Are we ready to move away from nature? The rapamycin story
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We have seen it all in cancer treatment. We work with tree extracts, marine sponges, viruses, soil extracts, and many other things. Nature has giving us the tools to treat this threatening disease and will continue to do so if we have an open mind and are willing to learn; and we have gained extensive knowledge from the rapamycin story. It all started in a far-far away Island (Easter Island) with a soil bacteria and the identification of a microcyclic antibiotic with antifungal properties.
Twenty years later. We know (or we think we know) the target of rapamycin (TOR), the TOR complexes, the upstream and downstream effectors, the elements that activate or inhibit the pathway, and we start seeing the promising effects of targeting mammalian target of rapamycin(mTOR) not only in cancer but also other conditions such as inflammation and aging. We have the mother compound rapamycin approved for graft rejection, and we have rapamycin-coated arterial stents. We have three rapamycin analogs with improved pharmacological properties and we use them to treat various malignancies [1, 2, 3, 4]. We all have seen patients benefiting from the treatment with rapalogs and doing remarkably well for prolonged time with almost no change in the quality of life. We are very familiar with the toxicity profile of rapalogs and we believe they are safe and compatible with prolonged use .
We are further fascinated about how the rapamycin story unfolds as we learn about rapalogs prolonging life-span in animals or reducing the inflammation [6, 7]. We also start to understand the mechanisms of resistance to mTOR inhibitors  as well as the potential role of biomarkers to help identifying early the responding patients or predicting the response .
However, we are not entirely satisfied with the efficacy seen with rapalogs in cancer, and therefore we keep looking for methods to overcome resistance or better combine the rapalogs. Rather, we already started looking for “replacements”, for new agents small molecules targeting TOR complexes, which are currently in development with the hope that their efficacy will increase without further toxicities . Have rapalogs already failed us or rather have we failed to better develop them or to take our time to understand all the complex connections between pathways and to acknowledge serendipity in clinical work? Are we really moving away from nature in the favor of synthetic drugs? Are we really at the end of the amazing rapamycin story as we know it? It is hard to believe. As of now, rapamycin is considered to be a selective inhibitor of mTOR, therefore less likely to have unexpected systemic toxicity. However, recent research shows us that TOR complexes could both be targeted by rapalogs depending on the dose and possibly on the duration of exposure, thus achieving that “most wanted” TORC1 and 2 inhibition. Therefore, it seems that further understanding of the best dose, schedule of administration, and combinations will allow us to better use the rapalogs. We may discover other mechanisms of action of rapamycin and we may also learn how to use these drugs in other conditions such as Alzheimer’s disease.
The question is: are we able to accept the idea that we performed clinical trials without answering all the important questions? Are we ready to go back and clarify now with new technologies and improved vision what the exact target is, what biomarkers of response or resistance we have and what is the best dose and schedule to utilize for rapalogs? If the answer is “yes”, then the rapamycin story will continue and will culminate with a happy ending and maybe even with a “happily ever after”. If however the answer is “no” then we will likely continue to perform new studies with new drugs for new mTOR inhibitors without achieving something fundamentally different or really changing the paradigm of drug development.
The rapamycin story is one of the most surprising, enticing, satisfying and unique stories in the history of medicine. And the end is not near.
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