Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in ...women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (
H. pylori
) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as
H. pylori
eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.
Exportin 1 (XPO1), also known as chromosome region maintenance protein 1, plays a crucial role in maintaining cellular homeostasis via the regulated export of a range of cargoes, including proteins ...and several classes of RNAs, from the nucleus to the cytoplasm. Dysregulation of this protein plays a pivotal role in the development of various solid and haematological malignancies. Furthermore, XPO1 is associated with resistance to several standard-of-care therapies, including chemotherapies and targeted therapies, making it an attractive target of novel cancer therapies. Over the years, a number of selective inhibitors of nuclear export have been developed. However, only selinexor has been clinically validated. The novel mechanism of action of XPO1 inhibitors implies a different toxicity profile to that of other agents and has proved challenging in certain settings. Nonetheless, data from clinical trials have led to the approval of the XPO1 inhibitor selinexor (plus dexamethasone) as a fifth-line therapy for patients with multiple myeloma and as a monotherapy for patients with relapsed and/or refractory diffuse large B cell lymphoma. In this Review, we summarize the progress and challenges in the development of nuclear export inhibitors and discuss the potential of emerging combination therapies and biomarkers of response.
Trafficking of biological material across membranes is an evolutionary conserved mechanism and is part of any normal cell homeostasis. Such transport is composed of active, passive, export through ...microparticles, and vesicular transport (exosomes) that collectively maintain proper compartmentalization of important micro- and macromolecules. In pathological states, such as cancer, aberrant activity of the export machinery results in expulsion of a number of key proteins and microRNAs resulting in their misexpression. Exosome-mediated expulsion of intracellular drugs could be another barrier in the proper action of most of the commonly used therapeutics, targeted agents, and their intracellular metabolites. Over the last decade, a number of studies have revealed that exosomes cross-talk and/or influence major tumor-related pathways, such as hypoxia-driven epithelial-to-mesenchymal transition, cancer stemness, angiogenesis, and metastasis involving many cell types within the tumor microenvironment. Emerging evidence suggests that exosome-secreted proteins can also propel fibroblast growth, resulting in desmoplastic reaction, a major barrier in effective cancer drug delivery. This comprehensive review highlights the advancements in the understanding of the biology of exosomes secretions and the consequence on cancer drug resistance. We propose that the successful combination of cancer treatments to tackle exosome-mediated drug resistance requires an interdisciplinary understanding of these cellular exclusion mechanisms, and how secreted biomolecules are involved in cellular cross-talk within the tumor microenvironment.
Novel targeted therapeutics alone or in rational combinations are likely to dominate the future management of various hematological neoplasms. However, the challenges currently faced are the ...molecular heterogeneity in driver lesions and genetic plasticity leading to multiple resistance pathways. Thus, progress has overall been gradual. For example, despite the advent of targeted agents against actionable drivers like FLT3 in acute myeloid leukemia (AML), the prognosis remains suboptimal in newly diagnosed and dismal in the relapsed/refractory (R/R) setting, due to other molecular abnormalities contributing to inherent and acquired treatment resistance. Nuclear export inhibitors are of keen interest because they can inhibit several active tumorigenic processes simultaneously and also synergize with other targeted drugs and chemotherapy. XPO1 (or CRM1, chromosome maintenance region 1) is one of the most studied exportins involved in transporting critical cargoes, including tumor suppressor proteins like p27, p53, and RB1. Apart from the TSP cargo transport and its role in drug resistance, XPO1 inhibition results in retention of master transcription factors essential for cell differentiation, cell survival, and autophagy, rendering cells more susceptible to the effects of other antineoplastic agents, including targeted therapies. This review will dissect the role of XPO1 inhibition in hematological neoplasms, focusing on mechanistic insights gleaned mainly from work with SINE compounds. Future potential combinatorial strategies will be discussed.
Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over ...90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.
•Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are common in cancer.•KRAS remains a challenging therapeutic target.•Recently, several novel compounds against individual KRAS ...alterations have emerged.•Initial activity of AMG 510 and MRTX 849 appears promising in KRAS G12C NSCLC.•Single agent and combination studies are ongoing to evaluate their safety and efficacy.
Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target.
Among the different known mutations; the KRASG12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRASG12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRASG12C at the cysteine at residue 12, keeping KRASG12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019.
Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps.
It has been almost two decades since the first link between microRNAs and cancer was established. In the ensuing years, this abundant class of short noncoding regulatory RNAs has been studied in ...virtually all cancer types. This tremendously large body of research has generated innovative technological advances for detection of microRNAs in tissue and bodily fluids, identified the diagnostic, prognostic, and/or predictive value of individual microRNAs or microRNA signatures as potential biomarkers for patient management, shed light on regulatory mechanisms of RNA–RNA interactions that modulate gene expression, uncovered cell‐autonomous and cell‐to‐cell communication roles of specific microRNAs, and developed a battery of viral and nonviral delivery approaches for therapeutic intervention. Despite these intense and prolific research efforts in preclinical and clinical settings, there are a limited number of microRNA‐based applications that have been incorporated into clinical practice. We review recent literature and ongoing clinical trials that highlight most promising approaches and standing challenges to translate these findings into viable microRNA‐based clinical tools for cancer medicine.
This article is categorized under:
RNA in Disease and Development > RNA in Disease
microRNAs are short noncoding regulatory RNAs with important roles in cancer biology. microRNAs are informative biomarkers for early cancer detection and treatment decisions. microRNAs are being evaluated in clinical trials as new drugs for personalized cancer medicine.
Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the ...chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).
•The gut microbiome plays an important role in host immune response.•Alterations in lung bacterial content may influence COPD and asthma.•Gut microbiota has shown to alter effects of cancer therapy ...in murine models.•NSCLC patients responding to checkpoint inhibitors had higher microbiome diversity.•Best approaches to modulate the gut microbiome are under investigation.
The gut microbiome is a collection of diverse bacteria that normally reside within the gastrointestinal tract. In recent years, the relationship between the gut microbiome, and fluctuations in it, and overall health has been an intense area of interest in medical research. In addition to having a barrier role in the gastrointestinal tract, there appears to be an immune function of gut microbiota, with a correlation between dysbiosis of gut microbiota and certain inflammatory and malignant disease states of the gastrointestinal system. We have also seen evidence that the gut microbiome can impact response to immunotherapy in melanoma patients.
Evidence has also emerged to show that the lung has a microbiome of its own. In this review we will explore the relationship between the gut and lung microbiomes, known as the gut-lung axis, and the potential effects of this axis on anticancer therapy in lung cancer, including checkpoint inhibitors.
KRAS mutations are among the most commonly occurring mutations in cancer. After being deemed undruggable for decades, KRAS G12C specific inhibitors showed that small molecule inhibitors can be ...developed against this notorious target. At the same time, there is still no agent that could target KRAS G12D which is the most common KRAS mutation and is found in the majority of KRAS-mutated pancreatic tumors. Nevertheless, significant progress is now being made in the G12D space with the development of several compounds that can bind to and inhibit KRAS G12D, most notably MRTX1133. Exciting advances in this field also include an immunotherapeutic approach that uses adoptive T-cell transfer to specifically target G12D in pancreatic cancer. In this mini-review, we discuss recent advances in KRAS G12D targeting and the potential for further clinical development of the various approaches.
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