Current Cancer Drug Targets - Volume 15, Issue 4, 2015

Breast cancer is the most common malignancy in women worldwide and the second leading cause of cancer deaths after lung cancer. As in other malignancies, aneuploidy is a common feature of breast cancer and influences its behavior. Aneuploidy has been linked to inappropriate activity of the spindle assembly checkpoint (SAC), a surveillance mechanism that, in normal cells, prevents anaphase onset until correct alignment of all chromosomes at the metaphase is achieved. Interestingly, the widely used anti-microtubule drugs, vinca alkaloids and taxanes, kill cancer cells through chronic arrest in mitosis as a consequence of chronic SAC activation. Deregulated SAC has been reported in breast cancer in many reports and presents an attractive therapeutic strategy. We present here a review of the current knowledge on the SAC defects and the underlying molecular mechanisms in breast cancer, and discuss the potential of SAC components as targets for breast cancer therapies.

Chemotherapy is widely used for cancer treatment; however, it causes unwanted side effects in patients. To avoid these adverse effects, nanocarriers have been developed, which can be loaded with the chemotherapeutic agents, directed to the cancer site and, once there, are exposed to stimuli that will trigger the drug release. Liposomes can be chemically modified to increase their circulation time, their stability, and their sensitivity to specific stimulus. Additionally, ligands can be conjugated to their surface, allowing for their specific binding to receptors overexpressed on the surface of cancer cells and the subsequent internalization via endocytosis. Using a triggering mechanism, including temperature, ultrasound, enzymes or a change in pH, the release of the drug is controlled and induced inside the cells, hence avoiding drug release in systemic circulation, which in turn reduces the undesired side effects of conventional chemotherapy. Ultrasound has been widely studied as a drug release trigger from liposomes, due to its well-known physics and previous uses in medicine. This review focuses on liposome-based drug delivery systems, using different trigger mechanisms, with a focus on ultrasound. The physical mechanisms of ultrasound release are also investigated and the results of in vitro and in vivo studies are summarized.

Novel anti-androgens and androgen biosynthesis inhibitors have been developed to treat castration-resistant prostate cancer. However, knowledge of androgen deprivation therapy (ADT) has not been developed in the criticism, including information regarding the adverse effects of hormonal therapy. We hypothesize that there are ethnic differences in the efficacy and adverse effects of ADT; therefore, this review summarizes the experience of ADT, mainly in Japan. A risk stratification instrument, the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score, was developed based on the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database. It revealed that clinical outcomes were substantially better for males treated with ADT in Japan compared with those in the United States. Moreover, there were small survival differences in patients with localized and locally advanced cancer who received local therapy and primary ADT in another Japanese cohort study. In terms of adverse effects, including bone loss and cardiovascular risk, ADT appears to be better tolerated in Japanese populations than in Western cohorts. An ongoing randomized controlled trial of a trimodality treatment comprising brachytherapy, external beam radiation therapy, and neoadjuvant with or without adjuvant ADT in patients with localized high-risk prostate cancer will provide novel insights regarding adjuvant ADT. As a future perspective, the optimal selection of the type of primary ADT, including combining androgen blockade and novel hormonal compounds, adjusted according to each patient’s clinicopathological background, may provide better clinical outcomes in patients with advanced prostate cancer.

The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK, etc.). Clinical use of ALK inhibitors for “ALK-rearranged” lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK-gene rearrangement, can be oncogenic. Thus, ALK mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK-mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK mutation studies in various cancer types.

Cell-penetrating peptides (CPPs) have been previously shown to be powerful transport vector tools for the delivery of a large variety of cargoes through the cell membrane, as well as other physiological membranes. And since they’re relatively cell-, receptor- and energy-independent, CPPs have unique advantages in facilitating drugs entry into cells. This paper briefly reviews the discovery, mechanism and classification of CPPs, and especially focuses on the specific limitations of CPPs and their potential applications for tumor-targeted delivery of biologically active molecules, imaging agents and carriers.

Background: Glioblastoma multiforme (GBM) is the most malignant histological type of glioma. It exhibits an extremely aggressive action including invasion of large zones of brain parenchyma. Even after the application of surgery, radio and chemotherapy, the effect and survival for patients with GBM continue to be very poor. The PI3K/AKT/mTOR is a key pathway in the regulation of the proliferation of cancer cells. This is the reason to consider the mTOR inhibitors such as rapamycin analogs as an encouraging therapy for malignant glioma, but current investigations suggest that single inhibition of mTOR may be insufficient. For this reason, there is a need for the use of more than one agent rationally combined. Methods: In this study, we have evaluated the therapeutic potential of the combination of two different drugs: intraperitoneal rapamycin and convection enhanced delivery of nanoliposomes containing the topoisomerase I inhibitor CPT-11. The effect was analyzed by flow cytometry, cell growth, immunocytochemistry and immunohistochemistry, and rodent orthotopic xenograft survival analysis. Results: The combination presented remarkable efficacy in a survival study. We present an increase in survival of 6-fold in xenotransplanted animals without rise in toxicity. Conclusion: In summary, we propose a very powerful new combination therapy for glioma.