A5076913129- Nuclear Structure and Function
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Pancreatic and Hepatic Oncology Research
- Cancer Research and Treatments
- Glioma Diagnosis and Treatment
- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Cellular transport and secretion
- Advanced biosensing and bioanalysis techniques
- Genetic factors in colorectal cancer
- Genetic and Kidney Cyst Diseases
- Cancer Genomics and Diagnostics
- Innovative Microfluidic and Catalytic Techniques Innovation
- Renal and related cancers
- HIV/AIDS drug development and treatment
- RNA and protein synthesis mechanisms
- Parvovirus B19 Infection Studies
- Prostate Cancer Treatment and Research
- Microtubule and mitosis dynamics
- Genomics and Rare Diseases
- Evolution and Genetic Dynamics
- Acute Lymphoblastic Leukemia research
- Autophagy in Disease and Therapy
- Acute Myeloid Leukemia Research
Dana-Farber Cancer Institute
2019-2021
KU Leuven
2015-2021
Rega Institute for Medical Research
2015-2021
Broad Institute
2020
Harvard University
2019-2020
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...
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...
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor Nuclear Export (SINE) compounds (selinexor analogs) restores antitumor activity multiple TSPs leading suppression PDAC in vitro orthotopic models.We evaluate synergy...
Few therapies target the loss of tumor suppressor genes in cancer. We examine CRISPR-SpCas9 and RNA-interference loss-of-function screens to identify new therapeutic targets associated with genomic genes. The endosomal sorting complexes required for transport (ESCRT) ATPases VPS4A VPS4B score as strong synthetic lethal dependencies. is essential cancers harboring adjacent SMAD4 on chromosome 18q tumors co-deletion CDH1 (E-cadherin) 16q. demonstrate that more than 30% selectively require or...
Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is aggressive non-Hodgkin very poor prognosis that typically affects infected individuals stages immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect targeting a single process common both diseases. Inhibition exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors...
Exportin-1 (CRM1/XPO1) is a crucial nuclear export protein that transports wide variety of proteins from the nucleus to cytoplasm. These cargo include tumor suppressors and growth-regulatory factors as such XPO1 considered potential anti-cancer target. From this perspective, inhibition XPO1-mediated by selective inhibitor (SINE) compounds has shown broad-spectrum activity. Furthermore, clinical candidate SINE, selinexor, currently in multiple phase I/II/IIb trials for treatment cancer....
// Amro Aboukameel 1 , Irfana Muqbil 2 Erkan Baloglu 3 William Senapedis Yosef Landesman Christian Argueta Michael Kauffman Hua Chang Trinayan Kashyap Sharon Shacham Jasper E. Neggers 4 Dirk Daelemans Elisabeth I. Heath and Asfar S. Azmi Wayne State University School of Medicine, Detroit, MI, USA Detroit Mercy, Karyopharm Therapeutics Inc, Newton, MA, KU Leuven Department Microbiology Immunology, Laboratory Virology Chemotherapy, Rega Institute for Medical Research, Herestraat, Belgium...
While drug resistance mutations provide the gold standard proof for target engagement, deconvolution of inhibitors identified from a phenotypic screen remains challenging. Genetic screening functional in-frame by tiling CRISPR-Cas nucleases across protein coding sequences is method identifying drug's and binding site. However, applicability this approach constrained availability nuclease sites genetic regions that mediate upon mutation. In study, we show an enhanced AsCas12a variant...
(Cell Reports 33, 108493-1–19.e1–e16; December 15, 2020) In the originally published version of this paper, CHMP4B sgRNA sequence listed in STAR Methods section was incorrect. The incorrect 5′-TCGATGGCACAAGCCATGAA, which is an designed to target CHMP2A. correct CHMP4B-targeting that used experiments for paper 5′- TATCAACCATCGAGTTCCAG. This change does not affect data or conclusions study and now appears online. authors apologize any inconvenience error may have caused. Synthetic Lethal...
Abstract Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports a wide variety of different cargo proteins including tumor suppressors out cell's nucleus. Inhibition XPO1 function consequently restores nuclear localization these and promising therapeutic strategy for cancer. Selective inhibitor export (SINE) compounds are inhibitors XPO1-mediated with potent anti-cancer activity. The oral clinical candidate SINE selinexor (KPT-330) currently in Phase-II/IIb...
Abstract Human Exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports a variety of different cargo proteins out cell's nucleus. Inhibition XPO1-mediated export results in nuclear retention including tumour suppressor and novel therapeutic strategy for cancer. Selinexor, an orally bioavailable XPO1 inhibitor, effectively demonstrates potent activity against multiple types Here we directly demonstrate high selectivity selinexor inside living cells. Selinexor binds to...
<p>Movie S1</p>
<p>Supplementary Table 1 - EC50 values for KPT-8602 and KPT-330 in different leukemia cells Supplementary 2 wild-type versus XPO1C528S mutant cell lines Figure S1 High content images of HeLa stably expressing the NLS-AcGFP-NES reporter treated with concentrations or S2 Effect treatment on normal peripheral blood NSG mice</p>
<p>Movie S2</p>
<p>Supplementary Table 1 - EC50 values for KPT-8602 and KPT-330 in different leukemia cells Supplementary 2 wild-type versus XPO1C528S mutant cell lines Figure S1 High content images of HeLa stably expressing the NLS-AcGFP-NES reporter treated with concentrations or S2 Effect treatment on normal peripheral blood NSG mice</p>
<p>Movie S2</p>
<p>Movie S1</p>