Targeting mitochondria as a therapeutic target in cancer

Knowledge of re-programming in cancer cells with metabolic differences from their normal counterparts has resulted in new examination of therapeutic approaches. Several studies of the role of tumor mitochondria in cancer have led to the development of non-genotoxic therapies which target mitochondrial proteins, function. The now well-established functions of mitochondria in apoptosis provide novel targets for tumor cell suicide. Mitochondria serve as a central hub for responses to cellular stress as well as injury. The alterations in cancer cells which result in protection from apoptosis can be targeted to inhibit proliferation. Because of the reprogramming of cancer cell metabolism involving increased glycolysis, it appears that blocking InsP(3)R Ca(2+) release or adaptive pathways in response to hypoxia by targeting HIF-1 or metabolic enzymes encoded by the HIF-1 gene represents a feasible therapeutic approach to cancer. A very early in vitro event found in tumor cells following resveratrol addition is an increase in intracellular Ca(2+), measurable within seconds. Ca(2+) release is also observed with non-toxic flavonoids and a goal to identify the sentinel targets of resveratrol as a model compound involved in calcium activation seems worthwhile. New findings of the relationship between autophagy and apoptosis are discussed. The contribution of reactive oxygen species (ROS) generated by mitochondria is also considered. New data as to how cyclophilins and VDAC are involved in mitochondrial hexokinase protection of factors that induce apoptosis are reviewed. In addition, chemotherapeutic approaches based on Akt-activated mTORC1 are described, and their relationship to the role of aerobic glycolysis in this protection.     

DNA repair deficiency as a therapeutic target in cancer

Inhibitors of DNA repair proteins have been used in cancer therapy, mostly to potentiate the effects of cytotoxic agents. However, tumor cells frequently exhibit deficiencies in the signalling or repair of DNA damage. These deficiencies probably contribute to pathogenesis of the disease, but they also present an opportunity to target the tumor. Recently, inhibitors of poly(ADP-ribose) polymerase (PARP) have been shown to be highly selective for tumor cells with defects in the repair of double-strand DNA breaks (DSBs) by homologous recombination, particularly in the context of BRCA1 or BRCA2 mutation. It seems likely that other DNA repair processes can be targeted in a similar manner. These synthetic lethal approaches highlight how an understanding of DNA repair processes can be used in the development of novel cancer treatments.     

Nucleo-cytoplasmic transport as a therapeutic target of cancer

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.     

Metabolic reprograming of cancer as a therapeutic target

Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.     

Claudin-4 as therapeutic target in cancer

BackgroundIntercellular junctional complexes such as adherens junctions and tight junctions are critical regulators of cellular polarity, paracellular permeability and metabolic and structural integrity of cellular networks. Abundant expression analysis data have yielded insights into the complex pattern of differentially expressed cell-adhesion proteins in epithelial cancers and provide a useful platform for functional, preclinical and clinical evaluation of novel targets.Scope of reviewThis review will focus on the role of claudin-4, an integral constituent of tight junctions, in the pathophysiology of epithelial malignancies with particular focus pancreatic cancer, and its potential applicability for prognostic, diagnostic and therapeutic approaches.Major conclusionsClaudin-4 expression is widely dysregulated in epithelial malignancies and in a number of premalignant precursor lesions. Although the functional implications are only starting to unravel, claudin-4 seems to play an important role in tumour cell invasion and metastasis, and its dual role as receptor of Clostridium perfringens enterotoxin (CPE) opens exciting avenues for molecular targeted approaches.General significanceClaudin-4 constitutes a promising molecular marker for prognosis, diagnosis and therapy of epithelial malignancies.     

Titin as a potential novel therapeutic target in colorectal cancer

Colorectal cancer (CRC) is identified as a primary cause of death around the world. The current chemotherapies are not cost-effective. Therefore, finding novel potential therapeutic target is urgent. Titin (TTN) is a muscle protein that is critical in hypertrophic cardiomyopathy. However, its role in CRC is not well understood. The study focused on exploring the possible role of TTN in CRC carcinogenesis. TTN mRNA and protein expression levels presented an obvious downregulation in CRC tissue samples, relative to normal control (p < 0.05). TTN expression significantly correlated with the clinical stage (normal vs. Stage 1, p < 0.05; normal vs. Stage 4, p < 0.05), node metastasis (normal vs. N1, p < 0.05; N1 vs. N2, p < 0.05), histological type (normal vs. adenocarcinoma, p < 0.05), race (Caucasian vs. Asian, p < 0.05; African-American vs. Asian, p < 0.05) and TP53 mutation (normal vs. TP53 mutation, p < 0.05), considering The Cancer Genome Atlas database. However, for patients who had higher TTN expression, the overall survival was remarkably shorter than patients who had low TTN expression. Furthermore, TTN was lowly expressed in four CRC cell lines. TTN overexpression facilitated CRC cells in terms of the proliferation, metastasis and invasion. Based on gene set enrichment analysis, the ERB pathway might be responsible for TTN-related CRC. Besides, TTN was involved in the response to azacitidine. Overall, TTN might serve as a potential novel therapeutic target for treating and overcoming chemotherapy resistance in CRC.     

Cancer stem cells as a therapeutic target in bladder cancer

Bladder cancer is one of the most prevalent genitourinary cancers responsible for about 150,000 deaths per year worldwide. Currently, several treatments, such as endoscopic and open surgery, appended by local or systemic immunotherapy, chemotherapy, and radiotherapy are used to treat this malignancy. However, the differences in treatment outcome among patients suffering from bladder cancer are considered as one of the important challenges. In recent years, cancer stem cells, representing a population of undifferentiated cells with stem-cell like properties, have been eyed as a major culprit for the high recurrence rate in superficial papillary bladder cancer. Cancer stem cells have been reported to be resistant to conventional treatments, such as chemotherapy, radiation, and immunotherapy, which induce selective pressure on tumoral populations resulting in selection and growth of the resistant cells. Therefore, targeting the therapeutic aspects of cancer stem cells in bladder cancer may be promising. In this study, we briefly discuss the biology of bladder cancer and then address the possible relationship between molecular biology of bladder cancer and cancer stem cells. Subsequently, the mechanisms of resistance applied by cancer stem cells against the conventional therapeutic tools, especially chemotherapy, are discussed. Moreover, by emphasizing the biomarkers described for cancer stem cells in bladder cancer, we have provided, described, and proposed targets on cancer stem cells for therapeutic interventions and, finally, reviewed some immunotargeting strategies against bladder cancer stem cells.     

Platelet cancer cell interplay as a new therapeutic target

The interaction between circulating tumor cells and platelets is a key factor in cancer metastasis. These interactions, driven by a variety of receptors, support circulating tumor cells by protecting them from immune detection, cushioning them from shear stress, and promoting their arrest at the endothelium. Additionally, platelets have been shown to accumulate in the primary tumors, promoting tumor growth and angiogenesis by releasing growth factors. Furthermore, tumor cells can interact with platelets by inducing aggregation, which further protects cancer cells. However, the platelet cancer cell interplay also offers new approaches to develop targeted therapies. The accumulation of platelets in tumors has successfully been leveraged to deliver chemotherapeutics and imaging agents. Likewise, these platelet-based interactions have been utilized to target cancer cells in circulation. Although these current systems have limitations including drug loading and storage, leveraging platelet-cancer cell interactions to effectively target circulating tumor cells and tumors shows great promise for future cancer treatments.     

Assessment of TANK-binding kinase 1 as a therapeutic target in cancer

TANK-binding kinase 1 (TBK1) is central to multiple biological processes that promote tumorigenesis including cell division, autophagy, innate immune response and AKT-pro survival signaling. TBK1 is well studied and most known for its function in innate immunity. However, the serine threonine protein kinase received significant attention as a synthetic lethal partner and effector of the major oncogene, RAS. This review summarizes newly identified cancer promoting functions of TBK1 and evaluates the therapeutic potential of targeting TBK1 in cancer.     

Tumor vasculature as a therapeutic target in non-small cell lung cancer

Despite developments in conventional (chemo)radiotherapy and surgery, survival of non-small cell lung cancer (NSCLC) patients remains poor. Treatments with targeted molecular drugs offer novel therapeutic strategies. Bevacizumab, a recombinant anti-vascular endothelial growth factor (VEGF) antibody, is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC. However, a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain. Furthermore, novel agents targeting the pre-existing NSCLC vasculature (i.e. vascular disrupting agents, VDAs) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies. Herein, we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC.     

Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer

Growth factor receptors (GFRs) are often aberrantly expressed in tumor cells,and altered GFR expression and activity contribute to the pathogenesis of many types of cancer.A variety of mechanisms have ...     

Abnormal lipid synthesis as a therapeutic target for cancer stem cells

Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.