Oncotarget

Linked-In: Design and Efficacy of Antibody Drug Conjugates in Oncology ABSTRACT The use of antibody drug conjugates (ADCs) as targeted chemotherapies has successfully entered clinical practice and holds great promise. ADCs consist of an antibody and toxin-drug combined together via a chemical linker. While the antibody and drug are of vital importance in the direct elimination of cancer cells, more advanced linker technology was instrumental in the delivery of more potent drugs with fewer side effects. Here, we discuss the preclinical experience as well as clinical trials, with a specific emphasis on the clinical outcomes and side effects, in addition to linker strategies for five different ADCs, in order to describe different approaches in the development of this new class of anticancer agents. Brentuximab vedotin is approved for use in Hodgkin’s lymphoma and Trastuzumab emtansine is approved for breast cancer. Combotox, Inotuzumab Ozogamicin, and Moxetumomab Pasudotox are in various

Geminin overexpression induces mammary tumors via suppressing cytokinesis. ABSTRACT Aneuploidy plays an important role in the development of cancer. Here, we uncovered an oncogenic role for geminin in mitotic cells. In addition to chromatin, tyrosine phosphorylated geminin also localizes to centrosome, spindle, cleavage furrow and midbody during mitosis. Geminin binding to Aurora B prevents its binding to INCENP, and thus activation leading to lack of histone H3-(serine 10) phosphorylation, chromosome condensation failure, aborted cytokinesis and the formation of aneuploid, drug resistance cells. Geminin overexpressing human mammary epithelial cells form aneuploid, aggressive tumors in SCID mice. Geminin is overexpressed in more than half of all breast cancers analyzed. The current study reveals that geminin is a genuine oncogene that promotes cytokinesis failure and production of aneuploid, aggressive breast tumors when overexpressed and thus a worthy therapeutic target (oncotarget) f

Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells ABSTRACT Glioblastoma multiforme (GBM) is a highly invasive and deadly brain tumor.  Tumor cell invasion makes complete surgical resection impossible and reduces the efficacy of other therapies.  Genome-wide analyses of mutations, copy-number changes, and expression patterns have provided new insights into genetic abnormalities common in GBM.  We analyzed published data and identified the invasion and motility pathways most frequently altered in GBM. These were most notably the focal adhesion and integrin signaling, and extracellular matrix interactions pathways.  We mapped alterations in each of these pathways and found that they included the catalytic  PIK3CA  and regulatory  PIK3R1  subunit genes of the class IA PI3K.  Knockdown of either of these genes separately in GBM cell lines by lentiviral-mediated shRNA expression resulted in decreased proliferation, migration, and i

Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment ABSTRACT Recent clinical evidence revealed that the use of beta-blockers such as propranolol, prior to diagnosis or concurrently with chemotherapy, could increase relapse-free and overall survival in breast cancer patients. We therefore hypothesized that propranolol may be able to increase the efficacy of chemotherapy either through direct effects on cancer cells or via anti-angiogenic mechanisms. In vitro proliferation assay showed that propranolol (from 50-100 μM) induces dose-dependent anti-proliferative effects in a panel of 9 human cancer and “normal” cell lines. Matrigel assays revealed that propranolol displays potent anti-angiogenic properties at non-toxic concentrations (<50 μM) but exert no vascular-disrupting activity. Combining chemotherapeutic drugs, such as 5-fluorouracil (5-FU) or paclitaxel, with propranolol at the lowest effectiv

Chronic myeloid leukemia stem cells in the era of targeted therapies: resistance, persistence and long-term dormancy ABSTRACT Targeted therapies of chronic myeloid leukemia (CML) using tyrosine kinase inhibitors (TKI) have profoundly changed the natural history of the disease with a major impact on survival.  Molecular monitoring with  BCR-ABL  quantification shows that a status of undetectable molecular residual disease (UMRD) is obtained in a significant minority of patients. However, it remains unclear whether these patients are definitively cured of their leukemia. Imatinib mesylate withdrawal trials have demonstrated the rapid appearance of the malignant clone in the majority of the patients whereas some patients remain in a state of UMRD. It has clearly been demonstrated that the most primitive stem cells are refractory to all TKIs used in clinical practice. In addition, long-term dormancy is one of the most fundamental characteristics of hematopoietic stem cells. In this context

Mouse Models to Interrogate the Implications of the Differentiation Status In the Ontogeny of Gliomas ABSTRACT Glioblastoma Multiforme (GBM) is the most common and lethal of human primary central nervous system (CNS) tumors, with a median survival of 14-16 months despite optimal surgery, radiation and chemotherapy. A reason for this dismal prognosis is insufficient understanding of the ontogeny of GBMs, which are highly heterogeneous at a pathological level. This pathological diversity, between and within GBMs as well as varying grades of gliomas, has not been fully explained solely on the grounds of oncogenic stimulus. Interaction with the tumor microenvironment is likely a source of this pathological heterogeneity, as well as the inherent characteristics of the tumor cell of origin. Currently, controversy exists on whether the initial transformed cell is a differentiated astrocyte, progenitor or neural stem cell. Putative Cancer Stem Cells (CSCs), which have features of normal stem c

Targeting cancer with peptide aptamers ABSTRACT A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but also peptide aptamers are relatively recent agents. Peptide aptamers are seldom described but represent attractive agents that can inhibit a growing panel of oncotargets including Heat Shock Proteins. Potential pitfalls and coming challenges towards successful clinical trials are presented such as optimizing the delivery of peptide aptamers thanks to Nanotechnology.  https://www.oncotarget.com/article/297/   oncotarget. impact factor  When general population discuss contemporary medicine, accuracy plays one of the most important roles and human lives are literally dependent on it. Hereby, any researches pertaining to medicine are necessary to meet the highest standards. The issue today is that any res

A Chemical Biology Approach to Developing STAT Inhibitors: Molecular Strategies for Accelerating Clinical Translation ABSTRACT STAT transcription factors transduce signals from the cell surface to the nucleus, where they regulate the expression of genes that control proliferation, survival, self-renewal, and other critical cellular functions.  Under normal physiological conditions, the activation of STATs is tightly regulated.  In cancer, by contrast, STAT proteins, particularly STAT3 and STAT5, become activated constitutively, thereby driving the malignant phenotype of cancer cells.  Since these proteins are largely dispensable in the function of normal adult cells, STATs represent a potentially important target for cancer therapy.  Although transcription factors have traditionally been viewed as suboptimal targets for pharmacological inhibition, chemical biology approaches have been particularly fruitful in identifying compounds that can modulate this pathway through a variety of mec

Xenotropic murine leukemia virus-related virus (XMRV) in prostate cancer cells likely represents a laboratory artifact ABSTRACT The prevalence of xenotropic murine leukemia virus-related virus (XMRV) in human population and its involvement in prostate cancer are subjects of ongoing research and debate. 22Rv1, which is a human cell line that serves as a common model of androgen-independent prostate cancer, was recently reported to carry infectious copies of XMRV. 22Rv1 was derived from a prostate cancer xenograft CWR22 that was serially passaged in immunodeficient mice. Based on the analysis of the DNA from CWR22 and 22Rv1, we present evidence against the presence of XMRV in CWR22 and, by inference, the tumor, from which CWR22 and 22Rv1 were established. While the presence of XMRV in 22Rv1 is likely to be an artifact, it may be a significant factor in determining the biological properties of this cell line. This consideration warrants additional caution for the interpretation of the rel