This paper seems on the surface a massive “promo piece” for eRapa. The authors are massively conflicted.
“The University of Texas Health Science Center at San Antonio has been awarded a patent, U.S. Patent Application No. 13/128,800, by inventors Zelton Dave Sharp and Randy Strong, for an encapsulated rapamycin formulation used in this paper.”
I also take issue with their model of rapamycin and it’s impact on hallmarks of aging, especially cancer. I assume they are implicitly referencing prevention vs treatment. It’s interesting they call out “adult cancer” and not cancer in general. I guess the general thinking is we’re not going to give children rapamycin prophylactically as a longevity intervention.
A review of the HUMAN literature on sirolimus use (therapeutic dosing) is not so cut and dry like many of the cancer prone murine models.
Can Rapamune cause cancer?
“Although rare, it’s possible. Rapamune has a boxed warning Trusted Source for increased risk of certain cancers, as well as infections, due to a weakened immune system. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). Studies of Rapamune reported a few instances of lymphoma (cancer of the lymph system) and skin cancer occurring.”
https://labeling.pfizer.com/showlabeling.aspx?id=139
“Increased susceptibility to infection and the possible development of lymphoma and other malignancies (particularly of the skin) may result from immunosuppression (5.1). Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Rapamune for prophylaxis of organ rejection in patients receiving renal transplants.
“13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.”
Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data (2014)
“To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus”
Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis (2015)
“Twenty RCTs and two observational studies were eligible for meta-analysis, including 39,039 kidney recipients overall. After excluding NMSCs, there was no overall association between sirolimus and incidence of other cancers (IRR = 1.06, 95% CI = 0.69–1.63). However, sirolimus use had associations with lower kidney cancer incidence (IRR = 0.40, 95% CI = 0.20–0.81), and higher prostate cancer incidence (IRR = 1.85, 95% CI = 1.17–2.91). A decrease in the overall cancer incidence with use of Sirolimus [outcomes improve to ~26% decrease in cancer rates when prostate cancer was excluded], suggesting that Sirolimus use may be beneficial in the “high cancer-risk” patients”
“This data is exemplified in our Kaplan–Meier survival curves which show that 10–12 years following transplantation, cancer-free survival is improved in patients maintained on Sirolimus. It should be noted that patient survival is equivalent for this length of time, but cancer-related mortality is increased in patients maintained on steroids when compared with sirolimus patients [Table 3]. Therefore, the effects of Sirolimus use may compound over time, allowing for improved cancer-free survival but also delaying the development of cancer and improving cancer-related outcomes. Given these findings, we may begin to see improvements in patient survival 15 and 20 years following initiation of Sirolimus compared to their steroid-based cohorts. Finally, previous studies have determined that sirolimus-based regimens are associated with increased patient, non-cancer mortality [32]. The increased risk of mortality on Sirolimus-exposed patients [HR 1.4–1.7] appears to have resulted from increases in cardiovascular risk as well as infectious complications. An inherent weakness of our study is the use of a historical control cohort consisting of patients transplanted in 2002 and maintained on chronic steroids. It is possible that the differences in outcomes from our two groups may be unrelated to either Sirolimus or steroid exposure over time”
Sirolimus use improves cancer-free survival following transplantation: A single center 12-year analysis (2020)
“From 2003 to 2015, 563 kidney transplant recipient had steroids discontinued by post-operatively and maintained on Sirolimus, Tacrolimus [Tac], and Mycophenolate Mofetil [MMF]. We compared cancer-related outcomes with that of our 65 historical controls (chronic steroids) maintained on Tac, MMF and steroids. Maintenance immunosuppression protocols were Sirolimus (8–10 ng/ml, 24h trough on daily dosing). Patients maintained on chronic immunosuppression with Sirolimus developed statistically-significant lower levels of post-transplant lymphoproliferative disease (PTLD, 5.88% vs. 0.5%; p < 0.05) with no difference in rates of other post-transplant malignancies. Cancer-free survival as well as cancer-free mortality were also improved 10–12 years post-transplant (p = 0.05, p < 0.05). However, long-term patient survival was equivalent in both cohorts (p = 0.22). Patients were followed up to 12 years post-transplantation and monitored for new cancer diagnoses. For skin, breast, cervical, urothelial, and prostate cancers, the prevalence of post-transplant diagnoses were statistically equivalent between the standard [steroid-based] and SBP groups (p > 0.05). The greatest difference in post-transplant cancer diagnoses between the groups was observed in the PROSTATE cancer category, with an increase in diagnoses within the sirolimus group (0% vs.1.76% p = 0.27, Table 3). There is some precedence in the literature for reporting increased risks of prostate cancer in sirolimus-based immunosuppression regimens at 6 months to 5 years post-transplantation [10,11]. While our data shows increased prostate cancer diagnoses in the sirolimus group, this difference is not statistically significant 12 years post-transplantation. However, our 12-year follow-up data did demonstrate a statistically significant difference in the rates of post-transplant lymphoproliferative disorder (PTLD) in the control [steroid-based] vs. SBP groups (5.88% vs. 0.5%, respectively, p < 0.05, Table 3). Additionally, the rate of cancer-related mortality in the sirolimus-based group was also found to be significantly lower (2.94% vs. 0.025%, p = 0.01).”
But are transplant studies good for HEALTHY persons translation???
Regulatory T cells and cancer: an undesired tolerance (2014)
“The incidence of cancer is markedly increased in organ transplant patients. An excess risk of cancer is constantly observed after solid-organ transplantation. A cancer rate similar to that of people 20–30 years older without transplants portrays the importance of the problem. A cancer-related immune phenotype is associated with kidney transplant recipients. More precisely, regulatory T cell (Treg) expansion, a lower B-cell proportion with a larger sub-population of memory B cells, and a higher proportion of CD3+ γδ T cells in cancer patients. Treg expansion had not only the best predictive value for cancer occurrence but also predicted cancer recurrence, correlated with histological grading, and reversed after cancer resection. Although these results have important implications for monitoring and therapeutics, they also raise several questions concerning the nature of these cells, their related prognosis, the effects of immunosuppressive drugs, and subsequent implications for treatment.”
Cancer Risks in Solid Organ Transplant Recipients: Results from a Comprehensive Analysis of 72 Cohort Studies (2020)
“Compared with the general population, solid organ transplant recipients displayed a 2.68-fold cancer risk standard incident ratio (SIR 2.68); renal transplant recipients displayed a 2.56-fold cancer risk, liver transplant recipients displayed a 2.45-fold cancer risk, heart and/or lung transplant recipients displayed a 3.72-fold cancer risk. The increased cancer risk of solid organ transplant recipients is associated with tumour mutation burden, suggesting that iatrogenic immunosuppression may contribute to the increased cancer risk in transplant recipients.”
Organ Transplant and Skin Cancer Risk
“Organ transplant patients (MAC: on chronic sirolimus) are at a higher risk — up to a 100-fold higher — for developing skin cancer compared to the general population. Transplant patients tend to develop a skin cancer called squamous cell carcinoma and Kaposi sarcoma. Many patients also develop a skin cancer called basal cell carcinoma and melanoma. This higher risk is caused by IMMUNOSUPPRESSIVE medications, which are essential to transplant patients to prevent graft rejection and optimize graft survival. Because these medications suppress the immune system that fights off infection and prevents the development of cancer, transplant recipients are at elevated risk for infection and CERTAIN CANCERS.”
These real world human clinical data are quite sobering. Even long term THERAPEUTIC dosing Sirolimus use (10X+ higher than typical longevity rapamycin users 5 mg/week +/-) is not associated with significant improvement in cancer rates reduction (in transplant cohorts), all cause mortality reduction, although lower rates of certain cancer specific mortality, but higher than others?
But do these trials patients TRULY represent good “healthy” controls? It’s impossible to tease out, as immunosuppression is a fundamental treatment paradigm. But then, why would we expect HEALTHY persons taking chronic therapeutic dosing to have different cancer rates IF the immunosuppression is the underlying reason for the INCREASED cancer burden?
“Immunosuppressive drugs have the potential to cause immunodeficiency, which can increase susceptibility to opportunistic infection and DECREASE cancer immunosurveillance”
Sirolimus after kidney transplantation (2014)
https://www.researchgate.net/publication/268879875_Sirolimus_after_kidney_transplantation
“An uncertain future for sirolimus and other mTOR inhibitors The risk of cancer is increased after kidney transplantation and is predominantly attributed to oncogenic immunosuppression. It is a leading cause of death for kidney allograft recipients, and analyses of transplant registry data suggest that mortality related to cancer is on the increase”
The human clinical data does not appear to fully support the mice rapamycin longevity data translation, but MANY confounders. And when one additionally factors the far lower intermittent weekly doses, the absolute translation benefit becomes quite difficult to quantify as it relates to cancer (the mice longevity data we are using for translation).
In this washout period, immunosuppression is probably my biggest concern on restart. One thought is to restart with similar very high (or higher) IM+IN dose to get a huge spike (100 ng/mL+) cMAX in tissue levels, most especially blood brain barrier penetration, huge mTORC1 inhibition pulse, but then letting sirolimus washout before next dose, to reduce mTORC2 inhibition, and immunosuppression before next dose. I will let the labs dictate, but for example, 4 weeks before next dose.
Regarding rapamycin and BBB penetration. Very clearly, one needs a relatively very high dose to penetrate.
Interpreting Mammalian Target of Rapamycin and Cell Growth Inhibition in a Genetically-Engineered Mouse Model of Nf1-Deficient Astrocytes (2011)
“Rapamycin was administered at the indicated doses (2 mg/kg, 5 mg/kg, or 20mg/kg) by daily intraperitoneal (i.p) injections of rapamycin dissolved in ethanol (5 days per week for 2 weeks total). Brain rapamycin levels are exponentially correlated with blood rapamycin levels. One of the major obstacles in translating preclinical drug studies to human clinical trials is a relative paucity of reported blood and target tissue drug levels. These observations demonstrated that intraperitoneal rapamycin administration increases both blood and brain levels. However, brain rapamycin levels were exponentially correlated with blood rapamycin levels”
“Phospho-S6 is not a reliable biomarker of rapamycin inhibition in the brain. No significant phospho-S6 reduction was observed at the 2mg/kg/day rapamycin dose. Similar to S6 activation, 4EBP1 phosphorylation was unchanged at the 2mg/kg/day dose, whereas significant reductions were observed both at 5 and 20mg/kg/day rapamycin doses. Collectively, these data demonstrate that inhibition of mTOR downstream signaling in the brain requires AT LEAST 5mg/kg/day rapamycin treatment”. To determine whether AKT activation was seen in the brain following rapamycin treatment, we measured AKT Ser473 phosphorylation in vivo, and found a 4-fold increase in AKT activation at 5mg/kg/day, but not at 2 or 20mg/kg/day. These results suggest that AKT activation might counteract the growth suppressive effects of rapamycin mediated mTOR inhibition. Collectively, these results suggest that effective brain glial cell growth inhibition by rapamycin REQUIRES DOSES that inhibit BOTH TORC1 (S6; 4EBP1, and STAT3) and TORC2 (AKT) downstream pathways.”
And this paper, which delivered rapamycin levels in the brain, showed cognitive improvements in wild type mice.
Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice (2012)
“Mice were fed chow containing microencapsulated rapamycin in the chow resulting in an average dose of 2.24 mg rapamycin per kg body weight/day (MAC: HED 13.7mg PER DAY equivalent 75kg human, ergo therapeutic dosing). C57BL/6J mice fed a diet containing 14 ppm encapsulated rapamycin had rapamycin brain concentrations of 8.65 ± 0.66 ng/mg wet weight, similar to the rapamycin levels found in plasma in the same animals. Adequate plasticity requires that TOR activity be within a range that allows for appropriate regulation of protein synthesis at synaptic sites. Our results suggest that an approximate 30% reduction in TOR activity in brain for 16 weeks or longer improves performance of C57BL/6 mice in tasks that involve long-term plasticity and are dependent on hippocampus or on hippocampus and prefrontal cortex. It is therefore conceivable that brain mTOR activity levels that are adequate during the reproductive years may become detrimental as mammals age (Blagosklonny, 2010). In agreement with this hypothesis, we and others previously showed that chronic (> 16 weeks) inhibition of mTOR activity by rapamycin in brain preserves cognitive function in mice modeling AD, possibly by increasing autophagy. In summary, the results of the present study demonstrate that chronic feeding with encapsulated rapamycin enhances memory in young C57BL/6 mice and delays cognitive decline associated with aging. Moreover, our results show that long-term feeding with encapsulated rapamycin has concomitant anxiolytic and antidepressant-like effects. Our findings are consistent with prior studies showing that long-term rapamycin treatment rescued learning and memory in mice modelling AD”
