Project description:Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. The initiation and progression of CRC is a multi-step process that proceeds via precursor lesions to carcinoma, with each stage characterized by its distinct molecular and tissue microenvironment changes. Precursor lesions of CRC, aberrant crypt foci, and adenoma exhibit drastic changes in genetic, transcriptomic, and proteomic profiles compared to normal tissue. The identification of these changes is essential and provides further validation as an initiator or promoter of CRC and, more so, as lesion-specific druggable molecular targets for the precision chemoprevention of CRC. Mutated/dysregulated signaling (adenomatous polyposis coli, β-catenin, epidermal growth factor receptor, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein53, Akt, etc.), inflammatory (cyclooxygenase-2, microsomal prostaglandin E synthase-1, inducible nitric oxide synthase, and other pro-inflammatory mediators), and metabolic/growth factor (fatty acid synthase, β-Hydroxy β-methylglutaryl-CoA reductase, and ornithine decarboxylase) related targets are some of the well-characterized molecular targets in the precision chemoprevention of CRC. In this review, we discuss precursor-lesion specific targets of CRC and the current status of pre-clinical studies regarding clinical interventions and combinations for better efficacy and safety toward future precision clinical chemoprevention. In addition, we provide a brief discussion on the usefulness of secondary precision chemopreventive targets for tertiary precision chemoprevention to improve the disease-free and overall survival of advanced stage CRC patients.
Project description:Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. This scenario highlights the need to develop novel therapies and/or treatment strategies to reduce the mortality associated with TNBC. The neoadjuvant setting provides a model for rapid assessment of treatment efficacy with smaller patient accruals and over shorter periods of time compared to the traditional adjuvant setting. In addition, a clear surrogate endpoint of improved survival, known as pathologic complete response, already exists in this setting. Here, we review current data from completed and ongoing neoadjuvant clinical trials for TNBC.
Project description:Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic.
Project description:AimThis review aims to summarize and discuss some of the most relevant clinical trials in epidemiology, diagnostics, and treatment of hypertension published in 2020 and 2021.Data synthesisThe trials included in this review are related to hypertension onset age and risk for future cardiovascular disease, reliability of different blood pressure monitoring methods, role of exercise-induced hypertension, treatment of hypertension in patients with SARS-CoV-2 infection, management of hypertension high-risk patient groups, e.g., in the elderly (≥80 years) and patients with atrial fibrillation, and the interplay between nutrition and hypertension, as well as recent insights into renal denervation for treatment of hypertension.ConclusionsHypertension onset age, nighttime blood pressure levels and a riser pattern are relevant for the prognosis of future cardiovascular diseases. The risk of coronary heart disease appears to increase linearly with increasing exercise systolic blood pressure. Renin-angiotensin system blockers are not associated with an increased risk for a severe course of COVID-19. In elderly patients, a risk-benefit assessment of intensified blood pressure control should be individually evaluated. A J-shaped association between cardiovascular disease and achieved blood pressure could also be demonstrated in patients with atrial fibrillation on anticoagulation. Salt restriction and lifestyle modification remain effective options in treating hypertensive patients at low cardiovascular risk. Sodium glucose co-transporter 2 inhibitors and Glucagon-like peptide-1 receptor agonists show BP-lowering effects. Renal denervation should be considered as an additional or alternative treatment option in selected patients with uncontrolled hypertension.
Project description:Mitochondrial disorders comprise a molecular and clinically diverse group of diseases that are associated with mitochondrial dysfunction leading to multi-organ disease. With recent advances in molecular technologies, the understanding of the pathomechanisms of a growing list of mitochondrial disorders has been greatly expanded. However, the therapeutic approaches for mitochondrial disorders have lagged behind with treatment options limited mainly to symptom specific therapies and supportive measures. There is an increasing number of clinical trials in mitochondrial disorders aiming for more specific and effective therapies. This review will cover different treatment modalities currently used in mitochondrial disorders, focusing on recent and ongoing clinical trials.
Project description:Tremendous effort has been put forth over the past 2 decades in understanding the pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH). Although multiple potential targets for drug development exist, there have been no approved therapies for NAFLD/NASH. Lipotoxicity, owing to increased delivery of fatty acids to the liver, and hepatic de novo lipogenesis are key drivers of disease pathogenesis. Moreover, genetics, environmental factors, and comorbid conditions converge to determine disease progression in individual patients. Given the complexity and heterogeneity of disease pathogenesis, numerous therapeutic targets have emerged and have been tested in clinical trials. Early trial failures have provided key lessons and foundational insights to move the field forward. Current ongoing phase 3 trials and emerging phase 2 trials are reasons for optimism, and 2 drugs, obeticholic acid and resmetirom, are being evaluated for accelerated approval by the US Food and Drug Administration this year. This article highlights key features of NASH pathophysiology and drug targets, the lessons learned from completed trials, and the current landscape of phase 2 and 3 clinical trials in NASH.
Project description:The success of sorafenib has spurred an explosive increase of clinical trials testing novel molecular targets and other agents in the treatment of hepatocellular carcinoma (HCC). The paradigm of the studies has been characterized by three noticeable changes. First, the molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for advanced HCC treatment. Agents targeting EGFR, FGFR, PI3K/Akt/mTOR, TGF-β, c-Met, MEK, IGF signaling, and histone deacetylase have been actively explored. Second, the target indication has shifted from advanced stage to early or intermediate stages of disease. The feasibility of combining locoregional therapies and targeted agents, and the use of novel agents after curative treatments are currently under active investigation. Finally, the therapeutic strategy has shifted from monotherapy to combination targeted therapy. We aim to provide a comprehensive overview of newly disclosed and ongoing clinical trials for the treatment of HCC.
Project description:Observational data suggest that lower folate status is associated with an increased risk of colorectal neoplasia, implying that folate may be useful as a chemopreventive agent. We conducted a combined analysis of three large randomized trials of folic acid supplementation for the prevention of metachronous adenomas in patients with an adenoma history. Participants included 2,632 men and women who had a history of adenomas randomized to either 0.5 or 1.0 mg/day of folic acid or placebo and who had a follow-up endoscopy 6 to 42 months after randomization [mean = 30.6 (standard deviation = 8.1) months]. We used random-effects meta-analysis to estimate risk ratios (RRs) and 95% confidence intervals (CIs). The RR comparing folic acid versus placebo was 0.98 (95% CI = 0.82-1.17) for all adenomas and 1.06 (95% CI = 0.81-1.39) for advanced lesions. Folic acid was associated with a nonsignificant decreased risk of any adenoma among subjects in the lowest quartile of baseline plasma folate (≤ 11 nmol/L) and no effect among individuals in the highest quartile (> 29 nmol/L, p for trend = 0.17). There was a nonsignificant trend of decreasing risk of any adenoma associated with folic acid supplements with increasing alcohol intake. During the early follow-up reported here, more deaths occurred in the placebo group than in the folic acid group (1.7% vs. 0.5%, p = 0.002). In conclusion, after up to 3.5 years of folic acid use, there is no clear decrease or increase in the occurrence of new adenomas in patients with a history of adenoma.
Project description:TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.