Current Opinion in Pharmacology最新文献

Mutations in RyR alter the cell's Ca²⁺ homeostasis and can cause serious health problems for which few effective therapies are available. Until recently, there was little structural context for the hundreds of mutations linked to muscular disorders reported for this large channel. Growing knowledge of the three-dimensional structure of RyR starts to illustrate the fine control of Ca²⁺ release. Current efforts directed towards understanding how disease mutations impinge in such processes will be crucial for future design of novel therapies. In this review article we discuss the up-to-date information about mutations according to their role in the 3D structure, and classified them to provide context from a structural perspective.

Store-Operated Ca²⁺ entry (SOCE) is recognized as a key mechanism in muscle physiology necessary to refill intracellular Ca²⁺ stores during sustained muscle activity. For many years the cell structures expected to mediate SOCE in skeletal muscle fibres remained unknown. Recently, the identification of Ca²⁺ Entry Units (CEUs) in exercised muscle fibres opened new insights into the role of extracellular Ca²⁺ in muscle contraction and, more generally, in intracellular Ca²⁺ homeostasis. Accordingly, intracellular Ca²⁺ unbalance due to alterations in SOCE strictly correlates with muscle disfunction and disease. Mutations in proteins involved in SOCE (STIM1, ORAI1, and CASQ1) have been linked to tubular aggregate myopathy (TAM), a disease that causes muscle weakness and myalgia and is characterized by a typical accumulation of highly ordered and packed membrane tubules originated from the sarcoplasmic reticulum (SR). Achieving a full understanding of the molecular pathways activated by alterations in Ca²⁺ entry mechanisms is a necessary step to design effective therapies for human SOCE-related disorders.

Congenital myopathies are rare and severe genetic diseases affecting the skeletal muscle function in children and adults. They present a variable spectrum of phenotypes and a genetic heterogeneity. Subgroups are defined according to the clinical and histopathological features and encompass core myopathy, centronuclear myopathy, nemaline myopathy and other rare congenital myopathies. No approved treatment exists to date for any congenital myopathies. To tackle this important unmet need, an increased number of proof-of-concept studies recently assessed the therapeutic potential of various strategies, either pharmacological or genetic-based, aiming at counteracting muscle weakness or/and cure the pathology. Here, we list the implicated genes and cellular pathways, and review the therapeutic approaches preclinically tested and the ongoing/completed clinical trials for the different types of congenital myopathies.

Myopathies related to variations in the RYR1 gene are genetic diseases for which the therapeutic options are sparse, in part because of the very large size of the gene and protein, and of the distribution of variations all along the sequence. Taking advantage of the progress made in the gene therapy field, different approaches can be applied to the different genetic variations, either at the mRNA level or directly at the DNA level, specifically with the new gene editing tools. Some of those have already been tested in cellulo and/or in vivo, and for the development of the most innovative gene editing technology, inspiration can be sought in other genetic diseases.

About half of colorectal cancers harbor mutations in the KRAS gene. The presence of these mutations is associated with worse prognosis and, until now, the absence of matched targeted therapy options. In this review, we discuss clinical efforts to target KRAS in colorectal cancer from studies of downstream inhibitors to recent direct inhibitors of KRAS^G12C and other KRAS mutants. Early clinical trial data, however, suggest more limited activity for these novel inhibitors in colorectal cancer compared to other cancer types, and we discuss the role of receptor tyrosine kinase signaling and parallel signaling pathways in modulating response to these inhibitors. We also review the effect of KRAS mutations on the tumor-immune microenvironment and efforts to induce an immune response against these tumors.

The INhibitor of Growth (ING) proteins (ING1, ING2, ING3, ING4 and ING5) are a family of epigenetic regulators. Their decreased expression in numerous cancers led to identifying the ING proteins as gatekeeper tumor suppressors as they regulate cell cycle progression, apoptosis and senescence. Subsequently, they were also described as caretaker tumor suppressors through their involvement in DNA replication and the DNA damage response (DDR). Recent studies have identified new interactions of the ING proteins with proteins or pathways implicated in cell proliferation, the maintenance of stem cells pluripotency or the DDR. Furthermore, the ING proteins have been identified as regulators of ribosomal RNA synthesis and of mRNA stability and as regulators of mitochondrial DNA transcription resulting in the regulation of metabolism. These new findings highlight new antitumorigenic activities of the ING proteins that are potential targets for cancer treatment.

Hypogonadism is frequent with a prevalence of 2% in the general population. Hypogonadism may derive from any condition able to disrupt the hypothalamic-pituitary-testis (HPT) axis at one or more levels. Hypogonadism may be classified according to the age of onset, its potential reversibility and level of the HPT axis damage. The latter categorization is useful to decide on the treatment. Damages to the hypothalamus-pituitary may benefit from either GnRH, gonadotropin or T therapy with the former carrying the advantage of stimulating spermatogenesis. Conversely, when the testis is damaged, T therapy is the only option and restoration of spermatogenesis is not possible. Therefore, the choice of therapy is primarily based on the diagnosis and patients’ needs and both should be carefully considered.

Polycystic ovary syndrome is a prevalent endocrinopathy involving androgen excess, and anovulatory infertility. The disorder is also associated with many comorbidities such as obesity and hyperinsulinemia, and an increased risk of cardiovascular complications. Reproductive, endocrine, and metabolic symptoms are highly variable, with heterogenous phenotypes adding complexity to clinical management of symptoms. This review highlights recent findings regarding emerging therapies for treating polycystic ovary syndrome, including i) pharmacological agents to target androgen excess, ii) modulation of kisspeptin signalling to target central neuroendocrine dysregulation, and iii) novel insulin sensitisers to combat peripheral metabolic dysfunction.

Stomach cancer is an aggressive disease and represents a global health problem. The majority of patients with localised disease present with locally advanced cancer that requires multimodality treatment. Chemoradiotherapy delivered after D2 gastrectomy has been evaluated in a number of clinical studies and best evidence, thus far, does not support its use in the post-operative setting. Data from currently recruiting and ongoing trials with exploratory translational endpoints are eagerly awaited to direct the use of chemoradiotherapy in the neoadjuvant setting. Radiotherapy can be effective in the palliation of symptoms associated with advanced gastric cancer. Furthermore, Stereotactic Body Radiotherapy has the potential to provide long term disease control in a proportion of gastric cancer patients with oligometastatic liver disease.