This kinase was subsequently recognized as an important biological regulator. Indeed, this kinase regulates cell growth, proliferation, motility and survival, as well as gene transcription and protein synthesis that are activated in response to hormones, growth factors and nutrients. Results from preclinical studies have indicated that factors antagonizing the mTOR pathway exert an antitumor effect on lung cancer. Furthermore, primary clinical trials of mTOR inhibitors have demonstrated that the inhibitors may be effective against lung carcinoma. The present study explores the association between mTOR and lung carcinogenesis and describes the clinical trials of mTOR inhibitors.

Information related to the previous publication:

mTOR (mechanistic target of rapamycin) is a component of the phosphatidylinositol 3-kinase (PI3K) cell survival pathway. The mTOR pathway ligand-bound activation leads to the activation of PI3K. PI3K subsequently phosphorylates Akt, which is de-phosphorylated by PTEN.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through apoptosis. Evidence suggests that this enzyme also helps control cell migration, adhesion of cells to surrounding tissues, and angiogenesis. Additionally, it plays a role in maintaining the stability of a cell’s genetic information. All of these functions help prevent uncontrolled cell growth that can lead to the formation of tumors. Loss of PTEN is connected with a diminished prognosis in NSCLC (Non-small cell lung cancer, the most common type of lung cancer), likely due to the enhanced downstream signaling of the PI3K/Akt/mTOR pathway. The two mTOR complexes, mTORC1 and mTORC2, are each involved in cell growth.

mTORC1, which consists of mTOR, Raptor, GβL (mammalian lethal with SEC13 protein 8) and domain-containing mTOR-interacting protein (DEPTOR), is partially inhibited by rapamycin; it unifies multiple signals that indicate the availability of growth factors, nutrients and energy in order to promote cellular growth and catabolic processes during stress. Growth factors and hormones, such as insulin, use Akt to signal mTORC1, which inactivates tuberous sclerosis complex 2 to prevent inhibition of mTORC1. Active mTORC1 exerts numerous downstream biological effects, including the translation of mRNA by phosphorylating downstream targets, such as 4E-BP1 and p70 S6 kinase, the suppression of autophagy, ribosome biogenesis, and activation of transcription that leads to increased mitochondrial activity.

mTORC2, which consists of mTOR, Rictor, GβL, Sin1, PRR5/Protor-1 and DEPTOR, promotes cell survival through the activation of Akt. mTORC2 regulates cytoskeletal dynamics, and ion transport and growth, by activating PKCα and phosphorylating SGK1, respectively. mTOR is a downstream target of EGFR and MET signaling, and is therefore considered to be a therapeutically attractive target for the treatment of various types of cancer.

Other interesting factors are the members of the serum- and glucocorticoid-regulated kinase (SGK) family. This family consists of three members, SGK1, SGK2 and SGK3, all displaying serine/threonine kinase activity and sharing structural and functional similarities with the AKT family of kinases. SGK1 was originally described as a key enzyme in the hormonal regulation of several ion channels and pumps. Over time, growing and impressive evidence has been accumulated, linking SGK1 to the cell survival, de-differentiation, cell cycle control, regulation of caspases, response to chemical, mechanical and oxidative injury in cancer models, as well as to the control of mitotic stability. Much evidence shows that SGK1 is over-expressed in a variety of epithelial tumors. More recently, many contributions to the published literature demonstrate that SGK1can mediate chemo-and radio-resistance during the treatment of various human tumors,

 

ADITIONAL INFORMATION TAKEN FROM WIKIPEDIA (June 2019):

Rapamycin arrests fungal activity at the G1 phase of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in T-lymphocytes. It is used as an immunosuppressant following organ transplantation. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit T-cell receptor (TCR) and IL-2 receptor signaling pathways, respectively. The two natural products were used to discover the FK506- and rapamycin-binding proteins, including FKBP12, and to provide evidence that FKBP12–FK506 and FKBP12–rapamycin might act through gain-of-function mechanisms that target distinct cellular functions. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK506 and rapamycin behave as reciprocal antagonists. These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade.

In 1991, calcineurin was identified as the target of FKBP12-FK506. That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993, followed by studies in 1994, when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues. Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2), in studies published in October 1993.

The protein now called mTOR was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini. FRAP1 was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein. In homage to the original discovery of the TOR protein in yeast that was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1991 in Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German. Similarly, with subsequent discoveries, the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed to mTOR, which stands for a mechanistic target of rapamycin.

The discovery of mTOR opened the door to the molecular and physiological study of the mTOR pathway. It had a catalytic effect on the growth of the field of chemical biology of small molecules.

FUNCTIONS OF THE mTOR PATHWAY

mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids. mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and it is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers. Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12. The FKBP12–rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.

The mTOR Complex 1 (mTORC1) functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., l-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress.

The mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR (RICTOR), MLST8, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1). mTORC2 has been shown to function as an important regulator of the actin cytoskeleton  mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival. Phosphorylation of Akt’s serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1 and leads to full Akt activation. In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates the insulin-like growth factor 1 receptor (IGF-IR) and insulin receptor (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR.

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin.

The serum- and glucocorticoid-regulated kinase (SGK) family consists of three members, SGK1, SGK2 and SGK3, all displaying serine/threonine kinase activity and sharing structural and functional similarities with the AKT family of kinases. SGK1 was originally described as a key enzyme in the hormonal regulation of several ion channels and pumps. Over time, growing and impressive evidence has been accumulated, linking SGK1 to the cell survival, de-differentiation, cell cycle control, regulation of caspases, response to chemical, mechanical and oxidative injury in cancer models as well as to the control of mitotic stability. Much evidence shows that SGK1 is over-expressed in a variety of epithelial tumors. More recently, many contributions to the published literature demonstrate that SGK1can mediate chemo-and radio-resistance during the treatment of various human tumors.


Posted in Edition 74 - July 2019, Subject Review
Previous Editions
Images
Instructivo para mandar imágenes
CLICK AQUI
RSS Feed