Midostaurin

Approximately 40-45% of younger and 10-20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is particularly gloomy for patients with relapsed and/or refractory disease (cure rates no higher than 10%). Allogeneic hematopoietic stem cell transplantation (HSCT), the only realistic hope of cure for these patients, is an option for only a minority. In recent years, much has been learned about the genomic and epigenomic landscapes of AML, and the clonal architecture of both de novo and secondary AML has begun to be unraveled. These advances have paved the way for rational drug development as new "drugable" targets have emerged. Although no new drug has been approved for AML in over four decades, with the exception of gemtuzumab ozogamycin, which was subsequently withdrawn, there is progress on the horizon with the possible regulatory approval soon of agents such as CPX-351 and midostaurin, the Food and Drug Administration "breakthrough" designation granted to venetoclax, and promising agents such as the IDH inhibitors AG-221 and AG-120, the smoothened inhibitor glasdegib and the histone deacetylase inhibitor pracinostat. In our practice, we treat most patients with relapsed/refractory AML on clinical trials, taking into consideration their prior treatment history and response to the same.

Chondrocytes rapidly lose their phenotypic expression of collagen II and aggrecan when grown on 2D substrates. It has generally been observed that a fibroblastic morphology with strong actin-myosin contractility inhibits chondrogenesis, whereas chondrogenesis may be promoted by depolymerization of the stress fibers and/or disruption of the physical link between the actin stress fibers and the ECM, as is the case in 3D hydrogels. Here we studied the relationship between the actin-myosin cytoskeleton and expression of chondrogenic markers by culturing fibroblastic chondrocytes in the presence of cytochalasin D and staurosporine. Both drugs induced collagen II re-expression; however, renewed glycosaminoglycan synthesis could only be observed upon treatment with staurosporine. The chondrogenic effect of staurosporine was augmented when blebbistatin, an inhibitor of myosin/actin contractility, was added to the staurosporine-stimulated cultures. Furthermore, in 3D alginate cultures, the amount of staurosporine required to induce chondrogenesis was much lower compared to 2D cultures (0.625 nM vs. 2.5 nM). Using a selection of specific signaling pathway inhibitors, it was found that PI3K-, PKC- and p38-MAPK pathways positively regulated chondrogenesis while the ERK-pathway was found to be a negative regulator in staurosporine-induced re-differentiation, whereas down-regulation of ILK by siRNA indicated that ILK is not determining for chondrocyte re-differentiation.

The purpose of this study was to evaluate the anti-head and neck squamous cell carcinoma (anti-HNSCC) cell activity by C6 ceramide and multikinase inhibitor PKC412. Experiments were performed on HNSCC cell lines (SQ20B and SCC-9) and primary human oral carcinoma cells. Results showed that PKC412 inhibited HNSCC cell proliferation without provoking apoptosis activation. Cotreatment of C6 ceramide significantly augmented PKC412-induced lethality in HNSCC cells. PKC412 decreased Akt-mammalian target of rapamycin (mTOR) activation in HNSCC cells, facilitated with cotreatment of C6 ceramide. In contrast, exogenous expression of a constitutively active Akt restored Akt-mTOR activation and attenuated lethality by the cotreatment. We propose that Mcl-1 is a primary resistance factor of PKC412. The cytotoxicity of PKC412 in HNSCC cells was potentiated with Mcl-1 short hairpin RNA knockdown, but was attenuated with Mcl-1 overexpression. Intriguingly, C6 ceramide downregulated Mcl-1 in HNSCC cells. In vivo, PKC412 oral administration inhibited SQ20B xenograft tumor growth in severe combined immunodeficient mice. The antitumor activity of PKC412 was further sensitized with coadministration of liposomal C6 ceramide.