X-linked inhibitor of apoptosis protein as a therapeutic target

Dysregulation of apoptosis has been shown to contribute to many diseases, including cancer formation, development and resistance, as well as neurodegenerative and autoimmune disorders. One mechanism through which tumour cells are believed to acquire resistance to apoptosis is by overexpression of X-linked inhibitor of apoptosis protein (XIAP), which belongs to a family of inhibitor of apoptosis proteins. When XIAP is overexpressed, cancer cells are rendered resistant to apoptosis, both intrinsically and in response to chemotherapy and radiotherapy. Significant progress has been made in targeting XIAP therapeutically, both directly and indirectly through the modulation of other molecules involved in the apoptotic pathway. This review introduces XIAP from its molecular origins, discusses its modulation and potential as a novel drug target, and considers future therapeutic perspectives.     

The role of dynamin-related protein 1 in cancer growth: a promising therapeutic target?

Mitochondrial functions are altered in many human diseases including cancer. Development of mitochondria-targeted therapies, either through restoring normal mitochondrial function or promoting mitochondrial-induced cell death, is one of the attractive strategies to improve the outcome of cancer treatment. Recent advances have revealed the important functional involvement of mitochondrial dynamics in cancer biology. Dynamin-related protein 1 (Drp1), a member of the dynamin family of GTPases required for mitochondrial fission, has been found upregulated in certain types of cancers, such as lung and breast cancers. In addition, the roles of Drp1 in cell cycle progression, genome instability, cell migration and apoptosis in cancer cells have also been recently uncovered. These findings raise the possibility of targeting Drp1-mediated mitochondrial fission as an effective therapy for treating cancer. This article explores the function of Drp1 in cancer cells and discusses the theoretical basis for the development of potential targeted therapy.     

Apoptosis signal-regulating kinase 1 as a therapeutic target

Introduction: All organisms are ordinarily exposed to various stresses. It is important for organisms to possess appropriate stress response mechanisms and to maintain homeostasis because the disruption of a stress response system can cause various diseases. Apoptosis signal-regulating kinase 1 (ASK1) is one of the stress-responsive MAP3Ks. ASK1 plays an important role in the response to reactive oxygen species (ROS), endoplasmic reticulum stress and pro-inflammatory cytokines, and it is involved in the pathogenesis of various diseases.

Areas covered: In this review, the authors describe recent literature concerning the intricate and elaborate regulation system of ASK1, the function of ASK1 during a cellular stress response and the involvement of ASK1 in many diseases, including cancer, neurodegenerative diseases, infections, diabetes and cardiovascular diseases.

Expert opinion: In certain disease conditions, ASK1 plays a protective role, whereas ASK1 can exacerbate the pathology of other diseases. Although ASK1 is involved in various diseases, there is no therapy or drug that targets ASK1 for use in a clinical setting. Recently, ASK1 inhibitors (K811 and MSC2032964A) have emerged, and their therapeutic potentials have been tested in vivo. ASK1 is currently receiving considerable attention as a new therapeutic target.     

PAK as a therapeutic target in gastric cancer

Importance of the field: Gastric cancer is one of the most common causes of cancer death worldwide. P21-activated kinases (PAKs), regulators of cancer-cell signalling networks, play fundamental roles in a range of cellular processes through their binding partners or kinase substrates.

Areas covered in this review: The complex regulation of PAKs through their upstream or downstream effectors in human cancers, especially in gastric cancer, are described and the identified inhibitors of PAKs are summarized.

What the readers will gain: The structural differences and activation mechanisms between two subgroups of PAK are described. Both groups of PAKs play complicated and important roles in human gastric cancer, which indicated a possible way for us to identify the specific inhibitors targeting PAKs for gastric cancer.

Take home message: PAKs play important roles in progression of many cancer types, the full mechanisms of PAKs in gastric cancer are still unclear. It seems there are different roles for two groups of PAKs in cancers. Group I PAKs play their functions mostly through their specific substrates, however, many binding partners that are independent of phosphorylation by group II PAKs were identified. Finding specific inhibitors of PAKs will help us discover the roles of PAKs and target these kinases in human gastric cancer.     

Caspase-3 as a therapeutic target for heart failure

Introduction: Heart failure is a condition with significant morbidity and high mortality. It is likely to become unmanageable in the rapidly increasing aging population, due mainly to lack of effective treatment. Apoptosis is one of the major mechanisms causing cardiomyocyte loss in the failing hearts of both human patients and animal models. Thus, anti-apoptosis has been proposed as a provocative new concept for preventive and therapeutic strategies for heart failure.

Areas covered: This review summarizes evidence that apoptotic cells in heart are not completely committed to death. They are likely to be targeted for reversing the cardiac dysfunction. Drugs that inhibit the progression of apoptosis help restore systolic function, reverse remodeling or even prevent heart failure. Inhibitors of caspase-3, the major executors of apoptosis, have been shown to hold great promises for apoptosis interruption in heart tissues.

Expert opinion: Although the underlying cause and the pathophysiological role of apoptosis remain elusive, antiapoptotic therapy has emerged as an enigma for heart failure. Caspases promote the progressive loss of contractile function in heart failure by facilitating the degradation of myofibrillar proteins. Selective inhibition of the proteolytic functions of caspase-3 may represent an attractive approach to attenuate or reverse heart failure.     

siRNA作为基因治疗药物的研究难题

RNA干扰（RNAi）现象的发现与研究，为基因治疗带来新的契机，虽然小干扰RNA（siRNA）较单链反义寡核苷酸显示了更好的稳定性与基因沉默效果，但却同样面临基因治疗药物存在的共同问题，如体内的靶向性与有效性、完善的定量分析方法等等。因此，siRNA作为治疗药物还有诸多困难需要克服。目前的研究主要集中在：修饰方式与递送系统研究，以提高siRNA体内的稳定性与靶向性；siRNA定量分析方法学研究，以考察其体内药动学行为并进一步阐明其体内作用机制。     

Glucocorticoid-induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy

Introduction: Triggering of the glucocorticoid-induced TNFR-related gene (GITR) increases the activation of T lymphocytes and other immune system cells; furthermore, its ligand, GITRL, delivers signals in the cells where it is expressed.

Areas covered: This review describes the effects of GITR/GITRL triggering/inhibition in conventional T cells, regulatory T cells (Tregs), monocytes/macrophages, endothelial cells and other cells of the immune system. GITR triggering appears to be an approach for promoting tumor rejection, treating infection and boosting vaccinations in several murine models. GITR inhibition may be useful for inhibiting inflammation and autoimmune disease development.

Expert opinion: The exciting antitumor activity of anti-GITR mAbs depends on CD8⁺ effector T cell activation and inhibition/deletion of tumor-infiltrating Tregs. Whether one of these effects is more relevant is still under debate. Inhibition of GITR triggering plays an interesting anti-inflammatory role, but the potential effect of long-term treatment is to be investigated. The use of adjuvants able to trigger GITR is promising regarding new vaccines. Finally, caution is recommended when translating the findings of experimental murine models to human diseases; biologicals modulating human GITR/GITRL system can behave differently from those modulating the murine GITR/GITRL system.     

The human organic cation transporter OCT1 and its role as a target for drug responses

Abstract

The human organic cation uptake transporter OCT1, encoded by the SLC22A1 gene, is highly expressed in the liver and reported to possess a broad substrate specificity. OCT1 operates by facilitated diffusion and allows the entry of nutrients into cells. Recent findings revealed that OCT1 can mediate the uptake of drugs for treating various diseases such as cancers. The levels of OCT1 expression correlate with the responses towards many drugs and functionally defective OCT1 lead to drug resistance. It has been recently proposed that OCT1 should be amongst the crucial drug targets used for pharmacogenomic analyses. Several single nucleotide polymorphisms exist and are distributed across the entire OCT1 gene. While there are differences in the OCT1 gene polymorphisms between populations, there are at least five variants that warrant consideration in any genetic screen. To date, and despite two decades of research into OCT1 functional role, it still remains uncertain what are the define substrates for this uptake transporter, although studies from mice revealed that one of the substrates is vitamin B1. It is also unclear how OCT1 recognizes a broad array of ligands and whether this involves specific modifications and interactions with other proteins. In this review, we highlight the current findings related to OCT1 with the aim of propelling further studies on this key uptake transporter.     

KSR as a therapeutic target for Ras-dependent cancers

Introduction: Targeting downstream effectors required for oncogenic Ras signaling is a potential alternative or complement to the development of more direct approaches targeting Ras in the treatment of Ras-dependent cancers.

Areas covered: Here we review literature pertaining to the molecular scaffold Kinase Suppressor of Ras (KSR) and its role in promoting signals critical to tumor maintenance. We summarize the phenotypes in knockout models, describe the role of KSR in cancer, and outline the structure and function of the KSR1 and KSR2 proteins. We then focus on the most recent literature that describes the crystal structure of the kinase domain of KSR2 in complex with MEK1, KSR-RAF dimerization particularly in response to RAF inhibition, and novel attempts to target KSR proteins directly.

Expert opinion: KSR is a downstream effector of Ras-mediated tumorigenesis that is dispensable for normal growth and development, making it a desirable target for the development of novel therapeutics with a high therapeutic index. Recent advances have revealed that KSR can be functionally inhibited using a small molecule that stabilizes KSR in an inactive conformation. The efficacy and potential for this novel approach to be used clinically in the treatment of Ras-driven cancers is still being investigated.     

Non-histone nuclear factor HMGB1 as a therapeutic target in colorectal cancer

Introduction: High-motility group box (HMGB)-1 is the focus of recent cancer research. HMGB1 plays a critical role in cancer development, progression, and metastasis by activation of cancer cells, enhancement of tumor angiogenesis, and suppression of host anti-cancer immunity. HMGB1 is a relevant target for cancer treatment.

Areas covered: This review aims to overview the biological feature and diverses role in cancer of HMGB1. HMGB1 is a non-histone chromosomal protein, a secretory protein binding to the receptor for advanced glycation end products in cancer cells and monocyte-lineage immune cells, and a DNA presenting chaperon for toll-like receptors. HMGB1 enhances proliferation, motility, invasion and survival of cancer cells. In contrast, HMGB1 induces apoptosis in monocyte-lineage immune cells and inhibits tumor-infiltrating macrophages and dendritic cells, lymph node sinus macrophages and liver Kupffer cells to attenuate anti-cancer immune responses and anti-metastatic organ defense. Then the novel techniques for inhibiting HMGB1 are reviewed.

Expert opinion: Various techniques targeting HMGB1 are subjected to trial. HMGB1 targeting is a potential therapeutic techniqueagainst cancer development, progression, and especially metastasis. Technical breakthroughs in application of HMGB1 targeting to human diseases are now urgently required.     

The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer

Introduction: Immunotherapy is emerging as a powerful approach in cancer treatment. Preclinical data predicted the antineoplastic effects seen in clinical trials of programmed death-1 (PD-1) pathway inhibitors, as well as their observed toxicities. The results of early clinical trials are extraordinarily promising in several cancer types and have shaped the direction of ongoing and future studies.

Areas covered: This review describes the biological rationale for targeting the PD-1 pathway with monoclonal antibodies for the treatment of cancer as a context for examining the results of early clinical trials. It also surveys the landscape of ongoing clinical trials and discusses their anticipated strengths and limitations.

Expert opinion: PD-1 pathway inhibition represents a new frontier in cancer immunotherapy, which shows clear evidence of activity in various tumor types including NSCLC and melanoma. Ongoing and upcoming trials will examine optimal combinations of these agents, which should further define their role across tumor types. Current limitations include the absence of a reliable companion diagnostic to predict likely responders, as well as lack of data in early-stage cancer when treatment has the potential to increase cure rates.     

GLUT1 as a therapeutic target in hepatocellular carcinoma

Primary hepatocellular carcinoma (HCC) is one of the most fatal cancers in humans with rising incidence in many regions around the world. Currently, no satisfactory curative pharmacological treatment is available, and the outcome is mostly poor. Recently, we have shown that the glucose transporter GLUT1 is increased in a subset of patients with HCC and functionally affects tumorigenicity. GLUT1 is a rate-limiting transporter for glucose uptake, and its expression correlates with anaerobic glycolysis. This phenomenon is also known as the Warburg effect and recently became of great interest, since it affects not only glucose uptake and utilization but also has an influence on tumorigenic features like metastasis, chemoresistance and escape from immune surveillance. Consistent with this, RNA-interference-mediated inhibition of GLUT1 expression in HCC cells resulted in reduced tumorigenicity. Together, these findings indicate that GLUT1 is a novel and attractive therapeutic target for HCC. This review summarizes our current knowledge on the expression and function of GLUT1 in HCC, available drugs/strategies to inhibit GLUT1 expression or function, and potential side effects of such therapeutic strategies.     

cIAP2 as a therapeutic target in colorectal cancer and other malignancies

Colorectal cancer is one of the most common malignancies worldwide and 70% of tumors are resectable, but patients with metastatic diseases cannot be cured with current treatment modalities. Inhibition of the apoptotic pathway is one of the factors that may be responsible for carcinogenesis and drug resistance, and the inhibitor of apoptosis protein (IAP) family is thought to prevent apoptosis through inhibition of direct caspases and pro-caspases. Recently an increasing amount of evidence has been accumulated regarding cIAP2 and other IAP proteins of the antiapoptotic pathway and NF-κB signal transduction. IAPs are abnormally regulated and expressed in the majority of human malignancies at elevated levels. As a result, they have recently been reported to be therapeutic targets. The downregulation of cIAP2 efficiently enhances apoptosis through the activation of caspase 3/7 and 5-fluorouracil (5-FU) sensitivity in colorectal cancer cells exposed to 5-FU. This report reviews the evidence for cIAP2 and other IAP molecules as a therapeutic target for malignancies including colorectal cancer. So far, the information on colorectal cancer is limited; so this study includes other malignancies as well, in order to summarize the current knowledge of drug development targeting IAP molecules and provide an overview of the future course.