Rapamycin (Sirolimus)

We’re busy updating our review of rapamycin (sirolimus) and will provide a rating when that’s complete. While we’re working, we share a summary from our predecessor website, Beyond Conventional Cancer Therapies. The information we share here was last updated in August 2021.

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Rapamycin (Sirolimus)

Rapamycin is a soil-derived antibiotic that binds to a target protein enzyme (mTOR) that controls cell growth, proliferation and survival. By blocking certain functions of the mTOR enzyme, rapamycin reduces cell growth. It therefore may be useful in treating or preventing proliferative diseases, including cancer.

Rapamycin received US FDA approval in 2003 for use in preventing acute rejection in kidney transplantation.¹Hardinger K, Brennan DC. Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors. UpToDate. September 19, 2019. Viewed April 21, 2020.

Also known by these names: Rapamune

Treating the Cancer

Working against cancer growth or spread, improving survival, or working with other treatments or therapies to improve their anticancer action

Everolimus and Rapamycin: The conventional cancer treatment everolimus (Medline Plus) is a later generation of rapamycin (sirolimus). Along with temsirolimus, everolimus is a derivative of sirolimus approved for treating renal cell carcinoma. A number of clinical studies have investigated the use of everolimus in cancers including breast and colorectal. European Medicines Agency (EMA) has approved everolimus (Afinitor®) for the treatment of hormone receptor-positive, HER2/neu-negative advanced breast cancer,²Hasskarl J. Everolimus. Recent Results in Cancer Research. 2018;211:101-123. and the US Food and Drug Administration approved use in treatment of postmenopausal women with advanced hormone receptor-positive, HER-2 negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.³Center for Drug Evaluation and Research. Application Number: NDA 22-334/S-016. US Food and Drug Administration. July 20, 2012. Viewed March 6, 2019. Compared to everolimus, rapamycin is not only less expensive, but it may be less toxic. Integrative oncologist and BCCT advisor Dwight McKee, MD, considers using rapamycin with patients who demonstrate upregulated mTOR. See his Commentary below.

In many cancers, an intracellular signaling pathway important in regulating the cell cycle (the PI3K-AKT pathway) is overactive. This overactive pathway reduces normal cell death (apoptosis) and allows cells to grow abnormally. Rapamycin can inhibit cells that express the active form of AKT,⁴Xu G, Zhang W, Bertram P, Zheng XF, McLeod H. Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. International Journal of Oncology. 2004;24(4):893–900. and is therefore being investigated as a cancer treatment or adjuvant (supplemental) therapy.

Clinical Evidence

• High response and cancer control rates when rapamycin and hydroxychloroquine were added to metronomic chemotherapy (also called low-dose chemotherapy) for refractory metastatic solid tumors (bladder, breast, colon, head and neck, lung and prostate) in a small group of patients who didn’t respond to first-line metronomic chemotherapy⁵Chi KH, Ko HL et al. Addition of rapamycin and hydroxychloroquine to metronomic chemotherapy as a second line treatment results in high salvage rates for refractory metastatic solid tumors: a pilot safety and effectiveness analysis in a small patient cohort. Oncotarget. 2015;6(18):16735–16745.
• Tolerated by most patients when used with the chemotherapy drug bevacizumab, at lower cost than other mTOR inhibitors, but without significant treatment effects in patients with pathologically confirmed advanced solid tumors for which standard curative or palliative measures either do not exist or were no longer effective⁶Cohen EE, Sharma MR et al. A phase I study of sirolimus and bevacizumab in patients with advanced malignancies. European Journal of Cancer. 2011;47(10):1484–1489.

Lab and Animal Evidence

• Enhanced response to erlotinib (used to treat certain types of non-small cell lung cancer), inhibiting cell growth pathways in cell and animal models⁷Buck E, Eyzaguirre A et al. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Molecular Cancer Therapeutics. 2006;5(11):2676–2684.
• Variable response rates for different tumor types, from melanoma zero percent to ovarian 41 percent⁸Xu G, Zhang W, Bertram P, Zheng XF, McLeod H. Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. International Journal of Oncology. 2004;24(4):893–900.

Breast Cancer

• Increased anticancer effect when used with herceptin (a drug used to treat HER2-positive cancers including HER2-positive breast cancer) compared to either drug alone in breast cancer cells overexpressing HER2-neu (a protein involved in cell growth)⁹Wang LH, Chan JL, Li W. Rapamycin together with herceptin significantly increased anti-tumor efficacy compared to either alone in ErbB2 over expressing breast cancer cells. International Journal of Cancer. 2007;121(1):157–164.
• Stopped growth in breast carcinoma cells in cell studies and reduced growth of breast cancer cells grafted into animals, when given with cotylenin A¹⁰Kasukabe T, Okabe-Kado J, Kato N, Sassa T, Honma Y. Effects of combined treatment with rapamycin and cotylenin A, a novel differentiation-inducing agent, on human breast carcinoma MCF-7 cells and xenografts. Breast Cancer Research. 2005;7(6):R1097–R1110.

Head and Neck Cancer

• Antitumor activity in animal models of head and neck squamous cell carcinoma comparable to the more expensive derivative temsirolimus¹¹Hu M, Ekshyyan O et al. Efficacy and comparative effectiveness of sirolimus as an anticancer drug. Laryngoscope. 2011;121(5):978–982.

Kidney Cancer

• Enhanced effects of cancer treatments gefitinib and erlotinib (EGF receptor inhibitors) in suppressing cell growth¹²Costa LJ, Gemmill RM, Drabkin HA. Upstream signaling inhibition enhances rapamycin effect on growth of kidney cancer cells. Urology. 2007;69(3):596–602.

Lung Cancer

• Enhanced effects of EGF receptor inhibitors against non-small-cell lung cancer cells¹³Gorzalczany Y, Gilad Y et al. Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: a beneficial strategy to combat non-small cell lung cancer. Cancer Letters. 2011;310(2):207–215.

Pancreatic Cancer

• Reduced epidermal growth factor-induced HCCR expression in pancreatic cancer cells; HCCR expression plays a key role in pancreatic tumor progression¹⁴Xu Z, Zhang Y et al. Epidermal growth factor induces HCCR expression via PI3K/Akt/mTOR signaling in PANC-1 pancreatic cancer cells. BMC Cancer. 2010;10:161.

Optimizing Your Terrain

Creating an environment within your body that does not support cancer development, growth or spread

• Metabolic response with short-course radiotherapy in rectal cancer patients¹⁵Buijsen J, van den Bogaard J et al. A phase I-II study on the combination of rapamycin and short course radiotherapy in rectal cancer. Radiotherapy & Oncology. 2015;116(2):214–220.

Access

Use requires a prescription from a licensed physician. Generic rapamycin is considerably less expensive than its analogs temsirolimus and everolimus (Affinitor).

Dosing

BCCT does not recommend therapies or doses, but only provides information for patients and providers to consider as part of a complete treatment plan. Patients should discuss therapies with their physicians, as contraindications, interactions and side effects must be evaluated. 

Dosage information and recommendations are available from these sources:

• Drugs.com:
  • Rapamune Dosage
  • Sirolimus Dosage

Integrative Programs, Protocols and Medical Systems

Rapamycin is not yet listed in any of the protocols or systems that BCCT references. However, see Dwight McKee’s comments below.

Commentary 

From integrative oncologist and BCCT advisor Dwight McKee, MD, April 23, 2020: Rapamycin is not FDA-approved for any cancer indications, so its use would still be considered off-label use in cancer. I prefer it to everolimus and temsirolimus because of its much lower toxicity. Because of its very long half life, it can be dosed weekly. I have usually recommended 5-8 mg, depending on body size. It’s very useful to combine resveratrol and/or its cousin pterostilbene (500 mg bid for resveratrol, 250 mg bid for peterostilbene), as they effectively block the downstream signalling pathways of mTOR (PI3K and PTEN). 

I would recommend weekly rapamycin and resveratrol/pterostilbene for cancers in which mTOR is upregulated, as indicated by genomics, RNA expression, and/or proteomics. It’s ALWAYS a good idea to get genomic, RNA and/or proteomic testing, as mTOR upregulation is not predictable. It’s also good to look at downstream PI3K and PTEN when determining who might benefit from rapamycin, though most oncologists tend to go with mTOR if it’s upregulated. I don’t go by which cancers everolimus is indicated for. A person’s mTOR status is much more specific.

Taking 3 to 4 mg of rapamycin (sirolimus) with 8 ounces of grapefruit juice can save money. In this dose range there are typically no side effects noted. A phase 1 trial which studied the effect of grapefruit juice as well as a drug (ketoconazole) on slowing the metabolism of sirolimus used much higher doses of sirolimus, which did produce some side effects, and also might be associated with some immune suppression.¹⁷ 3-4 mg taken with grapefruit juice weekly (or 6-8 mg without grapefruit juice) is adequate to suppress m-TOR signaling and allow other components of a comprehensive integrative approach to cancer treatment to work better, with no perceivable side effects or immunosuppression.

Cautions

Common Side Effects/Adverse Events

A high rate of grade 3 (severe and undesirable) adverse events has been found when used too soon after surgery; researchers recommended waiting six weeks after surgery before use.¹⁶Buijsen J, van den Bogaard J et al. A phase I-II study on the combination of rapamycin and short course radiotherapy in rectal cancer. Radiotherapy & Oncology. 2015;116(2):214–220.