sirolimus and nintedanib

In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. Conference proceedings from major cancer congresses (2007-2015) were handsearched. Sixteen randomized controlled trials were identified, mostly phase III. Overall, targeted therapies were associated with either improved [sunitinib, bevacizumab+interferon α (IFNα) and temsirolimus] or comparable (sorafenib) progression-free survival (PFS) versus IFNα monotherapy. Sunitinib demonstrated comparable PFS and overall survival to pazopanib, comparable PFS to sorafenib and shorter PFS compared with bevacizumab+IFNα (although no conclusions were made with regard to superiority/inferiority). Compared with sorafenib, tivozanib demonstrated a significantly longer PFS, and both tivozanib and axitinib demonstrated higher response rates. Nintedanib demonstrated comparable PFS and overall survival to sunitinib in a phase II trial. Temsirolimus, sunitinib and sorafenib treatment led to better HRQoL versus IFNα; pazopanib was associated with better HRQoL versus sunitinib. No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine kinase inhibitors.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Humans; Imidazoles; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Quality of Life; Quinazolines; Quinolines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sulfonamides; Sunitinib

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Doxycycline; Enzyme Inhibitors; Humans; Idiopathic Pulmonary Fibrosis; Immunosuppressive Agents; Indoles; Lung Diseases, Interstitial; Lymphangioleiomyomatosis; Pyridones; Sarcoidosis, Pulmonary; Sirolimus; Smoking; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha

Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.

Topics: Activin Receptors, Type II; Animals; Bone Morphogenetic Proteins; Disease Models, Animal; Endothelial Cells; Growth Differentiation Factor 2; Indoles; Mice; Mice, Knockout; Signal Transduction; Sirolimus; Smad1 Protein; Smad5 Protein; Smad8 Protein; Telangiectasia, Hereditary Hemorrhagic; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor Receptor-2