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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Other mTOR inhibitors were discovered after rapamycin including everolimus (AfinitorTM), temsirolimus (ToriselTM), and the experimental agent ridaforolimus (often described as the “rapalogs”). Everolimus (AfinitorTM) and temsirolimus (ToriselTM), both of which also have antiangiogenic effects, are typically used for the treatment of renal cancer, often in combination with other chemotherapeutic agents, although they have also been studied in other cancer types. For example, everolimus (AfinitorTM) is used for HR-positive breast cancer, neuroendocrine tumor (NET) of the stomach, and bowel, lung, pancreatic, and kidney cancers. Temsirolimus (ToriselTM) is used for advanced kidney cancer and mantle-cell lymphoma. These agents are described below in more detail. A related analogue, sirolimus (RapamuneTM), is used for post-transplant organ rejection and a rare non-cancer lung disorder called lymphangioleiomyomatosis, and is not discussed here.
Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Six hundred and twenty-six patients were randomized to receive IFNa dosed at 3–18 MU s/c three times per week, temsirolimus 25 mg weekly intravenously, or IFN and temsirolimus at reduced dose in combination. There was no significant difference in objective response rates between arms (4.8%, 8.6%, 8.1%), but PFS and OS data favored single-agent temsirolimus with a median OS of 10.9 months (95% CI: 8.6–12.7, HR 0.73 [0.58–0.92]; p = 0.0078) for single-agent treatment compared to 7.3 months for IFNa alone (95% CI: 6.1–8.8). Increased toxicity was seen in the combination arm with no improvement in efficacy. Side effects of temsirolimus included stomatitis, rash, peripheral edema, mild myelosuppression, hyperglycemia, and hyperlipidemia with pneumonitis being recognized as a rare but potentially important treatment-related adverse event. Single-agent temsirolimus is a first-line treatment option with phase III evidence to support its use in poor prognosis and non-clear-cell RCC.
Bannayan–Riley–Ruvalcaba Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Gabriela Maria Abreu Gontijo, Clóvis Antônio Lopes Pinto
The development of PI3K/Akt/mTOR inhibitors is an area of intense research in oncology, as this pathway promotes cellular survival and chemotherapeutic resistance in a variety of malignancies. Inhibition of proximal components of the pathway such as PI3K or Akt, while desirable, is currently not possible for patients with PHTS because there are no published clinical trials with these inhibitors in cancer patients. In addition, it is not clear if inhibitors or PI3K or Akt will be as tolerable as inhibitors of mTOR. Inhibitors of mTOR are the most clinically developed and may serve as viable agents to treat PHTS. Rapamycin, a specific mTOR inhibitor, is FDA approved to prevent transplant rejection and for use in drug-eluting cardiac stents. Temsirolimus, a rapamycin analog, is FDA approved for the treatment of advanced renal cell carcinoma [1].
Experimental drug treatments for hepatocellular carcinoma: clinical trial failures 2015 to 2021
Published in Expert Opinion on Investigational Drugs, 2022
Zachary J. Brown, D. Brock Hewitt, Timothy M. Pawlik
The mTOR inhibitors, everolimus and temsirolimus, have been combined with sorafenib to treat patients with advanced HCC. The combination of everolimus with sorafenib demonstrated no increased efficacy over sorafenib alone [67]. Similarly, temsirolimus with sorafenib was deemed safe, but did not achieve its target for efficacy [68]. MEK inhibitors, such as refametinib and trametinib have also been utilized in combination with sorafenib. In a phase I study, refametinib plus sorafenib therapy displayed an acceptable toxicity profile and stabilized disease in one-half of patients [69]. This combination was then studied in a phase II trial where refametinib monotherapy had an ORR of 0%, DCR of 56.3%, OS of 5.8 months, and PFS of 1.9 months. Refametinib plus sorafenib had an ORR of 6.3%, DCR of 43.8%, OS of 12.7 months, and PFS 1.5 months [70]. Similarly, trametinib in combination with sorafenib had limited anticancer activity. Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response with a median PFS and OS of 3.7 and 7.8 months, respectively [71].
Pembrolizumab plus axitinib for the treatment of advanced renal cell carcinoma
Published in Expert Review of Anticancer Therapy, 2021
Martina Spisarová, Bohuslav Melichar, Denisa Vitásková, Hana Študentová
Angiogenesis represents one of the essential hallmarks of cancer [16]. Anti-VEGF drugs including sunitinib, pazopanib and bevacizumab represented for more than a decade the basis of front-line therapy in patients with mRCC [11–13,17]. Until recently, temsirolimus, an mTOR inhibitor, was the only agent with an alternative mechanism of action and proven activity in the first-line setting that was, however, limited to patients with poor prognosis [18]. Moreover, the toxicity and necessity of weekly infusions has limited the use of temsirolimus. Therefore, the first-line therapy has been dominated for more than a decade by oral MTKIs. The spectrum of agents with predominant anti-VEGF mechanism of action active in the first-line setting has been subsequently widened with tivozanib [19] and cabozantinib [20]. Cabozantinib has also inhibitory activity on other potential target molecules, MET and AXL. Although cabozantinib appeared to be superior to sunitinib in a phase II trial [20], the potential of long-term disease control with anti-VEGF therapy appears to be limited with only few patients experiencing prolonged complete response [14].
Treating central nervous system lymphoma in the era of precision medicine
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ytel Garcilazo-Reyes, Maria-José Ibáñez-Juliá, Isaias Hernández-Verdin, Ludovic Nguyen-Them, Nadia Younan, Caroline Houillier, Khê Hoang-Xuan, Agusti Alentorn
On the other hand, it has been suggested the interest in blocking the PI3 K/mammalian target of rapamycin (PI3 K/mTOR) pathway to overcome resistance in CD79B mutated tumors. The PI3 K signaling pathway plays a critical role in oncogene-mediated tumor growth and proliferation and has regulatory functions in cell survival, apoptosis, protein synthesis, and glucose metabolism [35,36]. Down in this signalization pathway, it is found a serine-threonine protein kinase, mTOR. Temsirolimus is an mTOR inhibitor, that has been studied in R/R PCNSL, mTOR is now recognized as a unique and important target for cancer therapeutics. There is only one prospective study that investigated the mTOR inhibition in R/R PCNSL using temsirolimus. This phase II nonrandomized, open-label study used temsirolimus as a single-agent with a two-stage design. In the first stage, patients were treated with temsirolimus 25 mg intravenously once per week, if no common toxicity criteria grades 3 to 4 were observed, all following patients were treated with 75 mg once per week. Korfel and colleagues demonstrated a high radiographic response of 54%, but a low median PFS of only 2.1 months, suggesting a transient effect [37]. Even less encouraging results were reported with buparlisib. Buparlisib is an oral pan-PI3 K inhibitor that had shown antitumor activity in lymphoma cell lines and induced apoptosis in DLBCL [38]. However, in a phase II trial, there was a response rate of 25% a median PFS of 39 days an 100% of relapses [39].