Pharmacokinetics and pharmacodynamics of Hedgehog pathway inhibitors used in the treatment of advanced or treatment-refractory basal cell carcinoma.

INTRODUCTION: Sonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs)for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients. AREAS COVERED: This review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations. EXPERT OPINION: Although both HHIs act at the same molecular target in the Hedgehog pathway, there are significant differences in their pharmacokinetic profiles that may play a potential role in their efficacy and safety. Evidence-based recommendations serve to inform clinicians until direct comparative clinical trials of sonidegib versus vismodegib are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties.

Inducible Nitric Oxide Synthase and CD11b+Gr1+ Cells Impair Lymphatic Contraction of Tumor-Draining Lymphatic Vessels.

Background: Metastatic tumor cells spread through lymphatic vessels and colonize draining lymph nodes (LNs). It is known that tumors induce lymphangiogenesis to enhance lymphatic metastasis and that metastatic cancer cells are carried by lymph flow to LNs. Methods and Results: Here, we investigated the molecular and cellular regulation of collecting lymphatic vessel contraction in vessels draining a metastatic tumor using intravital microscopy. In tumor-draining collecting lymphatic vessels, we found vessel contraction was suppressed. The infiltration of peritumor tissue by inducible nitric oxide synthase positive and CD11b+Gr1+ myeloid cells played a critical role in the suppression of lymphatic contraction. Depletion of Gr1+ cells with an anti-Gr1 antibody improved contraction of tumor-draining lymphatic vessels. In addition, inducing tumor cell death restored lymphatic contraction in nude mice. Conclusions: These findings indicate that tumors contribute to regulation of lymphatic transport in a reversible manner, warranting further investigation into the role of impaired lymphatic transport in cancer progression.

Systemic administration of L-arginine benefits mdx skeletal muscle function.

A major consequence of muscular dystrophy is that increased membrane fragility leads to high calcium influx and results in muscle degeneration and myonecrosis. Prior reports have demonstrated that increased nitric oxide production via L-arginine treatment of normal and mdx mice resulted in increased expression of utrophin and increased activation of muscle satellite cells, which could ameliorate the dystrophic pathology. We delivered L-arginine to normal and mdx mice, and examined muscles for any functional changes associated with its administration. Treated mdx muscles were less susceptible to contraction-induced damage and exhibited a rightward shift of the force-frequency relationship. Immunoblotting revealed increases in utrophin and gamma-sarcoglycan in the treated muscles. There was also a decrease in Evans blue dye uptake, indicating a reduction in myonecrosis. However, there was no decrease in serum creatine kinase or the proportion of central nuclei, nor any improvement in specific force. Together, these results show that L-arginine treatment can be beneficial to mdx muscle function, perhaps through a combination of enhanced calcium handling and increased utrophin, thereby decreasing muscle degeneration.

Attenuation of skeletal muscle atrophy via protease inhibition.

Skeletal muscle atrophy in response to a number of muscle wasting conditions, including disuse, involves the induction of increased protein breakdown, decreased protein synthesis, and likely a variable component of apoptosis. The increased activation of specific proteases in the atrophy process presents a number of potential therapeutic targets to reduce muscle atrophy via protease inhibition. In this study, mice were provided with food supplemented with the Bowman-Birk inhibitor (BBI), a serine protease inhibitor known to reduce the proteolytic activity of a number of proteases, such as chymotrypsin, trypsin, elastase, cathepsin G, and chymase. Mice fed the BBI diet were suspended for 3-14 days, and the muscle mass and function were then compared with those of the suspended mice on a normal diet. The results indicate that dietary supplementation with BBI significantly attenuates the normal loss of muscle mass and strength following unloading. Furthermore, the data reveal the existence of yet uncharacterized serine proteases that are important contributors to the evolution of disuse atrophy, since BBI inhibited serine protease activity that was elevated following hindlimb unloading and also slowed the loss of muscle fiber size. These results demonstrate that targeted reduction of protein degradation can limit the severity of muscle mass loss following hindlimb unloading. Thus BBI is a candidate therapeutic agent to minimize skeletal muscle atrophy and loss of strength associated with disuse, cachexia, sepsis, weightlessness, or the combination of age and inactivity.

Two distinct conformers of the cyclic heptapeptide phakellistatin 2 isolated from the fijian marine sponge stylotellaaurantium.

The isolation, structure determination, and solution conformation of two conformers of the cyclic heptapeptide phakellistatin 2 (cyclo-[Phe1-cis-Pro2-Ile3-Ile4-cis-Pro5-Tyr6-cis-Pro7]) isolated from the Fijian marine sponge Stylotella aurantium are reported. The conformers can be isolated separately by HPLC and are stable in methanol solution over a period of weeks as determined by NMR. Their NMR spectra and mass spectral fragmentation patterns differ significantly. Their solution conformations were determined by NOE-restrained molecular dynamics calculations and indicated that the two conformers had different folds, hydrogen bonding patterns, and solvent accessible surfaces. These factors may contribute to the independent stability of the two conformers, and may explain the variable biological activity previously reported for phakellistatin 2.

Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice.

Duchenne muscular dystrophy is an X-linked degenerative disorder of muscle caused by the absence of the protein dystrophin. A major consequence of muscular dystrophy is that the normal regenerative capacity of skeletal muscle cannot compensate for increased susceptibility to damage, leading to repetitive cycles of degeneration-regeneration and ultimately resulting in the replacement of muscle fibers with fibrotic tissue. Because insulin-like growth factor I (IGF-I) has been shown to enhance muscle regeneration and protein synthetic pathways, we asked whether high levels of muscle-specific expression of IGF-I in mdx muscle could preserve muscle function in the diseased state. In transgenic mdx mice expressing mIgf-I (mdx:mIgf+/+), we showed that muscle mass increased by at least 40% leading to similar increases in force generation in extensor digitorum longus muscles compared with those from mdx mice. Diaphragms of transgenic mdx:mIgf+/+ exhibited significant hypertrophy and hyperplasia at all ages observed. Furthermore, the IGF-I expression significantly reduced the amount of fibrosis normally observed in diaphragms from aged mdx mice. Decreased myonecrosis was also observed in diaphragms and quadriceps from mdx:mIgf+/+ mice when compared with age-matched mdx animals. Finally, signaling pathways associated with muscle regeneration and protection against apoptosis were significantly elevated. These results suggest that a combination of promoting muscle regenerative capacity and preventing muscle necrosis could be an effective treatment for the secondary symptoms caused by the primary loss of dystrophin.