Rapamycin (Sirolimus) for Stage IV Cancer
Also known as: Sirolimus
Rapamycin and its analogs (rapalogs) directly inhibit mTORC1, a central growth signaling node hyperactivated in many cancers.
Mechanism of Action
The FKBP12-rapamycin complex inhibits mTORC1, blocking S6K1 and 4E-BP1 phosphorylation. This suppresses cap-dependent translation of oncogenic mRNAs (cyclin D1, c-Myc, HIF-1α), promotes autophagy-mediated tumor cell death, and inhibits angiogenesis through VEGF downregulation.
General mechanism: mTORC1 inhibitor via FKBP12 binding. Promotes autophagy, suppresses cap-dependent translation, reduces senescent cell accumulation.
Current Evidence
Rapalogs (everolimus, temsirolimus) are FDA-approved for renal cell carcinoma, breast cancer (everolimus + exemestane), and neuroendocrine tumors. Low-dose rapamycin is being explored for cancer prevention. Combination with checkpoint inhibitors is under investigation.
Clinical Status: Rapalogs FDA-approved for multiple cancers. Low-dose rapamycin studied for cancer prevention and longevity.
Safety Profile
Immunosuppression at high doses. Mouth sores, metabolic effects (lipids, glucose). Low-dose intermittent regimens better tolerated.
Key Research Questions
- Can intermittent low-dose rapamycin prevent cancer through autophagy enhancement?
- What is the optimal combination with checkpoint inhibitors?
- Does rapamycin-induced autophagy help or hinder anti-tumor immunity?
Frequently Asked Questions
Is rapamycin safe for cancer patients?
Rapamycin (sirolimus) is FDA-approved as an immunosuppressant and has been studied in cancer clinical trials. Its mTOR-inhibiting mechanism induces autophagy and suppresses tumor growth. Side effects include immunosuppression and metabolic changes. Always discuss with your oncologist.
What is the rapamycin dosage for longevity?
Longevity-focused protocols typically use 3-6mg once weekly (intermittent dosing), which differs from the daily immunosuppressive dose. The PEARL trial is studying 5mg weekly. Low-dose intermittent rapamycin aims to activate autophagy without chronic immunosuppression.
Rapamycin vs metformin for anti-aging
Rapamycin inhibits mTOR to promote autophagy and cellular recycling. Metformin activates AMPK to improve metabolic health. They target complementary pathways and some researchers propose combining them. Rapamycin has stronger preclinical longevity data; metformin has a longer safety record.