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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Rapamycin was shown to work by inhibiting mTOR by associating with its intracellular receptor FKBP12. The FKBP12-rapamycin complex then binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR. In addition, it inhibits angiogenesis, consistent with the observation that PI3K signaling is required for expression and secretion of the pro-angiogenic VEGF from endothelial cells. Many of the genetic translocations that underlie sarcomas are known to result in aberrant activation of the mTOR pathway leading to the production of large amounts of VEGF, and cancer cells of this type are particularly sensitive to rapamycin-based agents. Rapamycin can also induce apoptosis in sarcoma cell lines under some conditions, and experiments using mutant mTORs have confirmed that mTOR is the critical target for rapamycin-induced cell death. Thus, mTOR inhibitors of this type may inhibit tumor cell growth through multiple mechanisms.
Liver transplantation
Published in Mark Davenport, James D. Geiger, Nigel J. Hall, Steven S. Rothenberg, Operative Pediatric Surgery, 2020
Caroline Lemoine, Riccardo A. Superina
A detailed discussion of immunomodulatory regimens is beyond the scope of this chapter, but the overall strategy remains fairly simple: Minimizing adverse effects of immune suppressants, namely bacterial, viral, or fungal infection and malignancy while optimizing graft survival by preventing rejection. There is no universally accepted standard regimen immunomodulation following pediatric LT. At the authors’ center, a single preoperative dose of 10 mg/kg of methylprednisolone is administered. About 12 hours postoperatively, both mycophenolate (10 mg/kg/dose) and tacrolimus (0.1 mg/kg/dose) are given twice daily with a tacrolimus level desired range of 10–12 ng/mL. Methylprednisolone is tapered over the following month from 2.0–0.3 mg/kg per day and converted to an oral equivalent after return of bowel function. Mycophenolate is started immediately after surgery in order to reduce dependence on calcineurin inhibitors. Rapamycin can be added later. Anti-interleukin-2 receptor monoclonal antibodies, such as basiliximab, are sometimes used. Steroid-sparing regimens are becoming increasingly popular, but are not appropriate for patients with a history of autoimmune hepatitis.
Cancer Research Is Leading the Way
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Rapamycin was the first clinically approved inhibitor of the mTOR pathway; a pathway whose dysregulation is associated with many human diseases including: cancer, diabetes, obesity, neurological diseases, such as epilepsy and autism, and various genetic disorders (Li, Kim, and Blenis 2014). Rapamycin is FDA approved for use as an immunosuppressive agent in organ and bone marrow transplantation and several of its analogs, commonly referred to as “rapalogs”, have been evaluated for efficacy in various solid state tumors and lymphomas. The rapalog temsirolimus has received FDA approval for use in the treatment of advanced renal cell carcinoma (Kwitkowski et al. 2010). There is significant preclinical biological evidence to support that inhibition of the mTOR pathway may have positive benefit in the treatment of OSA. Given the challenges of studying rapamycin in a limited pediatric patient population, studies to optimize dosing and to identify safe and pharmacokinetically/pharmacodynamically relevant treatment regimens were first completed in canines (Paoloni and Mazcko et al. 2010). Further Phase II efficacy studies of rapamycin in canine OSA remain in progress. Since this time, pediatric clinical trials evaluating the rapalog, ridaforolimus, have also been performed for human OSA (Chawla et al. 2012, Demetri et al. 2013).
Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis
Published in Expert Opinion on Investigational Drugs, 2023
Loreto Martinez-Gonzalez, Ana Martinez
(NCT03359538) is a macrolide compound that was FDA-approved in 1999 as immunomodulatory agent. Rapamycin prevents organ transplant rejection, and it is used to treat a rare lung disease called lymphangioleiomyomatosis and perivascular epithelioid cell tumor [65]. It is known that rapamycin enhances proteins degradation by mTOR inhibition and autophagy activation, and this has been associated with beneficial effects in models of aging and neurodegeneration including ALS [14]. Initially, rapamycin shown detrimental effects in the SOD1G93A model accelerating motoneuron degeneration, shortening the lifespan of the ALS mice and without any effects on SOD1 aggregates [66]. However, it rescues TDP-43 mislocalization in cell cultures [67] and decreased TDP-43 aggregates both in flies and mice ALS models [68,69]. Based on that evidences, a clinical trial phase II was designed to study the biological response of rapamycin, in addition to riluzol, in 63 ALS patients randomized in three groups [70]. SOD1 positive ALS patients were excluded from the inclusion. The primary endpoint is an increase in regulatory Т cells (Treg) >30% comparing rapamycin and placebo. The study is completed and final results may provide valuable information for a larger study.
Recent trends in platelet membrane-cloaked nanoparticles for application of inflammatory diseases
Published in Drug Delivery, 2022
Zhengyu Fang, Jie Fang, Chunxiao Gao, Rui Gao, Peihong Lin, Wenying Yu
PM@NPs can be used not only in AS diagnosis but also in the targeted therapy of AS. Platelets have strong affinity with plaques and can thus naturally target AS-diseased regions, and NPs that potentially target AS can be designed by mimicking the inherent adhesion function of platelets. Rapamycin (RAP) has a strong anti-AS effect, but its clinical applications are limited by its low concentration and high toxicity at AS-diseased sites. Song et al. (2019) embedded PM on the surfaces of NPs loaded with RAP and constructed a drug delivery platform (RAP-PNPs) targeting atheromatous plaque. In the mouse model of AS, RAP-PNPs may preferentially accumulate at atheromatous plaques, compared with plaque-targeting efficiency of non-biomimetically-modified NPs loaded with RAP, plaque-targeting efficiency increased 4.98 times. In addition, RAP-PNPs therapy can significantly inhibit the formation of necrotic cores in plaques compared with RAP treatment in nude mice (35.3%) and RAP-NPs treatment (42.8%). These results indicate that RAP-PNPs effectively inhibits plaque, slows down the progression of plaques, and enhances the anti-AS efficacy of RAP. Huang et al. (2020) developed novel PM biomimetic NPs based on Janus mesoporous silica nanomotor MJAMS/PTX/AV for AS treatment (Figure 3). They found that PM coated nanomotors can reduce drug leakage before reaching the plaques, and MJAMS/PTX/AV can penetrate plaques, improve the retention of drugs at diseased regions, facilitate the short-term photothermal elimination of inflammatory macrophages and the long-term antiproliferative effects of drugs, and ensure efficient AS treatment.
Host-directed therapies for malaria and tuberculosis: common infection strategies and repurposed drugs
Published in Expert Review of Anti-infective Therapy, 2022
Piyush Baindara, Sonali Agrawal, O. L. Franco
Rapamycin was initially discovered as an antifungal metabolite produced by Streptomyces hygroscopicus. Rapamycin is an attractive candidate for host-directed therapy, as it has proven to be an effective means of suppressing immune responses. Bharatham et al., 2011 found that rapamycin inhibits the growth of P. falciparum in vitro through its binding to the parasite homolog of the mammalian FK506 binding protein [157]. In a mouse model of CM, experimental CM (ECM), rapamycin treatment blocked breakdown of the blood–brain barrier and brain hemorrhaging, and it also decreased the influx of both CD4+ and CD8+ T cells into the brain and the accumulation of parasitized red blood cells in the brain, thus increasing survival [161]. In the case of TB, in vivo studies on mice models demonstrated that rapamycin given at an early age did not significantly change life expectancy or susceptibility to disease; however, when given at a later age, the mice had better survival expectancy [187]. Rapamycin was also given to BCG-vaccinated mice and was reported to have an increased vaccination efficacy against Mtb infection, associated with autophagy, increased antigen presentation, and increased Th1-type immune response [188]. These results indicate that rapamycin may prove to be a highly selective adjunctive therapy for malaria as well as TB.