Rapamycin - for Cancer Prevention

I recently ran into this research paper and it has some really interesting stats on cancer prevention:

Rapamycin is an anti-cancer and anti-aging drug. Rapamycin extends life span in mice. Furthermore, rapamycin delays the onset of cancer in mice. Rapamycin and everolimus (a rapamycin analog) decrease the risk of cancer in humans, who receive these rapalogs to prevent transplant rejection. Therefore, rapalogs such as rapamycin are considered for both prevention of cancer and extension of healthy life span in humans

Every other day (e.o.d.) administration of 1.5 mg/kg rapamycin dramatically prevented cancer induced by tobacco carcinogen. We introduced intervals between treatments: e.o.d. (for practical convenience: 3 times per week) rapamycin was administrated bi-weekly (every other two weeks). Thus, mice were treated with 1.5 mg/kg × 3 times a week for 2 wk followed by a 2-wk break. We showed that this schedule delayed cancer and extended mean and maximal lifespan in mice.

Full Paper (PDF) Here:

Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

Another paper, with a focus on Skin Cancer:

RESULTS
Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group, and in 22 (39%) in the calcineurin-inhibitor group.

5 Likes

Interestingly, that paper, in the quote where it says “It was estimated that a 1.5mg/kg in mice corresponds to the therapeutic oral dose in humans” cites this paper: (full PDF linked from title of below paper)

Results: Rapamycin was administered on a daily (5 of 7 days) regimen beginning 26 weeks after NNK decreased tumor size, proliferative rate, and mTOR activity. Multiplicity was not affected. Comparing this regimen with an every-other-day (qod) regimen revealed that rapamycin levels were better maintained with qod administration, reaching a nadir of 16.4 ng/mL, a level relevant in humans.When begun 1week after NNK, this regimen was well tolerated and decreased tumor multiplicity by 90%. Tumors that did develop showed decreased phenotypic progression and a 74% decrease in size that correlated with decreased proliferation and inhibition of mTOR.

Conclusions: Tobacco carcinogen-induced lung tumors in A/Jmice are dependent upon mTOR
activity because rapamycin markedly reduced the development and growth of tumors. Combined with the Food and Drug Administration approval of rapamycin and broad clinical experience, these studies provide a rationale to assess rapamycin in trials with smokers at high risk to develop lung cancer.

Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors.

Clin Cancer Res 2007; 13:2281-9; PMID:17404113;
http://dx.doi.org/10.1158/1078-0432.CCR-06-2570

So - I checked out that paper to better understand their definition of “therapeutic dose”… and it says:

Combined with the results obtained byWislez et al. (20) and Yan et al. (21), our data provide a strong rationale to consider testing rapamycin in smokers who are at high risk to develop lung cancer. What are the issues that limit the application of these findings to a clinical trial? Perhaps the most practical issue is whether doses of rapamycin that achieve an antitumor effect in mice are achievable in humans. Our pharmacokinetic studyof two dosing regimens showed that although peak concentrations of 777 to 1,488 ng/mL were achieved, mTOR inhibition was maintained at trough rapamycin levels of 16.4 ng/mL with qod dosing. This concentration is achievable in humans at doses used for immunosuppression (27 - packet insert), but these levels were attained in conjunction with other immunosuppressive agents with the intent to maximize immunosuppression, raising the issue of whether or not doses of rapamycin that have antitumor efficacy also cause immune suppression.

A second issue that could limit application of anypreventive agent is toxicity. In addition to immunosuppression, other toxicities associated with administration of rapamycin or its analogues include vomiting, diarrhea, thrombocytopenia, rash, stomatitis, and hyperlipidemia (28). These toxicities differ from those associated with other preventive agents. For example, selective estrogen receptor modulators, such as tamoxifen, can reduce the incidence of breast cancer, but tamoxifen is associated with increased risk of endometrial cancer and thromboembolic events (29), thus limiting its use despite its effective chemopreventive activity.

Of the toxicities associated with rapamycin, the immunosuppressive effects of rapamycin are most important. Rapamycin (sirolimus) has a ‘‘black-box warning’’ from the Food and Drug Administration stating that its use is associated with increased risk of lymphoma development.5 However, the studies that provided the basis for that warning were done in combination with other immunosuppressive agents such as cyclosporine, making it difficult to attribute the relative contribution of rapamycin alone to the development of lymphoma. Although cyclosporine has been associated with tumor promotion (35, 36), the use of mTOR inhibitors in transplant patients maybe associated with tumor inhibition.

For example, a recent analysis of cancer incidence in over 30,000 kidneyallograft recipients reported a 3-fold lower incidence of all de novo malignancies in patients that were maintained on rapamycin as part of their therapy than those that did not receive rapamycin (37). This observation raises the possibility that rapamycin administered as a single agent may not be associated with an increased risk of lymphoma or other cancers.

3 Likes

@ RapAdmin

This is an amazing insight into Rapamycin from large scale population in clinical setting.

“For example, a recent analysis of cancer incidence in over 30,000 kidney allograft recipients reported a 3-fold lower incidence of all de novo malignancies in patients that were maintained on rapamycin as part of their therapy than those that did not receive rapamycin (37). This observation raises the possibility that rapamycin administered as a single agent may not be associated with an increased risk of lymphoma or other cancers.”

If you recall, one of the authors of the Sirolimus/GFJ study, currently practicing (oncologist) and using Rapamcyin for his patients, only referenced anemia and Interstitial Lung Disease, as risk factors (I believe he was speaking in constant dosing context). All reversible. Of course, you have the large sample population from Dr Green.

4 Likes

I dug down further into the paper referenced…

Conclusions.

Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and nonskin solid malignancy.

The 2.6 year de novo cancer incidence of 0.60% seen with the combined sirolimus/everolimus with or without cyclosporine/tacrolimus immunosuppression is substantially lower than the incidence seen with cyclosporine/tacrolimus immunosuppression in our study and in the ANZDATA report. The significant decrease in any posttransplant de novo cancer incidence was confirmed in the multivariate analysis, as there was a 60% reduced risk at 2.6 years posttransplantation (P =0.0002)

Rapamycin converted murine renal cancer cells from an invasive phenotype to a noninvasive phenotype that formed cell-to-cell adhesions (9). Additionally, it was shown that rapamycin directly inhibited proliferation of renal cancer cells in vitro, prevented metastatic tumor progression and prolonged survival of mice inoculated with murine renal cancer cells (9). A separate study of human renal cell cancer injected into SCID-beige mice reported that treatment with rapamycin alone or rapamycin plus cyclosporine resulted in significantly less pulmonary metastases and improved survival over that seen with controls (no treatment) or cyclosporine treatment (10). Rapamycin treatment was also associated with reduced TGF-β levels and VEGF-A expression that was associated with reduced tumor angiogenesis (10). Another independent study showed that rapamycin reduced VEGF production and decreased the size of hepatic metastases in mice undergoing adenocarcinoma cell injections into the portal vein (11)

Full PDF Paper for Download from Sci-Hub:

Maintenance Immunosuppression with Target-of-Rapamycin Inhibitors is Associated with a Reduced Incidence of De Novo Malignancies

https://sci-hub.hkvisa.net/10.1097/01.tp.0000184006.43152.8d

2 Likes

As I have posted before, I have previously been diagnosed as having chronic actinic keratosis due to over-exposure to sunlight when I was younger. Actinic keratoses are precursors to cancer. I have had regular (approx. quarterly) visits to see my dermatologist to have keratoses removed with cryogenic or other chemical treatments. Since I have been taking rapamycin the number of new actinic keratoses has been reduced to zero and I canceled my last appointment.

3 Likes

Thanks for sharing, what dose regime do you have?

Omg me too. I had a large (and growing one) that has practically disappeared!

2 Likes

The last 3 months I have been using 20 mg every 2 weeks just because I am already old. I will be cutting back to 10mg every 2 weeks on my next round.

2 Likes
3 Likes

Here are the different studies on that rapamycin decreases skin cancer risk (compared to other Immunosuppressant drugs)

2 Likes

As MK would say I am a ‘true believer’ in the benefits of rapamycin for skin cancer. I only wish I had before and after photos of my mole.

1 Like

Krister_Kauppi, thanks for the links to those articles.

The authors from the above paper state the following:

“More importantly, despite the reduction in risk of cancer seen in some patients, use of sirolimus was associated with a significantly increased risk of death in both conversion and de novo trial subgroups. Although a reduction in cancer was seen in patients converted to sirolimus, the increased risk of death highlights a concerning consequence of this strategy that was not evident from previous trials.”

1 Like

Brandy111
Any idea of the cause of death? Daily dosing is clearly not a good thing.

1 Like

Interesting… I will dig more into this.

We investigated the effect of sirolimus on development of cancer and on survival among transplant recipients using data from randomized trials. We hypothesized that sirolimus would be associated with a significant reduction in both malignancy and death.

The primary outcome was the development of any new malignancy after randomization. This outcome included any type of cancer (such as basal cell skin cancer, lymphoma, etc). Secondary outcomes included non-melanoma skin cancer, other cancer, and death.

Primary analysis

In total 243 patients developed a malignancy: 127 in the sirolimus group and 116 in the control group. The cumulative incidence of cancer was lower in the sirolimus group than in the control group

There was a 20% reduction in risk of malignancy in women compared with men

Overall, the causes of cancer were significantly different in the sirolimus and control groups (P=0.004; table C in appendix 1). There was a higher proportion of squamous (2.0% v 1.3%) and basal (1.4% v 0.79%) cell skin cancer in the control group compared with the sirolimus group, while there were more hematological malignancies in the sirolimus group

There were 202 deaths: 133 in the sirolimus group and 69 in the control group

Overall patient survival was significantly reduced in the sirolimus group (P=0.04; fig 4​4).). After multivariable adjustment, sirolimus use was associated with a 43% increased risk of death compared with the control group (adjusted hazard ratio 1.43, 1.21 to 1.71; P<0.001) (table 2​2).). The causes of death were significantly different in the two groups (P=0.002; table D in appendix 1). There were relatively few deaths attributed to malignancy, but the proportions were similar in the two groups (0.21% sirolimus, 0.19% control). There was a higher proportion of death from infection (0.58% v 0.15%) and cardiovascular disease (1.28% v 0.54%) in the sirolimus group compared with the control group.

Sirolimus use was associated with a 68% reduction in the risk of non-melanoma skin cancer (0.32, 0.24 to 0.42; P<0.001) and a 48% reduction in the risk of other cancers (0.52, 0.38 to 0.69; P<0.001). As with the overall analysis, sirolimus use was associated with an increased risk of death in the conversion trials

Discussion

Principal findings

This study included individual patient level data from 21 randomized trials comparing sirolimus with other immunosuppressive regimens in 5876 recipients of kidney transplant. There was a 40% reduction in the risk of malignancy and a 56% reduction in risk of non-melanoma skin cancer for those randomized to sirolimus.

Although a reduction in cancer was seen in patients converted to sirolimus, the increased risk of death highlights a concerning consequence of this strategy that was not evident from previous trials. By pooling individual patient data, we were able to perform survival analyses, not just on occurrence of cancer but also on overall survival of patients. Our findings help to clarify the benefits and harms associated with sirolimus use regarding reduction of malignancy after kidney transplantation.

As we observed no reduction in mortality related to cancer, the trade-off of fewer cancers with an increased mortality does not seem justified. Perhaps a subset of patients at greatest risk of cancer might benefit from this strategy, but this would be difficult to predict at the individual level

In patients who did not receive induction therapy, however, there was a significant reduction in cancer with no effect on mortality in those treated with sirolimus

For recipients of a transplant from a deceased donor, sirolimus was associated with a reduction in cancer and an increased risk of death similar to the overall findings. For recipients from living donors, however, sirolimus had a null effect with respect to mortality

Unlike the trial level subgroups (for example, de novo or conversion) patients were not randomized to treatment groups based on induction therapy or donor type. This is an important distinction as these subgroups might be imbalanced with respect to other factors that could influence occurrence of cancer or death. While interesting clinically, the findings from these subgroup analyses should be interpreted cautiously.

We could not identify the mechanism of cancer reduction in our analysis.

but we did see a consistent effect on cancer reduction regardless of whether the trial used high or low doses of sirolimus. Whether the reduction in malignancy was because of an overall reduction in immunosuppression, removal of oncogenic immunosuppression (such as cyclosporine), or a combination of these factors remains unknown

The excess risk of death associated with sirolimus could not be directly explained by our data. We found an increase in both cardiovascular deaths and deaths related to infection, the two most common causes of death in patients with kidney transplantation.7 Over-immunosuppression with sirolimus could have contributed to the increase in infection related mortality, but this could not be confirmed without data on drug concentration.

We did, however, see a significantly increased risk of death in the subgroup of trials that used high dose sirolimus.

Patients treated with sirolimus could have had higher net immunosuppression because of the increased risk of acute rejection seen in some of the included trials.2022 23 This in turn could have contributed to increased infection related mortality.

Although we did not have relevant individual patient level data, an increase in these known cardiac risk factors might have contributed to the increase in cardiovascular death seen in our analysis.

2 Likes

Interesting that there was also a high rate of hematological malignancies observed in mice receiving the highest dose of rapamycin tested in this study:

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.pdf (1.9 MB)

2 Likes

So it would seem that the most common causes of death in this population are infections and cardiovascular diseases. Daily rapamycin increased the risk so let’s hope that intermittent dosing solves this problem. It’s going to be hard to know for sure based solely on studies in mice.

3 Likes

Let’s also remember that this is a very sick population with multiple co- morbidities. When I worked on the renal ward they almost all had obesity, hypertension, diabetes, and sometimes smoked. In that scenario all risk factors should be aggressively managed to prevent heart disease. I particularly like the data demonstrating that the combination of gotu kola with pine bark extract essentially stops atherosclerosis in its tracks.
Life extension has written about this extensively on their site and magazines.

1 Like

It took a whopping dose and only manifested in females.

1 Like