Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins

The rapidly growing recognition of the role of oncogenic ROS1 fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective ROS1 inhibitors for use as molecularly targeted therapy. Using a multidisciplinary approach involving small molecule screening in combination with in vitro and in vivo tumor models, we show that foretinib (GSK1363089) is a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with ROS1-rearranged non–small-cell lung carcinoma, recently emerging clinical evidence suggests that patients may develop crizotinib resistance due to acquired point mutations in the kinase domain of ROS1, thus necessitating identification of additional potent ROS1 inhibitors for therapeutic intervention. We confirm that the ROS1^G2032R mutant, recently reported in clinical resistance to crizotinib, retains foretinib sensitivity at concentrations below safe, clinically achievable levels. Furthermore, we use an accelerated mutagenesis screen to preemptively identify mutations in the ROS1 kinase domain that confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data strongly suggest that foretinib is a highly effective ROS1 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with ROS1-driven malignancies is warranted.Receptor tyrosine kinases (RTKs) are critical mediators of extracellular signals that control key cell growth, survival, and motility pathways. Conversely, deregulated and constitutive RTK activation is responsible for the initiation and progression of many cancers. Multiple mechanisms contribute to aberrant RTK activation including chromosomal rearrangements, point mutations, and gene amplification. Oncogenic activation of the orphan RTK c-ros oncogene 1 (ROS1) is observed in a subset of patients with glioblastoma, non–small-cell lung cancer (NSCLC), and cholangiocarcinoma (1–5). In most cases, ROS1 signaling is activated by interchromosomal translocation or intrachromosomal deletion that results in N-terminal ROS1 fusion genes. Several ROS1 kinase fusion proteins have been identified, including the Fused in Glioblastoma–ROS1 (FIG–ROS) that was first discovered in a human glioblastoma cell line (2) and more recently in patients with NSCLC (4), cholangiocarcinoma (3), and serous ovarian carcinoma (6). The SLC34A2–ROS1 (SLC–ROS) fusion is present in a subset of patients with NSCLC (1, 7) and gastric cancer (8). Other ROS1 fusions include CD74–ROS1, EZR–ROS1, LRIG3–ROS1, SDC4–ROS1, and TPM3–ROS1 (5).Given the recent success of molecularly targeted therapies in treating cancers driven by oncogenic kinases, there is acute clinical momentum to identify inhibitors that selectively target ROS1 fusions. Because the ROS1 and Anaplastic Lymphoma Kinase (ALK) domains are partially homologous, the Food and Drug Administration (FDA)-approved ALK/MET kinase inhibitor crizotinib is being investigated via phase I/II clinical trials for its efficacy in ROS1-driven lung cancer patients (9). Although early results appear promising, consistent with the clinical experience of crizotinib in patients with ALK-positive lung cancer to date, as well as prior experience with kinase inhibitors in many other malignancies (10–13), recent evidence suggests that a subset of patients with crizotinib-treated ROS1 fusion-positive may acquire ROS1 kinase domain mutations that confer drug resistance, thus necessitating alternative therapeutic approaches.To identify additional and potentially more efficacious ROS1 inhibitors, we used an unbiased, high-throughput kinase inhibitor screening assay and discovered that foretinib (GSK1363089) and Gö6976 are potent inhibitors of ROS1. Foretinib selectively suppresses the growth of the SLC–ROS-driven human NSCLC cell line HCC78 and of FIG–ROS-driven murine cholangiocarcinoma, but not of EGFR-driven NSCLC or phosphatase and tensin homolog (PTEN)-suppressed murine cholangiocarcinoma cells. Further, treatment of tumor-bearing mice with foretinib resulted in specific and dramatic regression of FIG–ROS-driven tumors in contrast to non-FIG–ROS tumors that share similar histopathological features. Importantly, we also use a cell-based in vitro resistance screen to preemptively identify several ROS1 kinase domain point mutations that confer resistance to crizotinib and show that these crizotinib-resistant ROS1 mutants remain sensitive to foretinib. These data suggest that foretinib may provide an alternative front-line treatment for ROS1-positive tumors and an effective second-line approach for patients that develop crizotinib-resistant disease.     

REM sleep motor dysfunction in multiple system atrophy: with special emphasis on sleep talk as its early clinical manifestation

Various neurodegenerative diseases involving brainstemstructures as one of the main pathological lesions are reported to beassociated with REM sleep behaviour disorder. Full blown REM sleepbehaviour disorder can be diagnosed clinically, but REM sleep motordysfunction, a pathophysiological basis of REM sleep behaviourdisorder, is difficult to detect without all night polysomnography. Twenty one consecutive patients with multiple system atrophy with nocomplaints of nocturnal abnormal behaviours were clinically evaluatedto determine the presence of sleep related symptoms. All nightpolysomnography with video monitoring was performed toinvestigate REM sleep characteristics and patients' behaviours. In85.7% (18 of 21) of the patients' sleep talk started or increased around or after the clinical onset of the primary diseases. REM sleepwithout atonia occupied more than 15%(16.2%-100%) of the REM sleeptime in all but one patient. In 90.5% (19 of 21) of patients, motorevents such as sleep talk and various combinations of craniofacial,orofacial, or limb movements occurred at various frequencies mostlyduring REM sleep without atonia. In patients with multiple systematrophy, REM sleep motor dysfunction is a commonpolysomnographic finding which is otherwise overlooked, and sleeptalk may be its early clinical manifestation.

     

Three-dimensional quantitative structure–activity relationship CoMFA/CoMSIA on pyrrolidine-based tartrate diamides as TACE inhibitors

A series of pyrrolidine-based tartrate diamides having selective tumor necrosis factor-α converting enzyme (TACE) inhibitory activity was selected for the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies. Total 76 compounds were selected by considering a high deviation in the biological activity and structural variations. The quality and predictive power of 3D-QSAR, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for the atom-based, centroid/atom-based, data-based alignments were performed. Various models were developed with the help of these alignments. The best model was developed with data-based alignment. The optimal predictive CoMFA model was obtained with cross-validated r ² = 0.53 with six component, non-cross-validated r ² = 0.94, standard error of estimates 0.23, F-value = 121.98 and optimal CoMSIA model was obtained with cross-validated r ² = 0.53 with five components, non-cross-validated r ² = 0.93, standard error of estimates = 0.24 and F-value = 138.83. These models also showed the best test set prediction with predictive r ² value of 0.65 and 0.73, respectively. Thus, on the basis of predictive power COMSIA model appeared to be the best one. The statistical parameters from these models indicate that the data are being well fitted and also have high predictive ability. Moreover, the resulting 3D-CoMFA/CoMSIA contour maps provide useful guidance for designing of highly active TACE inhibitors.     

Efficacy and safety of two polyherbal combinations: E-MA-H and E-MA-HP in male sexual dysfunction

Efficacy and safety of 2 herbal products--E-MA-H at 2 dose levels, low (HLD) and high (HHD), and E-MA-HP (HP) capsules--versus placebo (PL) was evaluated in subjects with male sexual dysfunction. Males aged 21-60 with erectile dysfunction, premature ejaculation, or other form of sexual dysfunction were studied in this triple-blind, randomized, placebo-controlled, parallel-groups trial. Subjects received any one of the following 4 interventions: E-MA-H 2 capsules at night (HLD) for 60 days; E-MA-H 2 capsules twice daily for 30 days, followed by 2 capsules at night for 30 days (HHD); E-MA-HP (HP) 2 capsules twice daily for 60 days; or placebo (PL) 2 capsules twice daily for 60 days. All dosage regimens were standardized to 2 capsules twice daily by using 2 matching placebo capsules as the morning dose for HLD and on days 31-60 for HHD. Efficacy outcome measures were the international index of erectile function; index for premature ejaculation; erectile dysfunction inventory of treatment satisfaction; subjects' and investigators' global assessment. Safety was assessed through adverse events; hematology; blood chemistry. Of 148 subjects enrolled, 1 was excluded from analysis; data on the intention-to-treat population of 147 (PL = 36, HLD = 38, HHD = 37, HP = 36) were analyzed. There was a significant (P < 0.01) increase in the total international index of erectile function score (mean ± SEM) in subjects receiving HLD (16.28 ± 1.39), HHD (15.40 ± 1.22), and HP (18.55 ± 1.36) compared with PL (6.83 ± 1.52). The same pattern was seen with increase in index for premature ejaculation scores: HLD (9.68 ± 1.17), HHD (10.27 ± 1.05), HP (11.36 ± 1.20) versus PL (3.77 ± 1.04). There was no significant difference in effect among the active treatment groups. The incidence of adverse events was similar in all the groups. Laboratory evaluations did not show any clinically significant abnormality in any of the groups. Treatment with HLD, HHD, and HP is well tolerated, and more effective than placebo (P < 0.01), in subjects with erectile dysfunction, premature ejaculation, and other forms of sexual dysfunction.     

Comparison between clinical and audiological results of tympanoplasty with modified sandwich technique and underlay technique

Introduction

Surgical repair of the tympanic membrane, termed a type one tympanoplasty is a tried and tested treatment modality. Overlay or underlay technique of tympanoplasty is common. Sandwich tympanoplasty is the combined overlay and underlay grafting of tympanic membrane.

Stereotactic body radiation therapy (SBRT) for early-stage lung cancer in the elderly

Early-stage non-small cell lung cancer (NSCLC) is on the rise due to the implementation of screening guidelines for patients at risk for developing lung cancer. It is anticipated that as the US population continues to age, there will be a higher percentage of medically inoperable early-stage lung cancer patients. For this reason, noninvasive ablative therapies are necessary. Stereotactic body radiation therapy (SBRT) is an effective modality in addressing early-stage NSCLC. SBRT consists of high-dose radiation delivered over 3–5 treatments. Several randomized trials comparing surgery to SBRT in early-stage operable patients have unfortunately closed early due to poor accrual. However, a recent pooled analysis from 2 randomized trials (StereoTActic Radiotherapy and Radiosurgery Or Surgery for operable Early-stage non–small cell Lung cancer) comparing surgery to SBRT did show comparable local control and overall survival rates between surgery and SBRT, offering a very effective, noninvasive modality for older adult patients with early-stage NSCLC. In this review, we summarize the role of SBRT in early-stage NSCLC, in particularly applied to the older adult population.