The mammalian target of rapamycin or mTOR is gaining a lot of attention due to its profound effect on the growth phase of cells. When we eat, we are increasing mTOR production, which directs cell proliferation, growth, and repair. Likewise, mTOR decreases in times of stress such as caloric restriction (in normal cells). When mTOR is decreased, autophagy is increased. Autophagy or "eating of self" is a process by which cells perform self-degradation in times of stress in order to balance energy. This "cleanse" removes irregular proteins, organelles, and pathogens from within the cell. It appears that autophagy plays a major role in disease prevention including cancer, heart, liver, brain, autoimmune, and infectious diseases. Please see an interesting review by Glick, et al in the Journal of Pathology at the NCBI online. Importantly, certain cancers, through multiple genetic alterations, can activate mTOR, even in times of stress. Notably, in breast cancer, mTOR is an important mechanism of resistance to estrogen therapy.
What exactly does mTOR do at the cellular level?
mTOR is a serine/threonine kinase and member of the phosphatidylinosital 3-kinase (PI3K)-related kinase family. It is an important signal integrator that activates the biosynthesis of proteins and lipids as well as the growth factor mediated cell cycle transition from the G1 to S phase. This is what causes cell growth and proliferation.
There are 2 complexes that make up mTOR. The mTOR cellular complex 1 (mTORC1) is inhibited by cellular stress such as hypoxia, nutrient deprivation, and DNA damage in normal cells. However, in cancer cells, mTORC1 appears to be more acutely sensitive to rapamycin. mTORC2 appears to play a vital role in the activity of SGKs (serum and glucocorticoid-induced protein kinases), which are members of the AGK family of kinases whose activity is stimulated by growth factors and other agonists. It does this, in part, by supporting ENaC (epithelial sodium channel). It is not as acutely sensitive to rapamycin (mTOR inhibition).
When mTOR is overactive such as in states of excess nutrition or, even as a heritable trait, the risk of diseases such as depression, neurodegeneration, type 2 diabetes (due to reduced insulin sensitivity), obesity, and cancer increases. It also increases angiogenesis, intestinal inflammation (through Th1 and Th17 immunity), and glycolysis. Glycolysis causes a proliferation in T cell expansion, which increases immune activity. Reduced glycolysis causes and increase in T regulatory cells, which reduces the inflammatory response. As an aside, the mTOR pathway is profoundly more complicated than what I have attempted to summarize above. Please also see mTOR Pathways in Cancer and Autophagy in Vol 10, iss 1 of Cancers for more information.
Everolimus binds to an intracellular molecule called FKBP12 and forms a complex that inhibits mTOR. Therefore, it has garnered much interest of late in cancer treatment. In fact, Affinitor (the trade name for everolimus) is now approved for the treatment of adults with advanced renal cell carcinoma. There is a nice review of mTOR function and the impact of inhibitors such as sirolimus (a.k.a. rapamycin) and everolimus on metastatic breast cancers by Royce and Osman in Breast Cancer.
There are several trials evaluating the effects of Everolimus in stage IV breast cancer. The BOLERA-2 study showed a 4 month increase in disease free survival in patients with metastatic receptor-positive breast cancer when everolimus was used in combination with exemestane. Unfortunately, updated results did not reveal a significant increase in overall survival but there appeared to be some benefit. When given with tamoxifen, stage IV patients in the TAMRAD trial achieved a 4 month increase in disease free survival. Stage IV who progressed despite aromatase inhibitors were given everolimus and fulvestrant in the BRE-43 trial and experienced some improvement in disease free survival. See summary of trial at the PubMED.
Unfortunately, outcomes for patients with stage IV TNBC are less exciting. Please see a randomised neoadjuvant phase II study of 50 TNBC patients evaluating the addition of everolimus to standard neoadjuvant chemotherapy at the Annals of Oncology online. Pathologic complete response (pCR) did not significantly improve (pCR 25.9% without everolimus versus 30.4% with everolimus at 12 weeks, p=0.76) and mTOR inhibition did not correlate with response. The study did illustrate that serious adverse events (grade 3 and 4) were slightly but not significantly worse than chemotherapy alone with the exception of one case of grade 3 pneumonitis that responded to dose reduction. In addition, pCR was not demonstrated to be worse. The big question now is what was the overall outcome for these patients?
I wouldn't overlook the use of mTOR inhibition in early stage TNBC, however. What makes mTOR interesting for TNBC patients is potentially multifactorial. mTOR activation may be associated with increased testosterone Kanno, et. al. in the J. of ToxicologyYue, et. al. in Anticancer Research (and, subsequently, muscle mass and acne). Many triple negative tumors express testosterone and anti-androgen therapy is being explored as a potential therapy for patients with TNBC. In addition, mTOR activation may allow disseminated tumor cells to survive in a dormant state. By inhibiting this pathway, everolimus may help to reduce recurrence despite having no effect in cells that have metastasized (stage IV). Please see the closing remarks by Dr. DeMichele in slide 16 of the 23rd Life After Breast Cancer Conference at the Abramson Cancer Clinic. Information for the PENN-SURMOUNT, CLEVER, and related trials are available on the link.
A landmark trial worth mentioning is the phase III trial published in the New England Journal of Medicine by Dr. Halle Moore, et. al., Goserelin for Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy. 218 pre-menopausal women with ER-receptor negative disease were randomized to receive chemotherapy alone or with Goserelin (which, simply put, inhibits the production of estrogen, progesterone, and testosterone after around 21 days of treatment). In addition to preserving fertility, the disease-free survival and overall survival in these patients improved by about 50%. The study needs to be repeated and long term results reported as this secondary end point was unexpected. I'm anxiously awaiting for this to be done!
For the following section below, please also refer to selfhacked.com, where Joseph Cohen provides a summary of mTOR with resources.
What natural substances activate mTOR?
Excess calories, excess carbohydrates, protein (especially leucine), insulin, IGF-1, IL-6 (S, S2, Ghrelin, Leptin, oxygen, thyroid stimulating hormone (which is reduced by taking thyroid hormone) orexin, testosterone, and exercise (see sources below).
What substances or activities inhibit mTOR?
Protein restriction, caloric restriction, ketogenic diets, exercise (S, S2), steroids, metformin (S, S2), N-acetyl cysteine, resveratrol (see below: found in red grapes, red wine, etc.), aspirin and other COX-2 inhibitors, omega-3 fatty acids, extra virgin olive oil, curcumin, tea/EGCG (see below), caffeine, alcohol, pomegranate, reishi mushrooms, milk thistle (see below), oleanic acid, R-lipoic acid, fisetin, apigenin, quercetin, genistein, ursolic acid, anthocyanins, rhodiola, carnosine, strawberries, and others.
Milk thistle and strawberries
Milk thistle seeds have been used for over 2,000 years by European cultures to help protect the liver from toxins. The active compounds, collectively called silymarin, are the flavonoids silibinin, silidianin, and silcristin. In addition and, likely, via its anti-inflammatory effects, silymarin and silibinin are increasingly recognized as having anti-cancer activity. Much like green tea, grapes, berries, and curcumin, milk thistle inhibits the mammalian target of rapamycin (or mTOR). In fact, strawberries have gained recent fame for their effects on cancer. Please see the Randomized Phase II Trial of Lyophilized Strawberries in Patients with Dysplastic Precancerous Lesions of the Esophagus where 60 grams (the equivalent of about 2 bags of freeze-dried strawberries at the store) of freeze-dried strawberry powder daily for 6 months reduced esophageal dysplasia (pre-cancerous cells). See also the Study on Mice Demonstrates the Action of Strawberries Against Breast Cancer where European and Latin American scientists found a decrease in breast cancer tumor size in mice treated with a diet that was 15% strawberries.
What questions do we need to be asking for TNBC survivors now?
Firstly, what role do dormant tumor cells play in patients with early stage TNBC (and breast cancer in general) and, secondly, are these cells different from the primary tumor? If so, can different treatments (such as mTOR inhibitors) target DTCs even though responses are not so impressive for the primary tumor or stage IV disease?
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