A5075123916- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Cancer, Hypoxia, and Metabolism
- BRCA gene mutations in cancer
- Immune Cell Function and Interaction
- Amino Acid Enzymes and Metabolism
- interferon and immune responses
- Glycosylation and Glycoproteins Research
- Cancer therapeutics and mechanisms
- Advanced biosensing and bioanalysis techniques
- Cancer Mechanisms and Therapy
- Synthesis and Characterization of Heterocyclic Compounds
- Chronic Myeloid Leukemia Treatments
- Medical Imaging Techniques and Applications
- Adenosine and Purinergic Signaling
- Glioma Diagnosis and Treatment
- Colorectal Cancer Treatments and Studies
- Protein Degradation and Inhibitors
- Mechanisms of cancer metastasis
- Monoclonal and Polyclonal Antibodies Research
- Acute Lymphoblastic Leukemia research
- Acute Myeloid Leukemia Research
- Protein purification and stability
- Cytomegalovirus and herpesvirus research
Horizon Therapeutics (United States)
2023
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
2020-2022
University of Maryland, Baltimore
2017-2022
University of Baltimore
2017-2022
University of Washington
2011-2015
Significance We introduce a key role for low doses of DNA methyltransferase inhibitors (DNMTis) in reprogramming the repair transcriptome and creating homologous recombination defect (HRD), sensitizing to poly (ADP-ribose) polymerase (PARP) (PARPis) breast cancer gene (BRCA)-proficient nonsmall cell lung (NSCLC), which are not clinically responsive PARPis. The nonhomologous end-joining pathway is also downregulated by DNMTis, generating sensitivity radiation therapy (RT). significant...
(18)F-fluoromisonidazole ((18)F-FMISO) is the most widely used PET agent for imaging hypoxia, a condition associated with resistance to tumor therapy. (18)F-FMISO equilibrates in normoxic tissues but retained under hypoxic conditions because of reduction and binding macromolecules. A simple tissue-to-blood (TB) ratio suitable quantifying hypoxia. TB threshold 1.2 or greater useful discriminating volume (HV) tissue; TBmax maximum intensity region does not invoke threshold. Because elimination...
Significance Combining DNMTi with PARPi induces HRD in a BRCA-proficient setting. We now uncover an unexpected mechanism for generation of that joins drug induction broad, innate immune signaling to directly drive HRD. The findings have important translational implications broadening the scope therapy and potentially immunotherapy.
DNA methyltransferase inhibitors (DNMTis) reexpress hypermethylated genes in cancers and leukemias also activate endogenous retroviruses (ERVs), leading to interferon (IFN) signaling, a process known as viral mimicry. In the present study we show that subset of acute myeloid (AMLs) with mutations
Reduced NME1 expression in melanoma cell lines, mouse models of melanoma, and specimens human patients is associated with increased metastatic activity. Herein, we investigate the role repair double-stranded breaks (DSBs) choice double-strand break (DSBR) pathways cells. Using chromatin immunoprecipitation, was shown to be recruited rapidly directly DSBs generated by homing endonuclease I-PpoI. within 30 min, concert recruitment ataxia-telangiectasia mutated (ATM) protein, an early step DSBR...
This study presents a novel degradation pathway of human immunoglobulin G (IgG) molecule featuring light chain N-terminal asparagine. We thoroughly characterize this and investigate its charge profiles using cation exchange chromatography (CEX) capillary isoelectric focusing (cIEF). Beyond the well-documented asparagine deamidation into isoaspartic acid, aspartic succinimide intermediate, previously unreported clipping is uncovered. newly identified clipped IgG variant exhibits delayed...
Abstract DNA methyltransferase inhibitors (DNMTis), which transcriptionally activate hypermethylated genes in cancers and leukemias, also endogenous retroviruses (ERVs), leading to increased cytosolic double-stranded (ds) RNA interferon (IFN) signaling, a process termed viral mimicry. The tumor suppressor TP53 has been reported cooperate with methylation IFN signaling maintain transcriptional silencing of various repeat sequences, including ERVs. We now report that DNMTis, used treat acute...
Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have efficacy in a sub-set of triple negative breast cancers (TNBCs) with inherited mutations DNA double strand break repair (DSBR) genes, such as the BRCA1/2 genes homologous recombination (HR), through synthetic lethality. However, PARP failed for majority sporadic TNBCs intact BRCA1 genes. Therefore, novel targeted therapies must be explored. We recently reported that PARPi Talazoparib combination methyl transferase (DNMTi)s...
Abstract Poly (ADP-ribose) polymerase inhibitors (PARPis) are effective in a subset of triple negative breast cancers (TNBC) with BRCA gene mutations, which generates homologous recombination deficiencies (HRD), through synthetic lethality. However, PARPis fail for the majority sporadic TNBC intact BRCA1/2 genes and other BRCA-proficient cancers, including acute myeloid leukemia (AML). PARPi, Talazoparib (TAL), has potent PARP trapping ability, both mutant proficient TNBCs AML. We reported...
Poly (ADP-ribose) polymerase inhibitors (PARPis) are effective in a subset of triple negative breast cancers (TNBC) with BRCA gene mutations, which generates homologous recombination deficiencies (HRD), through synthetic lethality. However, PARPis fail for the majority sporadic TNBC intact BRCA1/2 genes and other BRCA-proficient cancers, including acute myeloid leukemia (AML). PARPi, Talazoparib (TAL), has potent PARP trapping ability, both mutant proficient TNBCs AML. We reported that...
Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) are FDA approved in a subset of patients with ovarian cancer or metastatic breast cancers who harbor BRCA gene mutations. Although these mutations, which generate homologous recombination deficiencies (HRD), have been the main predictor to PARPi sensitivity, responses therapy not durable and failed for majority sporadic triple negative (TNBC). We previously reported that DNA methyltransferase inhibitor (DNMTi) azacytidine (Aza)...