Cancer prevention with rapamycin
ABSTRACT
Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.
Introduction
The mTOR (Target of Rapamycin) pathway is involved in both cancer and aging. Furthermore, common cancers are age-related diseases, and their incidence increases exponentially with age. Rapamycin (sirolimus) and other rapalogs (temsirolimus, everolimus) may delay cancer by targeting directly pre-cancerous cells and by slowing down organism aging.
Figure 2: Rapamycin prevents cancer by slowing tumor progression (hypothetical schema). (A) Rapamycin slows tumor progression and delays cancer and death from cancer. (B) Rapamycin slows tumor progression and delays cancer. A person dies from another cause (e.g., cardiovascular disease, CVD) before cancer developed.
Cancer prevention in humans
Solid organ (kidney, liver, lung, heart) transplantation is associated with increased risk of cancer and especially of non-melanoma skin cancer.
Starting from 2004, numerous studies demonstrated that rapamycin and everolimus reduced the incidence of various cancers in organ transplant patients [26–34].
For example, Mathew et al. showed that Sirolimus (rapamycin) protected renal transplant patients from skin cancer even when given in combination with CsA (CsA increases incidence of skin cancer) [26].
Kauffman et al. also demonstrated that sirolimus and everolimus treatment is associated with a significantly decreased risk of any de novo malignancy and non-skin solid malignancy [27].
Piselli et al. also found that use of mTOR inhibitors significantly reduced the risk (by 46%) of all cancers combined [30].
mTOR inhibition was associated with a reduced risk of basal cell carcinoma of the skin after kidney transplantation [31]. Rapamycin (sirolimus) treatment was associated with decreased incidence of lymphoproliferative disorder after heart transplantation [34].
Rapamycin slows aging, thus delaying cancer further
Rapamycin can delay cancer not only by targeting precancerous/cancerous cells directly, but also by slowing down organismal aging [49]. It is theoretically predictable that rapamycin delays age-related diseases in part by slowing aging [50]. Certainly, rapamycin extends lifespan in other ways beyond preventing cancer.
In several dozen murine models, rapamycin robustly and reproducibly delays cancer and, in some cases, prevents cancer over a lifetime. It was repeatably proposed that clinical trials in high-risk populations are warranted. A decade-long treatment with rapamycin may be employed to prevent lung cancer in smokers and former smokers. However, decades-long trails are unlikely to be started in the near future. Accidental data on the use of rapamycin (Sirolimus) and everolimus in organ-transplant patients is consistent with their cancer-preventive effects. However, in these patients, their use in combination with other immunosuppressants makes interpretations difficult.
The experience of treatment of cancer patients with mTOR inhibitors is also in agreement with their cancer-preventive effects. Although rapalogs do not cure cancer and infrequently cause remission, they can slow down progression even in advanced tumors, and this activity is sufficient for cancer prevention. Also, long-term treatment with rapamycin slows down aging, a major risk factor for cancer (Figure 3). Notably, delaying cancer is form of cancer prevention. Consider a scenario: rapamycin delays cancer for 2 years, during which this person dies from myocardial infarction (Figure 2). In this case postponing cancer is cancer prevention.
View: https://www.youtube.com/watch?v=E8Md8yboSB0
ABSTRACT
Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.
Introduction
The mTOR (Target of Rapamycin) pathway is involved in both cancer and aging. Furthermore, common cancers are age-related diseases, and their incidence increases exponentially with age. Rapamycin (sirolimus) and other rapalogs (temsirolimus, everolimus) may delay cancer by targeting directly pre-cancerous cells and by slowing down organism aging.
Figure 2: Rapamycin prevents cancer by slowing tumor progression (hypothetical schema). (A) Rapamycin slows tumor progression and delays cancer and death from cancer. (B) Rapamycin slows tumor progression and delays cancer. A person dies from another cause (e.g., cardiovascular disease, CVD) before cancer developed.
Cancer prevention in humans
Solid organ (kidney, liver, lung, heart) transplantation is associated with increased risk of cancer and especially of non-melanoma skin cancer.
Starting from 2004, numerous studies demonstrated that rapamycin and everolimus reduced the incidence of various cancers in organ transplant patients [26–34].
For example, Mathew et al. showed that Sirolimus (rapamycin) protected renal transplant patients from skin cancer even when given in combination with CsA (CsA increases incidence of skin cancer) [26].
Kauffman et al. also demonstrated that sirolimus and everolimus treatment is associated with a significantly decreased risk of any de novo malignancy and non-skin solid malignancy [27].
Piselli et al. also found that use of mTOR inhibitors significantly reduced the risk (by 46%) of all cancers combined [30].
mTOR inhibition was associated with a reduced risk of basal cell carcinoma of the skin after kidney transplantation [31]. Rapamycin (sirolimus) treatment was associated with decreased incidence of lymphoproliferative disorder after heart transplantation [34].
Rapamycin slows aging, thus delaying cancer further
Rapamycin can delay cancer not only by targeting precancerous/cancerous cells directly, but also by slowing down organismal aging [49]. It is theoretically predictable that rapamycin delays age-related diseases in part by slowing aging [50]. Certainly, rapamycin extends lifespan in other ways beyond preventing cancer.
- Rapamycin delays numerous age-related diseases other than cancer. For example, rapamycin (sirolimus) or its analog (everolimus) attenuate atherosclerosis in rabbits [51], mice [52] and humans [53]. Thus, a prospective randomized trial showed that rapamycin (sirolimus) decreased carotid atherosclerosis in organ-transplant patients [53].
- Rapamycin extends lifespan in species that do not have cancer: the C. elegans worm [54], the freshwater cnidarian Hydra [55], and Daphnia magna [56]. Rapamycin also extends the lifespan of yeast [57].
- A brief treatment with rapamycin very early in life extends lifespan in mice [56, 58, 59]. There are no pre-cancer cells so early in life, and the treatment with rapamycin is brief. One explanation is that by re-programming development-driven aging, rapamycin retards aging and therefore delays cancer [20].
- Rapamycin slows geroconversion (acquisition of the senescent phenotype) in mammalian cells. First, geroconversion may be linked to organism aging [60]. Second, senescent stroma stimulates tumor growth [61–63]. Reversing the aging stromal phenotype with rapamycin prevents carcinoma initiation [61], and rapamycin suppressed the ability of senescent fibroblasts to stimulate tumor growth in mice [64, 65].
In several dozen murine models, rapamycin robustly and reproducibly delays cancer and, in some cases, prevents cancer over a lifetime. It was repeatably proposed that clinical trials in high-risk populations are warranted. A decade-long treatment with rapamycin may be employed to prevent lung cancer in smokers and former smokers. However, decades-long trails are unlikely to be started in the near future. Accidental data on the use of rapamycin (Sirolimus) and everolimus in organ-transplant patients is consistent with their cancer-preventive effects. However, in these patients, their use in combination with other immunosuppressants makes interpretations difficult.
The experience of treatment of cancer patients with mTOR inhibitors is also in agreement with their cancer-preventive effects. Although rapalogs do not cure cancer and infrequently cause remission, they can slow down progression even in advanced tumors, and this activity is sufficient for cancer prevention. Also, long-term treatment with rapamycin slows down aging, a major risk factor for cancer (Figure 3). Notably, delaying cancer is form of cancer prevention. Consider a scenario: rapamycin delays cancer for 2 years, during which this person dies from myocardial infarction (Figure 2). In this case postponing cancer is cancer prevention.
View: https://www.youtube.com/watch?v=E8Md8yboSB0
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