A5038643879- Nuclear Structure and Function
- Cancer-related Molecular Pathways
- RNA Research and Splicing
- Melanoma and MAPK Pathways
- Advanced Breast Cancer Therapies
- Pancreatic and Hepatic Oncology Research
- Cancer, Hypoxia, and Metabolism
- RNA modifications and cancer
- Colorectal Cancer Treatments and Studies
- Biochemical and Molecular Research
- Cancer, Lipids, and Metabolism
- Acute Myeloid Leukemia Research
- Neuroblastoma Research and Treatments
- PARP inhibition in cancer therapy
- Protein Kinase Regulation and GTPase Signaling
- Multiple Myeloma Research and Treatments
- Neuroendocrine Tumor Research Advances
- Prostate Cancer Treatment and Research
- Lung Cancer Treatments and Mutations
- Retinoids in leukemia and cellular processes
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- Cancer Mechanisms and Therapy
- Chronic Lymphocytic Leukemia Research
- Peptidase Inhibition and Analysis
Karyopharm Therapeutics (United States)
2014-2023
Wayne State University
2023
The Barbara Ann Karmanos Cancer Institute
2023
Mercer University
2014
Harvard University
2010-2013
Massachusetts General Hospital
2013
The University of Texas Southwestern Medical Center
2012
Fox Chase Cancer Center
2003-2005
<h3>Objectives</h3> Oesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved description genetic abnormalities OSCC, few targetable lesions have been identified, no molecular therapy available. This study aims to identify druggable candidates in this tumour. <h3>Design</h3> High-throughput small-molecule inhibitor screening was performed potent anti-OSCC...
Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in United States and one of relatively few whose incidence increasing. Because near universal resistance which occurs with use current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies this disease. Borrowing from studies on other malignancies, we have identified PAK4 NAD biosynthetic essential RCC growth. We now show, using dual PAK4/NAMPT...
Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing cells that have acquired aberrant survival, uncontrolled proliferation and block in normal hematopoietic cell differentiation. Standard chemotherapy often induces remissions AML patients, but the frequently relapses due to incomplete targeting leukemia-initiating (LICs), emphasizing need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which inhibited by drug selinexor, an...
The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 blocks its function. Treatment cancer cells selinexor results retention major tumor suppressor proteins cell cycle regulators, leading growth arrest apoptosis. Recently, we described the selection SINE compound resistant reported elevated expression...
Unraveling the mechanism of action and molecular target small molecules remains a major challenge in drug discovery. While many cancer drugs genetic vulnerabilities, loss-of-function screens fail to identify essential genes action. Here, we report CRISPRres, CRISPR-Cas-based screening approach rapidly derive resistance mutations genes. It exploits local variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair generate wide variety functional in-frame mutations. Using...
Abstract The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells but not normal human epithelia (HPDE). Gene copy number amplification studies PDAC patient cohorts confirmed PAK4 making it an attractive therapeutic target PDAC. We investigated antitumor activity novel allosteric modulators (PAM) on panel cell lines chemotherapy-resistant flow-sorted cancer stem (CSC). toxicity...
606 Background: The c-MYC (MYC) oncogene is a master transcription factor of tumor cell and microenvironment regulation; it often dysregulated in cancer, including HCC. OTX-2002 MYC-targeted Epigenomic Controller (MYC-EC), an mRNA drug substance encapsulated clinical lipid nanoparticle (LNP), designed to downregulate MYC expression pre-transcriptionally with high specificity durability, inhibiting viability while sparing normal cells. Methods: A first-in-human dose-escalation study...
Abstract Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast particularly difficult to treat. This due lack understanding the mechanisms behind disease, and consequently druggable targets. PAK4 plays critical roles in cell survival, proliferation, morphology. protein levels are high cells tumors, gene often amplified basal like cancers, which frequently negative. also overexpressed other types cancer, making it promising drug...
Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of nucleus. Inducing nuclear accumulation these by inhibiting XPO1 causes cancer cell death. First clinical validation pharmacological inhibition was obtained with Selective Inhibitor Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb trials when dosed 1 to 3 times weekly. The second-generation SINE KPT-8602 shows improved...
Abstract The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the major tumor suppressor proteins growth regulators such as p53, p21, p27. XPO1 also affects translation messenger RNAs critical oncogenes, including MYC, BCL2, MCL1, BCL6, by blocking initiation factor eIF4E. Early trials with venetoclax...
Resistance to BRAF inhibitor therapy places priority on developing inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms resistance. The CRM1 receptor mediates nuclear export critical proteins required for melanoma proliferation, survival, drug We hypothesize by inhibiting CRM1-mediated export, we alter function these resulting in decreased viability enhanced antitumoral effects. To test our hypothesis, selective inhibitors (SINE)...
The goal of this study was to examine the effects selinexor, an inhibitor exportin-1 mediated nuclear export, on DNA damage repair and evaluate cytotoxic selinexor in combination with damaging agents (DDAs) cancer cells.Selinexor reduced expression (DDR) proteins. This did not induce significant tested cell lines. Inhibition DDR protein resulted enhanced death when cells were pretreated DDAs. In contrast, detected that then vivo, single-agent docetaxel, or cisplatin treatment 66.7%, 51.5%,...
Abstract Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ a potential therapeutic target AML. We evaluated effect KPT-9274, p21-activated kinase 4/NAMPT inhibitor that possesses unique NAMPT-binding profile based on silico modeling compared earlier compounds pursued against this target. KPT-9274 elicited loss mitochondrial respiration...
// Asfar S. Azmi 1 , Yiwei Li Irfana Muqbil Amro Aboukameel William Senapedis 2 Erkan Baloglu Yosef Landesman Sharon Shacham Michael G. Kauffman Philip A. and Ramzi M. Mohammad Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School Medicine, Detroit, MI, USA Karyopharm Therapeutics Inc., Newton Centre, MA, Correspondence to: Mohammad, email: mohammar@karmanos.org Keywords: XPO1, miR-145, pancreatic cancer, proliferation, migration Received: March 26,...
Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome caused by mutations in TSC1 and TSC2. Hamartin tuberin, the products of TSC2, respectively, form heterodimers inhibit mammalian target rapamycin. Previously, we have shown that hamartin phosphorylated CDC2/cyclin B1 during G(2)/M phase cell cycle. Here, report localized to centrosome tuberin co-immunoprecipitate with mitotic kinase Plk1. Plk1 interacts N-terminus (amino acids 1-880), which contains two potential...
The principles of DNA nanotechnology and protein engineering have been combined to generate a new class artificial extracellular matrices. potential this material for ex vivo cellular scaffolding was demonstrated using experiments in which human cervical cancer cells were found adhere strongly, stay alive, grow with high migration rates. use our DNA/protein-based matrices makes these structures inherently amenable structural tunability. By single-stranded domains into the portions, we able...
XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 potential therapeutic target in melanoma using novel selective inhibitors export (SINE). In vitro effects SINE on cell growth and apoptosis were measured by MTS assay flow cytometry [Annexin V/propidium iodide (PI)], respectively human metastatic lines. Immunoblot analysis was used to measure localization The vivo activity oral evaluated NOD/SCID mice...
Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% 20%, prompting the need identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates nuclear export critical proteins required cancer proliferation and resistance. We hypothesize that...