Browsing by Author "Narendran, Aru"
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Item Open Access A Novel Combinatorial Strategy Targeting the EGFR and JAK2/STAT3 Pathways in GBM Brain Tumour Initiating Cells(2017) Jensen, Katharine; Weiss, Samuel; Luchman, H. Artee; Grewal, Savraj; Mahoney, Douglas; Narendran, AruGlioblastoma multiforme (GBM) is the most prevalent and aggressive primary adult brain tumour with a median survival of only 15 months. Despite aggressive treatment, long-lasting tumour control cannot be achieved and disease recurrence is inevitable. Brain tumour initiating cells (BTICs) are postulated to be at the root of disease initiation and recurrence, suggesting that BTIC targeting therapies are crucial to establishing tumour control. Resistance of cancer cells to targeted therapies can occur through the activation of compensating signalling pathways. Using a BTIC model of GBM, we identified the activation of signal transducer and activator of transcription (STAT)3 as a compensation mechanism in response to epidermal growth factor receptor (EGFR) inhibition. We showed that concurrent inhibition of EGFR and STAT3 was highly effective in vitro, as it dramatically decreased BTIC viability and neurosphere formation. Combined inhibition of EGFR and STAT3 resulted in the attenuation of both oncogenic signalling pathways. In vivo, systemic administration of the EGFR inhibitor, afatinib, and the JAK2 inhibitor, pacritinib, demonstrated favourable pharmacokinetic and pharmacodynamic properties, displaying blood-brain barrier penetration and on-target activity in orthotopic BTIC xenografts. Overall, these data provide a promising strategy to overcome EGFR inhibitor resistance by targeting two oncogenic pathways in combination.Item Open Access ATM-deficient cancer cells and targeted therapies(2018-07-09) Jette, Nicholas Ryan; Lees-Miller, Susan; Narendran, Aru; Senger, Donna L.; Bebb, Gwyn D.The driving principle behind precision medicine is to specifically target genetic variations that arise in tumorigenesis while leaving normal cells unaffected. Mutations in Ataxia Telangiectasia Mutated (ATM) may offer such a therapeutic target. ATM is mutated in a variety of tumor types and these mutations can lead to a dysfunctional protein, or protein deletion. ATM is an apex signaling kinase that responds to DNA double strand breaks, playing a direct role in DNA repair as well as the initiation of signaling cascades that can lead to cell cycle arrest and apoptosis. In recent years, several studies have shown that Poly ADP-Ribose Polymerase (PARP) inhibitors effectively target ATM-deficient tumors both invitro and invivo. These studies have been limited to mantle cell lymphoma, gastric cancer, colorectal cancer and breast cancer cell lines and the mechanism of sensitivity remains unclear. Here, I show that ATM-deficient lung and pancreatic cancer cell lines are sensitive to olaparib (a PARP inhibitor) and that ATM-deficient pancreatic cancer cell lines are sensitive to the PARP inhibitor Rucaparib as well as the ATR inhibitor VE-821. Using both lung and colorectal cancer cells, I also show that olaparib induces DNA damage and that olaparib causes an accumulation of G2 phase cells in ATM-deficient cells. Since olaparib is set to become a more commonly used chemotherapeutic, these findings are both important and relevant to its use in the clinic.Item Open Access Aurora Kinase Inhibition as a Novel Therapeutic Approach for the Treatment of Refractory Pediatric and Infant Leukemia(2014-01-30) Jayanthan, Aarthi Anita; Narendran, AruLeukemia is the most common pediatric malignancy, constituting more than 30% of all childhood cancers. Although cure rates have improved greatly, approximately one in four children relapse and survival rates post relapse are very low. Given this, more effective and innovative therapeutic strategies are needed in order to improve prognosis. Aurora kinases, a family of serine/threonine kinases essential for the regulation of several mitotic processes, have been identified as potential targets for cancer therapeutics. Elevated expression of Aurora kinases has been determined in several malignancies and is associated with aberrant mitotic activity, aneuploidy, alterations in chromosomal structure and genome instability. Based on this, a panel of Aurora kinase inhibitors was tested against pediatric leukemia cells and demonstrated variable cytotoxicity, the induction of apoptosis and changes in Aurora kinase activity. The dual Aurora-A/B inhibitor AT9283 was selected for further investigation, as it also targets FLT3, Jak2 and c-Abl, which are important in leukemogenesis. AT9283 promoted a polyploid phenotype, inhibited pathways involved in growth and survival and displayed synergistic activity with novel and conventional therapeutics. Of these therapeutics, ABT-737, a B–cell lymphoma 2 inhibitor, and BI 6727, a Polo-like kinase inhibitor, promoted increased Aurora kinase phosphorylation. Similarly, Aurora kinase inhibition promoted increased Bcl-2 phosphorylation and increased Plk-1 expression and activity. Furthermore, ABT-737 and BI 6727 displayed synergistic activity with several Aurora kinase inhibitors. This study establishes the effects and potential mechanisms of Aurora kinase inhibition on pediatric leukemia in vitro both as single agents and in combination with novel and conventional therapeutics targeting pathways involved in apoptosis and mitosis.Item Open Access The Impact of the Innate Immune System in Alveolar Soft Part Sarcoma(2022-11-15) Philippot, Alexis Marie; Senger, Donna; Chan, Jennifer; Monument, Michael; Narendran, AruAlveolar Soft Part Sarcoma (ASPS) is a rare pediatric malignancy which has characteristically poor clinical outcomes, largely due to a complete lack of chemotherapeutic treatment options, and a high likelihood of metastasis. Further, a lack of pre-clinical models has hampered progression in the understanding of the tumor’s biology and resistance to chemotherapies since it was originally described in 1952. After being in the privileged position of receiving ASPS tumor tissue from the lung metastasis of a 14-year-old female, the Senger laboratory successfully established an ASPS patient derived xenograft (PDX) model and corresponding cell line. Recent literature has suggested that the tumor microenvironment (TME) is implicated in the tumor progression of multiple soft tissue sarcomas, including ASPS; specifically, macrophage have been described as a prominent prognostic marker. Therefore, using this PDX model, we characterized the innate immune component of the TME with respect to the cell populations and cytokines secreted by both the tumor cells and stroma. Unsurprisingly, the PDX tumors were abundant in pro-tumor macrophage and pro-inflammatory cytokines. As data generated by the Senger laboratory had established the susceptibility of ASPS cells to proteasome inhibitor carfilzomib, carfilzomib was also evaluated for its anti-tumor implications on both the tumor cells and the innate immune microenvironment. After observing a number of anti-tumor changes to the macrophage within the TME following carfilzomib treatment, this chemotherapeutic significantly decreased tumor burden in ASPS PDX bearing mice suggesting the TME may be the Achille’s heel to this chemotherapy resistant sarcoma.Item Embargo ING5 affects mitosis and the DNA damage response in human and murine models(2024-04-30) Estanislau Dantas, Arthur; Riabowol, Karl; Luchman, Artee; Biernaskie, Jeff; Rancourt, Derrick; Narendran, Aru; Harkness, TroyThe INhibitor of Growth family (INGs 1-5) is part of lysine acetyltransferase and lysine deacetylase complexes. They are epigenetic readers that recruit these complexes to the H3K4Me3 mark of active transcription.. Several studies have implicated ING5 in stem cell maintenance in adult and cancer stem cells, cell cycle regulation, and DNA damage response pathways. Here, we investigate the roles of ING5 in two different systems: primary mouse embryonic fibroblasts (MEFs) derived from our Ing5-KO murine model and Brain Tumor Initiating Cells (BTIC cancer stem cells) derived from glioblastoma patients. We show that Ing5-KO MEFs have defects in the cell cycle, with cells accumulating in the G2/M phase of the cell cycle, and carry a higher DNA damage load than their WT counterparts. In addition, after exposure to oxidative stress Ing5-KO cells frequently have abnormal nuclei, defective mitosis and express increased levels of the p21 cyclin-dependent kinase inhibitor compared to WT. RNA-seq analysis of Ing5-KO MEFs revealed significant downregulation of the HOXA family of transcription factors and other transcription factors involved in development such as FOXD1, SOX5 and two transcription factors of the GATA family, indicating that ING5 is part of a network for the regulation of developmental transcription factors. ING5 was also detected on the promoters of SOX4 and GATA6 in primary human fibroblasts, established human embryonic kidney (HEK293) cells and a glioma stem cell.Item Open Access Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition(BioMed Central, 2011-12-29) Jayanthan, Aarthi; Bernoux, Delphine; Bose, Pinaki; Riabowol, Karl; Narendran, AruItem Open Access Polo-like kinase-1 (PLK-1) inhibitors as novel therapeutics in oral squamous cell carcinoma(2019-07-22) Sarkar, Subhanwita; Bose, Pinaki; Narendran, Aru; Bonni, Dr. Shirin; Childs, Sarah J.Polo-like kinase-1 (PLK-1) belongs to a family of conserved serine/threonine kinases and is an oncogenic protein in many cancers. Therefore, PLK-1 is an attractive therapeutic target and clinical trials are ongoing to test the efficacy of PLK-1 inhibitors in several cancer-types. Oral squamous cell carcinoma (OSCC) is a common head and neck cancer. OSCC is associated with frequent recurrences after initial curative therapy and overall poor prognosis. We analysed RNA sequencing data from The Cancer Genome Atlas (TCGA) and found that PLK-1 mRNA levels are elevated in OSCC compared to normal oral cavity squamous epithelium and high PLK-1 expression in OSCC is associated with worse survival. Based on these results, we tested the efficacy of PLK-1 inhibitors in a panel of ten OSCC cell lines. The PLK-1 inhibitor, volasertib effected cell death at low nanomolar concentrations in most tested OSCC cell lines but not in normal oral keratinocytes. Flowcytometry analysis showed that volasertib induces G2/M arrest in sensitive cell lines. Western blot analysis showed that levels of total PLK-1 and phospho PLK-1 were reduced after volasertib treatment in sensitive cell lines. Volasertib also triggered apoptosis confirmed by the cleavage of PARP and Caspase 3. Cell lines resistant to volasertib did not show any alteration in total PLK-1 and pPLK-1 after volasertib treatment. Post-operative radiotherapy is a common treatment modality in OSCC patients. In two OSCC cell lines that were refractory to volasertib treatment, a combination of volasertib and γ-radiation significantly lowered cell survival compared to volasertib or γ-radiation alone. Combination therapy with γ-radiation and volasertib in resistant cell lines resulted in S-phase arrest. Western blot analysis showed a significant reduction of total PLK-1 and pPLK-1 after combinatorial therapy. Apoptosis was induced in volasertib resistant cells as a result of combination therapy. Taken together, these in vitro studies establish the rationale for further investigation of volasertib efficacy in orthotopic OSCC xenograft models and clinical trials.Item Open Access Receptor Cross-Talk in the Biology & Therapeutics Of Pediatric Rhabdoid Brain Tumors(2014-05-02) Obaid, Halah; Narendran, AruAtypical teratoid rhabdoid tumor (ATRT) is a highly malignant brain tumor that usually affects very young children and typically causes death, despite very aggressive treatment. The biological properties contributing to tumor aggressiveness and resistance to common chemotherapeutic agents are currently unknown. Previous studies have shown the activation of Insulin like growth factor-I receptor (IGF-1R) in ATRT tumor specimens and cell lines. Additionally, angiogenesis is an established physiological mechanism that supports the survival and progression of brain tumors. Vascular endothelial growth factor receptor (VEGFR) signaling pathway is a major regulator of angiogenesis in brain tumors. We hypothesized that molecular interactions may exist between these two signaling pathways. Our findings show evidence for a novel IGF-1R/VEGFR-2 cross-talk in response to IGF-I mediated activation. Furthermore, we show evidence that the inhibition of IGF-1R/VEGFR-2 pathways by the small molecule inhibitors lead inhibition of cell migration properties and the initiation of apoptosis. Overall, the data generated in this set of studies present a framework to evaluate and utilize the receptor cross talk pathways to identify novel treatment approaches for ATRT in the future.Item Open Access Survivin as a Preferential Target for Cancer Therapy(Multidisciplinary Digital Publishing Institute, 2014-02-13) Mobahat, Mahsa; Narendran, Aru; Riabowol, KarlItem Open Access Targeting Selective Receptor Tyrosine Kinases in Refractory Embryonal Tumors of Childhood(2016) Singh, Anjali; Narendran, Aru; Kurz, Ebba; Krawetz, Roman; Bahlis, NizarEmbryonal tumors are a collection of biologically heterogeneous malignancies and the exact cellular origin of these tumors is not known. Neuroblastoma (NB) and atypical teratoid/rhabdoid tumor (AT/RT) are highly malignant tumors of embryonal origin that primarily affect infants and young children. Neuroblastoma is the most common type of extra cranial solid tumor in children. In the case of AT/RT, the survival rate of children affected by this disease is the lowest when compared to all embryonal tumors. Despite intensifying multimodal treatments, children affected with refractory AT/RT and NB have unacceptably high treatment failure and mortality rates. To improve the clinical outcome of these malignancies, it is important to identify the key molecules and cellular pathways responsible for tumor progression, survival and invasion. Many childhood cancers have high activation levels of selective receptor tyrosine kinase signaling pathways. Activation of these signaling pathways promotes cell proliferation, differentiation and cell survival. Therefore, receptor tyrosine kinases (RTKs) have become attractive therapeutic targets and the use of small molecule kinase inhibitors to block their signal transduction functions has led to the discovery of a number of novel therapeutics agents. This research presents the relevant background information on two pediatric neoplasms that we have selected to study and aims to provide the rationale for the development of useful new therapies for their treatment. Presented in details are the data with respect to the establishment of a screening approach to identify effective therapeutic agents with information on target validation and target modulation activities that can be utilized to design future clinical trials for these cancers.