Personalizing therapies for gastric cancer: Molecular mechanisms and novel targeted therapies

Globally,gastric cancer is the 4thmost frequently diagnosed cancer and the 2ndleading cause of death from cancer,with an estimated 990000 new cases and738000 deaths registered in 2008.In the advanced setting,standard chemotherapies protocols acquired an important role since last decades in prolong survival.Moreover,recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2(HER2)therapies.Trastuzumab,an anti-HER2 monoclonal antibody,was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy.Further,HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field.Thus,we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer,providing a comprehensive overview of molecular mechanisms and novel trials involved.     

Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias

Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50–70% of patients who achieve a complete remission, and only 20–30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20–30% transforming to AML. The advanced age of the majority of MDS patients limits the therapeutic strategies often to supportive care. To address these shortcomings, much effort has been directed toward the development of novel treatment strategies that target the evolution and proliferation of malignant clones. Presented here is an overview of molecularly targeted therapies currently being tested in AML and MDS patients, with a focus on FMS-like tyrosine kinase 3 inhibitors, farnesyltransferase inhibitors, antiangiogenesis agents, DNA hypomethylation agents, and histone deacetylase inhibitors.     

The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations

The authors review the genes, and their respective proteins, responsible for eight autoinflammatory conditions. Familial Mediterranean fever is caused by mutations in pyrin, which is the prototype of a new family of proteins belonging to the death-domain superfamily. This new group of proteins, which regulate apoptosis, inflammation, and cytokine processing, share an approximately 90-amino-acid N-terminal sequence called the PYRIN domain. Mutations in another PYRIN domain protein, termed cryopyrin, are responsible for three clinically defined illnesses, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and NOMID/CINCA. A related protein encoded by the gene is responsible for the Mendelian disorder, Blau syndrome, and also predisposes to Crohn disease. The gene responsible for PAPA syndrome has recently been identified as, and preliminary results from the authors' laboratory also implicate its protein product in these pathways. Lastly, the authors discuss the broadening genetic and clinical spectrum of TRAPS, an autoinflammatory syndrome resulting from mutations in the 55-kDa receptor for tumor necrosis factor.     

库欣病的分子机制及靶向药物

由垂体瘤分泌过多的促肾上腺皮质激素导致的库欣综合征,又称为库欣病,首选治疗为手术治疗,放射治疗和药物治疗为其辅助治疗,但疗效均有限.近年来关于库欣病发病机制的研究集中于调控细胞增殖的异常蛋白表达和调控激素分泌的异常信号转导,靶点主要为表皮生长因子受体(EGFR)、细胞周期蛋白E(CDK2/Cyclin E)和热休克蛋白90(HSP90),相应的靶向药物吉非替尼、roscovitine和水飞蓟素均能有效减小肿瘤体积,降低促肾上腺皮质激素水平.     

Hepatocellular carcinoma: locoregional and targeted therapies

HCC is a leading cause of morbidity and mortality worldwide. Advances in cancer screening and surveillance have allowed for earlier detection of tumors, affording greater treatment potential. The advent of locoregional therapies has generated greater treatment options for patients with HCC. Either alone or in combination as an adjuvant or neoadjuvant therapy, these novel approaches continue to hold promise for improving morbidity and/or mortality of patients with HCC. The emergence of systemic molecular targeted therapies increases the role of translational science. Whereas surgical resection and transplantation conventionally form the cornerstone of curative approaches, the advancement of locoregional therapies holds great promise in adding to the curative armamentarium.     

The use of statins in acute coronary syndromes: the mechanisms behind the outcomes

Lipid-lowering drugs, in particular statin treatments, have been shown to reduce the incidence of initial and recurrent coronary heart disease (CHD) events within several years of initiating therapy. This effect can be clinically detected within the first 1 to 2 years in randomized trials. Recent observational and clinical trial data suggest that lipid-lowering therapy initiated at the time of an acute coronary event can reduce recurrent events, and possibly all-cause mortality, in a much shorter period of time. The possible mechanisms by which this benefit occurs include the effect of reduced lipoprotein levels, as well as an independent effect of statins on endothelial function. Statins improve endothelial-dependent flow-mediated vasodilation by increasing the bioavailability of nitric oxide. They stabilize the plaque by modulating the inflammatory response within the vessel wall. They also decrease clot formation by decreasing the adherence of platelets to the ruptured plaque and by acting on the extrinsic coagulation cascade pathway. This review examines these effects of statins and lipoproteins on vascular function, as well as the clinical evidence supporting early treatment in acute coronary syndromes.     

Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies.     

The use of selective immunosuppressive therapy on myelodysplastic syndromes in targeted populations results in good response rates and avoids treatment-related disease progression

To determine the treatment response and disease progression in strictly selected patients with myelodysplastic syndrome undergoing immunosuppressive therapy (IST), patients were required to have an international prognostic scoring system [corrected] (IPSS) score ≤ 1.0 and at least one of the following conditions: (1) expression of the HLA-DR15 allele, (2) bone marrow (BM) cellularity of less than 30%, and (3) abnormal immune index of BM T-lymphocytes.The exclusion criteria were as follows: (1) ≥ 5% marrow myeloblasts, (2) poor karyotype, and (3) diagnosis of concurrent nonhematological malignancy. Patients received antithymocyte globulin followed by cyclosporine A (CsA) or CsA alone for at least 3 months. Seventy-one cases were analyzed. The total response rate was 77.5% (55/71 cases) with 11 complete responses. The response rate was positively correlated with the number of recruitment criteria met. Patients with an abnormal CD8, an abnormal CD4, or both had similar response rates. Patients who responded to treatment had significantly lower Th1 and Tc1 levels after treatment (P < 0.01 and P < 0.001, respectively), and six of eight patients with abnormal chromosomes did not show obviously abnormal clonal expansion when reassessed after IST. During the median observation period of 24 months, only two cases exhibited disease progression. At the median observation of 24 months, 35 of 55 responders (63.6%) maintained a hematological response, and 60 of 71 patients (84.5%) were still alive. The strictly selective use of IST may yield high response rates and can avoid treatment-related acute myeloid leukemia transformation. IST significantly reduces Th1 and Tc1 levels without causing malignant clonal expansion.     

Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with a multifactorial pathophysiology. Full comprehension of IBD pathology is still out of reach and, therefore, treatment is far from ideal. Nevertheless, components involved in IBD pathogenesis including environmental, genetic, microbial, and immunological factors are continuously being investigated and the improved knowledge contributes to the development of new therapies. In this article we review the aspects of the immunopathogenesis of IBD, with focus on mucosal immunity, and discuss mechanisms of action for current and emerging biological therapies.     

Efficacy and safety of combination targeted therapies in immune-mediated inflammatory disease: the COMBIO study

BackgroundUse of a combination of targeted therapies (COMBIO) in patients with refractory/overlapping immune-mediated inflammatory diseases (IMIDs) has increased, but reported data remain scarce. We aimed to assess effectiveness and safety of COMBIO in patients with IMIDs.MethodsWe conducted a French ambispective multicenter cohort study from September 2020 to May 2021, including adults’ patients with 1 or 2 IMIDs and treated at least 3-month with COMBIO.ResultsOverall, 143 patients were included. The most common IMIDs were Crohn's disease (63.6%), axial spondyloarthritis (37.7%), and ulcerative colitis (14%). Half of patients had only one IMID, of which 60% were Crohn's disease. Mean duration of COMBIO was 274.5±59.3 weeks, and COMBIO persistence at 104 weeks was estimated at 64.1%. The most frequent COMBIOs combined anti-TNF agents with vedolizumab (30%) or ustekinumab (28.7%). Overall, 50% of patients achieved significant and 27% mild-to-moderate improvement in patient-reported outcomes. Extended duration of COMBIO (aOR=1.09; 95% CI: 1.03-1.14; p=0.002) and diagnoses of two IMIDs (aOR=3.46; 95%CI: 1.29-9.26; p=0.013) were associated with significant improvement in patient-reported outcomes. Incidence of serious infection during COMBIO was 4.51 per 100 person-years (95% CI 2.20-8.27) and 5 COMBIOs were discontinued due to adverse events.ConclusionsCOMBIO can be effective and safe in patients with refractory/overlapping IMIDs.     

Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies

Endothelial cells control vascular homeostasis by generating paracrine factors that regulate vascular tone, inhibit platelet function, prevent adhesion of leukocytes, and limit proliferation of vascular smooth muscle. The dominant factor responsible for many of those effects is endothelium-derived nitric oxide (NO). Endothelial dysfunction characterized by enhanced inactivation or reduced synthesis of NO, alone or in combination, is seen in conjunction with risk factors for cardiovascular disease. Endothelial dysfunction can promote vasospasm, thrombosis, vascular inflammation, and proliferation of the intima. Vascular oxidative stress and increased production of reactive oxygen species contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase or the mitochondrial respiratory chain) and antioxidant enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase and paraoxonase). In addition, small-molecular-weight antioxidants might have a role in the defense against oxidative stress. Increased concentrations of reactive oxygen species reduce bioactive NO through chemical inactivation, forming toxic peroxynitrite, which in turn can uncouple endothelial NO synthase to form a dysfunctional superoxide-generating enzyme that contributes further to oxidative stress. The role of oxidative stress in vascular dysfunction and atherogenesis, and strategies for its prevention are discussed.     

Disease mechanisms and emerging therapies: protein kinases and their inhibitors in myocardial disease

Most clinically validated drugs for treating patients with cardiovascular disease target G-protein-coupled receptors (GPCRs) in the cell membrane. GPCRs engage and activate multiple intracellular signaling cascades, which are regulated by serine/threonine protein kinases. These protein kinases are cytoplasmic, more abundant than GPCRs, and have rapidly emerged as drug targets in cardiovascular diseases. One exciting potential advantage to targeting serine/threonine protein kinases rather than GPCRs is the capability of influencing more precisely the diverse biological responses that are initiated by a common GPCR. On the other hand, highly specific targeting of individual protein kinases for drug therapy presents some medicinal chemistry challenges. This concise review focuses on the biology of serine/threonine protein kinases in the cardiovascular system, discusses the current state of protein kinase inhibitor drug development for myocardial diseases, and illustrates some of the unique medicinal chemistry considerations in targeting protein kinases.