Current Cancer Drug Targets - Volume 17, Issue 1, 2017

The human leucine-rich repeats and immunoglobulin like domains (LRIG) are evolutionary conserved family of single-pass transmembrane proteins. LRIG gene family includes three members, LRIG1 (formerly LIG1), LRIG2 and LRIG3, all of which are differentially expressed in human tissues and have long been proposed to be tumor suppressors. However, recently accumulated evidence on LRIG protein expression in human cancer appears to be inconsistent with this belief, as LRIG proteins have been found to be upregulated in certain tumors. Moreover, LRIG3 has been shown to act in an opposite manner to LRIG1 and LRIG1, in turn, has been shown to attenuate LRIG3 activity by its proteolytic degradation. These remarkable observations underline and reveal the previously unappreciated complexity of LRIG family dynamics. In the current review, the role of LRIG proteins in various human cancers is summarized and their differential regulation and expression is brought to light in order to understand how these proteins are involved in the genesis and progression of human cancers. Moreover, this is the first compilation that highlights the therapeutic potential of LRIG1 and suggests the same to be undertaken for LRIG2 and LRIG3. By virtue of their potential in prognosis of several cancer types, as well as their role as probable therapeutic proteins or in enhancing the receptiveness of the cancer cells to anti-tumor agents, it is strongly proposed that LRIG analysis should be undertaken and consequently be employed as a part of potential cancer treatment strategies.

Glioblastoma multiforme is a common primary brain tumor, which exhibits an imbalance between glioma cell growth and glucose metabolism. Recent discoveries have found that the multiple pathways and downstream genes involved in the dysregulated metabolic pathway allow tumor to manifest and progress, which is critical to patients with glioblastoma associated with significant systemic and immunosuppression. Moreover, immune microenvironment is considered a major obstacle to generating an effective antitumor immune response. Therefore, identification of patient-specific tumor antigens through highly personalized approach, and effective combination with other therapeutic modalities such as molecular agents targeting tumor metabolic oncogene addiction and potent host immune modulators, may provide targets for more effective therapeutic strategies for glioblastoma. In this review, we aim to highlight the most recent findings regarding glucose uptake and proliferation, cell mobility and to expand our investigations and more comprehensively examine different aspects of glucose metabolism in glioblastoma, such as pentose phosphate pathway (PPP) and its enzymes, metabolic modulation of genetics and epigenetics and key metabolic regulators, importantly, tumor cell-induced glucose deprivation inhibits T-cell glycolysis and immunogenic functions. Furthermore, this review will concentrate on how to discover effective drug targets to regulate glucose metabolism in tumor and T cell growth for future glioblastoma therapies, and the challenges faced by the field of metabolism in tumor immune microenviroment.

MicroRNAs (miRNAs) control the expression of approximately 60% of protein-coding genes and regulate cell metabolism, proliferation, differentiation, and apoptosis. Notably, aberrant expression of miRNAs contributes to several diseases including cancer. Accumulating evidence indicates that miRNAs play important roles in EMT, genesis of cancer stem cells, cancer metabolism and carcinogenesis. Aberrant expression of miRNAs triggers tumor initiation, progression and poor prognosis of cancer patients. Accordingly, oncogenic miRNAs have emerged as diagnostic biomarkers and targets for novel anti-cancer drug discovery. However, the mechanisms of miRNAs contriving tumorigenesis are not completely understood. This review aims to clarify the identification of tumorspecific miRNAs, verification of oncogenic miRNA signatures, and dynamic study of oncogenic miRNAs in cancer initiation and development. Despite sound progress in miRNA-mediated anticancer therapy, several barriers like drug stability, immunogenicity, off-target effects and toxicities still remain. We hope our review could stimulate the further study of miRNAs in cancer research field, which may lead to new insights into the mechanisms of carcinogenesis and create new avenues for targeted cancer therapy.

Preclinical evaluation of drug combinations is challenging. In this mini-review we discuss the concept of synthetic lethality and how this can impact on the evaluation of drug combinations and its clinical development. We will also review novel combinations with immunologic agents and the concept of collateral lethality. We suggest that identification of synthetic lethality interactions including collateral lethality using novel drug combinations can speed up the drug development process. This approach may identify synergistic combinations in tumors with a specific molecular alteration, limiting toxicity to normal tissue. In addition, the combination of an immunotherapy with an agent targeting cancer cells have the potential for acting on different functions with no overlapping of toxicities. Here, we also discuss potential consequences of this approach in the design of early clinical studies.

UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-6 (pp-GalNAc-T6) is a member of the N-acetyl-D-galactosamine transferase family. It catalyzes the addition of N-acetyl-D-galactosamine to proteins, often the first step in O-glycosylation of proteins. Glycosylated proteins play important roles in vivo in the cell membrane. These are often involved in cell-cell adhesion, cytoskeleton regulation and immune recognition. pp-GalNAc-T6 has been shown to be upregulated in a number of types of cancer. Abnormally glycosylated forms of mucin 1 (a substrate of the enzyme), are used clinically as a biomarker for breast cancer. There is potential for other products of the pp-GalNAc- T6 catalyzed reaction to be used. It is also possible that pp-GalNAc-T6 itself could be used as a biomarker, since levels of this protein tend to be low in non-malignant tissues. pp- GalNAc-T6 has been implicated in malignant transformation and metastasis of cancer cells. As such, it has considerable potential as a target for chemotherapy. To date, no selective inhibitors of the enzyme have been identified. However, general inhibitors of the enzyme family result in reduced cell surface O-linked glycosylation and induce apoptosis in cultured cells. Thus, a selective inhibitor of pp-GalNAc-T6 is likely to target cancer cells and could be developed into a novel anticancer therapy.

Background: The antiangiogenic drug sunitinib has never been evaluated as single agent in untreated breast cancer patients. Objective: We aimed to characterize the activity of sunitinib, alone and with docetaxel, in untreated locally advanced or operable breast cancer and to uncover the mechanisms of response. Method: Patients were treated with an upfront window of sunitinib followed by four cycles of sunitinib plus docetaxel. Response, resistance and toxicity were evaluated according to standard clinical parameters, magnetic resonance imaging, positron emission tomography, standard pathology characterization, molecular pathology and gene expression profiling. Results: Twelve patients were included. We detected primary resistance to sunitinib in the upfront window in untreated breast cancer, as evidenced by four non-responding patients. At surgery, five patients had viable tumor in the breast and axilla, four had viable tumor cells in the breast alone and three were taken off study and thus not evaluated, due to unacceptable toxicity. Early functional imaging was useful in predicting response. There were no clinical complete responses. Comparison of tumor gene expression profiling data between early responders and non-responders allowed us to identify the up-regulation of VEGF and angiogenic pathways in non-responders. Specifically, in tumors resistant to single-agent sunitinib we detected a transcriptional response to hypoxia characterized by over-expression of several HIF1α target genes. Conclusion: In this report of single-agent sunitinib treatment in untreated localized breast cancer patients, we found evidence of primary resistance to sunitinib, likely mediated by up-regulation of hypoxia responsive genes.

Background: Glioblastoma has been reckoned as the prime cause of death due to brain tumours, being the most invasive and lethal. Available treatment options, i.e. surgery, radiotherapy, chemotherapy and targeted therapies are not effective in improving prognosis, so an alternate therapy is insistent. Plant based drugs are efficient due to their synergistic action, multi-targeted approach and least side effects. Methods: The anti-tumorous potential of Nardostachys jatamansi rhizome extract (NJRE) on U87 MG cell line was evaluated through various in vitro and in silico bio-analytical tools. Results: NJRE had a strong anti-proliferative effect on U87 MG cells, Its IC50 was 33.73±3.5, 30.59±3.4 and 28.39±2.9 μg/mL, respectively after 24, 48 and 72 h. NJRE at 30 μg/mL induced DNA fragmentation, indicating apoptosis, early apoptosis began in the cells at 20 μg/mL, whereas higher doses exhibited late apoptosis as revealed by dual fluorescence staining. NJRE at 60 and 80 μg /mL caused a G0/G1 arrest and at 20 and 40 μg/mL showed excessive nucleation and mitotic catastrophe in the cells. Immuno-blotting validated the apoptotic mode of cell death through intrinsic pathway. NJRE was harmless to normal cells. In silico docking of NJRE marker compounds: oroselol, jatamansinol, nardostachysin, jatamansinone and nardosinone have revealed their synergistic and multi-targeted interactions with Vestigial endothelial growth factor receptor 2 (VEGFR2), Cyclin dependent kinase 2 (CDK2), B-cell lymphoma 2 (BCL2) and Epidermal growth factor receptor (EGFR). Conclusion: A strong dose specific and time dependent anti-tumorous potential of NJRE on U87 MG cells was seen. The extract can be used for the development of safe and multi-targeted therapy to manage glioblastoma, which has not been reported earlier.

Background: Nimotuzumab is shown to be efficacious in advanced pancreatic cancer treatment, but its predictive marker has not been established. Objective: To investigate the impact of EGFR and KRAS status on antitumor efficacy of nimotuzumab and to explore its underlying mechanism. Methods: EGFR expressions of pancreatic cancer cell lines, BxPC3, Panc-1, and Patu-8988, were analyzed by Western blot and immunocytochemistry, and KRAS status was determined by gene sequencing. Anti-tumor effect of nimotuzumab were evaluated in vitro and in vivo. The expressions of related molecules in EGFR pathway and IL-6 was analyzed by Western blot, immunohistochemistry, and/or real-time PCR. Results: BxPC3 cells had wild type KRAS and high-level EGFR; Panc-1 cells had mutant KRAS (G13A) and low-level EGFR; Patu-8988 cells had mutant KRAS (G12V) and high-level EGFR. Nimotuzumab did not affect cell proliferation or apoptosis in vitro. Growth of BxPC3 and Patu-8988 xenografts were significantly inhibited by nimotuzumab, but not Panc-1 xenografts, compared with that of the control group. Expression of EGFR in BxPC3 and Patu-8988 xenografts was significantly reduced by nimotuzumab. The IL-6 expression in BxPC3 and Patu-8988 xenografts was higher than that in Panc-1 xenografts in the control group, and was significantly reduced by nimotuzumab. Conclusion: Pancreatic cancer cells with EGFR high expression were more sensitive to nimotuzumab in vivo. KRAS status had no impact on anti-tumor efficacy of nimotuzumab in pancreatic cancer cells.