This excellent tolerability is especially

This excellent tolerability is especially interesting in the light of the fact that intravenous administration of liposomal ponatinib was predicted to yield much higher plasma concentrations as compared to the orally administered free drug. In addition, liposomal drug dose in absolute numbers was ten-fold lower than that of free ponatinib (3 mg/kg versus 30 mg/kg), yet only this formulation resulted in significant antitumor activity. Hence, the lower amount of L-ponatinib seems to more specifically target the tumor as compared to oral free ponatinib. In conclusion, in the present study we have demonstrated that stable liposomal formulations of FGFR inhibitors can be generated and – at least in case of ponatinib – significantly improve therapeutic efficacy and decrease side effects in vivo. Consequently, the presented liposomal formulation of ponatinib might represent a possible strategy to reduce the toxicity and increase the antitumor efficacy of ponatinib in the clinical routine.
Acknowledgments
Introduction Breast cancer is a heterogeneous disease with multiple clinical presentations and tumor characteristics. In recent years, gene chenodeoxycholic acid receptor profiling studies have classified breast tumors into four different molecular subtypes (luminal A, luminal B, HER2 enriched, and basal-like), leading to a new classification of breast cancer with prognostic and therapeutic implications [1]. Developments in breast cancer biology over the last years have permitted deconstructing the molecular profile of the most relevant breast cancer subtypes. This has led to an increase in therapeutic options, including more effective personalized therapy for breast cancer and substantial improvements in patient outcomes [2]. To date, the US Food and Drug Administration (FDA) has only approved a limited number of targeted therapies for the treatment of breast cancer. In addition to endocrine therapy, these include: five anti-HER2 therapies (trastuzumab, lapatinib, neratinib, T-DM1, and pertuzumab), everolimus, palbociclib, ribociclib, and abemaciclib [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. However, other strategies targeting different tyrosine kinase receptors are currently under way. The fibroblast growth factor receptor (FGFR) family comprises five transmembrane receptors, all but one with tyrosine kinase activity. During the past few years, considerable research has confirmed the essential role of FGFR signaling in cancer cell proliferation, angiogenesis, and survival, and this pathway appears, therefore, to be an excellent target for cancer therapy [13].
The fibroblast growth factor (FGF)/FGFR signaling pathway FGFs and FGFRs are involved in different physiologic processes, such as embryonic development, regulation of angiogenesis, and wound repair, among others. Additionally, the FGF/FGFR signaling network plays a critical role in cancer cell proliferation, survival, differentiation, migration, and apoptosis. For these reasons, dysregulation of the FGF/FGFR pathway consistently has been associated with human cancers as well as many other developmental disorders [13], [14]. The human FGFR family contains four classical FGFRs (FGFR1, FGFR2, FGFR3, and FGFR4) encoded by four distinct genes (FGFR1-4). It is noteworthy to mention that in addition to the classical receptors encoded by FGFR genes, several isoforms with different ligand-binding affinities are generated through alternative splicing of FGFR1 through FGFR3. Each receptor comprises an extracellular domain, a transmembrane domain, and a tyrosine kinase cytoplasmic domain. The extracellular region consists of three immunoglobulin-like (Ig) domains (IgI, IgII, and IgIII) and an acid box, typically located between IgI and IgII. The IgII and IgIII domains constitute the FGF ligand-binding site [15]. Recently, a fifth member of the FGFR family has been discovered, the fibroblast growth factor receptor like 1 (FGFRL1 or FGFR5), that also contains three extracellular Ig-like domains but lacks the protein tyrosine kinase domain [16].