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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Based on the relative success of everolimus (AfinitorTM) and temsirolimus (ToriselTM), the analogue ridaforolimus (Figure 6.95) was developed by ARIAD Pharmaceuticals. It was designed to retain the antitumor activity of rapamycin and the related analogues but to have an improved pharmacological profile. Based on promising preclinical activity it was granted fast track approval status by the FDA in 2005 for treating soft-tissue and bone sarcomas, and in 2011 Merck (who had licensed ridaforolimus from Ariad) submitted an NDA to the FDA, and a Marketing Application to the EU. However, the applications were rejected, and data published in 2013 suggested that antitumor efficacy in metastatic sarcoma patients had been minimal.
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).
Uterine Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Claudia von Arx, Hani Gabra, Christina Fotopoulou
Mutations in PTEN, PIK3CA, and PIK3RI causing a consequent constitutive activation of PI3K/AKT/mTOR pathway occur in 40–60% of endometrioid cancers. Thus, mammalian target of rapamycin (mTOR) inhibitors (everolimus, temsirolimus, and ridaforolimus) have been evaluated in clinical trials with encouraging results in the recurrent disease setting. In particular, temsirolimus demonstrated a good activity in recurrent EC, especially if chemo-naïve, achieving a partial response (PR) and stable disease (SD) in 14% and 69% of the chemo-naïve population, respectively.123 Ridaforolimus also demonstrated significant activity in recurrent EC, with a clinical benefit achieved in 29% of women with recurrent or persistent endometrial cancer that had progressed after a previous treatment.124 Interestingly, ridaforolimus showed better disease control (35% versus 17%; p = 0.021) and an improved PFS (3.6 vs. 1.9 months; p = 0.008) compared with progestin or investigator choice chemotherapy in recurrent or metastatic EC that had progressed following at least one line of chemotherapy.125 Currently, mTOR inhibition combined with aromatase inhibition is under investigation in the GOG 3007 trial. In this trial, everolimus plus letrozole is compared with tamoxifen or medroxyprogesterone in recurrent EC, and preliminary results suggest more favorable PFS in the everolimus plus letrozole arm.126
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
Ridaforolimus is a sirolimus analog that was initially used to treat soft tissue and osteosarcoma before being extended to treat a wide range of solid and hematological malignancies229. A phase III trial evaluated the maintenance of disease control in advanced sarcoma with ridaforolimus. The median PFS was 17.7 weeks for ridaforolimus and 14.6 weeks for placebo. However, serious adverse effects (grade > 3) were more common with ridaforolimus (64.1% vs. 25.6%)230. Due to its poor risk-benefit profile, the US FDA has not approved ridaforolimus for the treatment of sarcoma. Ridaforolimus underwent subsequent clinical trials for the treatment of various malignancies, but its safety still restricts its clinical application. In patients with advanced endometrial cancer, single-agent ridaforolimus displayed anticancer activity and tolerable tolerability, with 13 patients (29%) attaining clinical benefit and a 6-month PFS rate of 18%231. Based on the positive clinical outcomes of this trial, a follow-up phase II trial was conducted in patients with endometrial cancer232. The median PFS for the ridaforolimus group was 3.6 months and 1.9 months for the control group (progestin or chemotherapy). However, the proportion of patients in the ridaforolimus group who discontinued treatment due to AE was 33%, compared to 6% in the control group, with typical grade 3 toxicities being hyperglycaemia, anaemia, and diarrhoea232. Thus, oral ridaforolimus has strong toxicity in advanced endometrial cancer. Currently, ridaforolimus has stopped development.
Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer
Published in Expert Opinion on Investigational Drugs, 2019
Fabio Barra, Giulio Evangelisti, Lorenzo Ferro Desideri, Stefano Di Domenico, Domenico Ferraioli, Valerio Gaetano Vellone, Franco De Cian, Simone Ferrero
Results extrapolated from clinical trials on ridaforolimus, another mTOR inhibitor, showed that patients receiving it as monotherapy (25 mg IV weekly) obtained a significantly longer PFS compared with those receiving the addition of megestrol (a progestin) and tamoxifen (3.6 vs. 1.9 months; HR = 0.53, p = 0.008). Moreover, there was a significant difference in the SD rate between the two groups (35% versus 17%, p = 0.02) [80]. In another Phase II trial, ridaforolimus (AP23573, 12.5 mg IV once daily for 5 consecutive days every 2 weeks) administered to women with recurrent EC previously treated with RT or CT obtained 7% of PR and 26% of SD. The most commonly reported adverse events were fatigue, anemia, mouth sores, and nausea or vomiting [81]. By contrast, another Phase II study enrolling patients who did not receive previous lines of CT for EC showed the modest activity of this drug (40 mg IV once daily for 5 consecutive days every 2 weeks). 8.8% of PR and 52.9% of SD were obtained; moreover, PTEN mutations with subsequent loss of function did not correlate with PR or SD [82].
The EluNIRTM Ridaforolimus Eluting Coronary Stent System
Published in Expert Review of Medical Devices, 2019
Panagiotis Savvoulidis, Gidon Perlman, Rodrigo Bagur
The EluNIR™ is the first DES with an elastomeric coating. The stent is coated with a proprietary durable polymer matrix, composed of poly n-butyl methacrylate (PBMA) and CarboSil® (DSM Biomedical, Exton, PA, USA) which is an elastomeric, biocompatible, silicone-modified polyurethane. The elastomeric coating minimizes coating irregularities and polymer damage such as peeling, cracking, and flaking, thereby allowing uniform elution of antiproliferative drug and potentially curbing the probability of inflammatory processes associated with ISR and ST (Figure 1). The coating contains ridaforolimus at a concentration of 1.1 μg/mm2. Ridaforolimus is a high-therapeutic index member of the ‘limus’ family of drugs. It is a non-prodrug analog of Rapamycin (Sirolimus), a macrocyclic lactone produced by Streptomyces hygroscopicus. Like Rapamycin, ridaforolimus permeates the cell membrane, binds to cytosolic FKBP12 and then to mTOR, a P13K-related protein kinase, which acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression, and cell survival. These effects are attributable to the inhibition of the multiple downstream effects of mTOR’s activity: synthesis of components required for macromolecular synthesis (such as ribosomes), cell size increase, and progression through the G1 phase of the cell cycle. Preclinical data suggest that by 90 days, nearly 90% of the drug was released and by 180 days >95% of the drug is eluted (Figure 2). Unlike previous DES, however, an initial peak (burst) concentration followed by diffusion does not occur. Rather, persistently low drug concentrations are measured in the surrounding vascular tissue for 3 months [24].