Papers by Reza Ghasemi, PhD
ErbB-3 (HER-3) receptor is involved in tumor progression and resistance to therapy. Development o... more ErbB-3 (HER-3) receptor is involved in tumor progression and resistance to therapy. Development of specific inhibitors impairing the activity of ErbB-3 is an attractive tool for cancer therapeutics. MP-RM-1, a murine monoclonal antibody targeting human ErbB-3, has shown anticancer activity in preclinical models. With the aim to provide novel candidates for clinical use, we have successfully generated a humanized version of MP-RM-1. The humanized antibody, named EV20, abrogates both ligand-dependent and ligand-independent receptor signaling of several tumor cell types, strongly promotes ErbB-3 down-regulation, and efficiently and rapidly internalizes into tumor cells. Furthermore, treatment with EV20 significantly inhibits growth of xenografts originating from prostatic, ovarian, and pancreatic cancers as well as melanoma in nude mice. In conclusion, we provide a novel candidate for ErbB-3-targeted cancer therapy.
Nectins are Ca2+-independent immunoglobulin-like cell adhesion molecules that compose a family of... more Nectins are Ca2+-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan–Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4High). At Kaplan–Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4High was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4Low/Negative is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.
ErbB-3 and its ligand NRG-1β are key players in driving oncogenic signaling and resistance to the... more ErbB-3 and its ligand NRG-1β are key players in driving oncogenic signaling and resistance to therapy through the activation of the PI3K/Akt pathway. We have recently reported that EV20, a humanized anti-ErbB3 antibody, possesses a marked antitumor activity in a variety of human tumor models, including pancreatic cancer (PC). Here, we report that despite epidermal growth factor receptor overexpression, PC cells are more sensitive to NRG-1β than EGF in terms of Akt activation and cell proliferation. Using stable ErbB-3-knocked down cells and EV20 in combination with trastuzumab, we showed that dual targeting of ErbB-2 and ErbB-3 was necessary to completely abrogate ErbB-3 signaling and to impair cell proliferation. Similarly, enhanced therapeutic efficacy of the antibody combination was seen in xenografts originating from K-Ras-mutated HPAF-II and SW1990 cells, without increasing the toxicity. These results indicate that dual targeting of ErbB-2 and ErbB-3 could represent a new therapeutic approach in PC.
Translational oncology, 2013
ErbB-3 (HER-3) receptor is involved in tumor progression and resistance to therapy. Development o... more ErbB-3 (HER-3) receptor is involved in tumor progression and resistance to therapy. Development of specific inhibitors impairing the activity of ErbB-3 is an attractive tool for cancer therapeutics. MP-RM-1, a murine monoclonal antibody targeting human ErbB-3, has shown anticancer activity in preclinical models. With the aim to provide novel candidates for clinical use, we have successfully generated a humanized version of MP-RM-1. The humanized antibody, named EV20, abrogates both ligand-dependent and ligand-independent receptor signaling of several tumor cell types, strongly promotes ErbB-3 down-regulation, and efficiently and rapidly internalizes into tumor cells. Furthermore, treatment with EV20 significantly inhibits growth of xenografts originating from prostatic, ovarian, and pancreatic cancers as well as melanoma in nude mice. In conclusion, we provide a novel candidate for ErbB-3-targeted cancer therapy.
Nutrition and cancer, 2013
Medical Oncology, 2010
The purpose of the present study is to evaluate the effects of arsenic trioxide (ATO) on human ac... more The purpose of the present study is to evaluate the effects of arsenic trioxide (ATO) on human acute promyelocytic leukemia NB-4 cells. Microculture tetrazolium test, bromodeoxyuridine (BrdU) cell proliferation assay, caspase 3 activity assay, cell-based nuclear factor kappa B (NF-κB) phosphorylation measurement by ELISA and real-time RT-PCR were employed to appraise the effects of ATO on metabolic activity, DNA synthesis, induction of programmed cell death and NF-κB activation. The suppressive effects of ATO on metabolic potential, cell proliferation and NF-κB activation were associated with induction of apoptosis in NB-4 cells. In addition, an expressive enhancement in mRNA levels of p73, cyclin-dependent kinase inhibitor 1A (p21), tumor protein 53-induced nuclear protein 1 (TP53INP1), WNK lysine deficient protein kinase 2 (WNK2) and lipocalin 2 coupled with a significant reduction in transcriptional levels of NF-κB inhibitor beta (IKK2), Nemo, BCL2-like 1 (BCL-XL), inhibitor of apoptosis protein 1 (cIAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin, Bcl-2, TIP60, ataxia telangiectasia (ATM), SHP-2 and sirtuin (SIRT1) were observed. Altogether, these issues show for the first time that ATO treatment could trammel cell growth and proliferation as well as induces apoptosis in NB-4 cells through induction of transcriptional levels of p73, TP53INP1, WNK2, lipocalin 2 as well as suppression of NF-κB-mediated induction of BCL-XL, cIAP2, XIAP and survivin. Furthermore, the inductionary effects of ATO on transcriptional stimulation of p73 might be through cramping the NF-κB module (through suppression of p65 phosphorylation as well as transcriptional hindering of IKK2, ATM and Nemo) along with diminishing the mRNA expression of TIP60, SHP-2 and SIRT1.
Anti-cancer Drugs, 2010
Glioblastoma multiforme remains one of the most devastating human malignancies because of its hig... more Glioblastoma multiforme remains one of the most devastating human malignancies because of its high infiltrative capacity. This study aimed to investigate the effects of silibinin on human glioblastoma U87MG cells. The microculture tetrazolium test, bromodeoxyuridine cell proliferation assay, cell-based nuclear factor kappa B (NF-jB) activation assessment, cathepsin B activity assay, gelatin zymography, and quantitative real-time reverse transcription-PCR were performed to appraise the effects of silibinin on the metabolic activity, DNA synthesis, NF-jB phosphorylation, cathepsin B activity, and gelatinolytic activity of U87 cells. Silibinin inhibited metabolic activity, cell proliferation, NF-jB activation, cathepsin B enzymatic levels, and gelatinase B activity in U87 cells. In addition, an expressive decrease in mRNA levels of matrix metalloproteinase-9, cathepsin B, urokinase plasminogen activator receptor, urokinase plasminogen activator, and intercellular adhesion molecule 1 coupled with a significant induction in transcriptional levels of stefin A was observed. Altogether, these issues show for the first time that silibinin treatment could trammel invasive features of a highly invasive human glioma cell line, U87, through suppression of NF-jB-mediated stimulation of matrix metalloproteinase-9. Furthermore, silibinin might cripple the activation of gelatinase B by cramping transcriptional and enzymatic activities of cathepsin B in U87 cells.
Medical hypotheses, 2012
Metastasis is the leading cause of cancer death, yet it is mechanistically considered a very inef... more Metastasis is the leading cause of cancer death, yet it is mechanistically considered a very inefficient process suggesting the presence of some sort of (e.g. systemic) routes for fuelling the process. The pre-metastatic niche formation is described as one such metastasis promoting route. Now, the emerging potentials of tumor-derived microvesicles (TDMVs), not only in formulating the pre-metastatic niche, but also conferring neoplastic phenotypes onto normal cells, has integrated new concepts into the field. Here, we note as an ancillary proposition that, exerting functional disturbances in other sites, TDMVs (we have termed them metastasomes) may aid foundation of the secondary lesions via two seemingly interrelated models: (i) tumor-organ-training (TOTr), training a proper niche for the growth of the disseminated tumor cells; (ii) tumor-organ-targeting (TOTa), contribution to the propagation of the transformed phenotype via direct or indirect (TOTr-mediated disturbed stroma) transformation and/or heightened growth/survival states of the normal resident cells in the secondary organs. Respecting the high content of the RNA molecules (particularly microRNAs) identified in the secretory MVs, they may play crucial parts in such ''malignant trait'' spreading system. That is, the interactions between tumor tissue-specific RNA signatures, being transferred via metastasomes, and the cell-type/tissue-specific RNA stockrooms in other areas may settle a unique outcome in each organ. Thus, serving as tumor-organ matchmakers, the RNA molecules may also play substantial roles in the seeding and tropism of the process.
Uploads
Papers by Reza Ghasemi, PhD