A5031486429- Acute Myeloid Leukemia Research
- Toxin Mechanisms and Immunotoxins
- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Polyamine Metabolism and Applications
- Immunotherapy and Immune Responses
- Axon Guidance and Neuronal Signaling
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- HER2/EGFR in Cancer Research
- Galectins and Cancer Biology
- Urinary and Genital Oncology Studies
- Acute Lymphoblastic Leukemia research
- Cancer-related molecular mechanisms research
- Cancer Cells and Metastasis
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Click Chemistry and Applications
- RNA modifications and cancer
- Cancer Treatment and Pharmacology
- Neuroblastoma Research and Treatments
- Immune cells in cancer
Mississippi State University
2023
Bicycle Therapeutics (United Kingdom)
2022
Epizyme (United States)
2014-2018
Abstract Multiple tumor types overexpress Nectin-4 and the antibody–drug conjugate (ADC), enfortumab vedotin (EV) shows striking efficacy in clinical trials for metastatic urothelial cancer, which expresses high levels of Nectin-4, validating as a target toxin delivery this indication. Despite excellent data little are reported EV other expressing tumors therapy can produce significant toxicities many patients, frequently leading to discontinuation treatment. Thus, additional approaches with...
DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation histones associated with well-characterized leukemic genes. Pinometostat (EPZ-5676), selective inhibitor DOT1L, clinical relapsed/refractory acute patients harboring rearrangements MLL gene. The observation responses subsequent relapses adult trial treating MLL-r motivated preclinical investigations into potential mechanisms pinometostat...
8515 Background: MM often presents at an advanced stage with a median survival of ~1 year. Treatments are limited; none clearly improve in second-line. In 40–60% patients (pts) BRCA1 associated protein 1 (BAP1) is inactive and linked to dependency on EZH2 (enhancer zeste-homolog 2). regulates gene expression prevent differentiation stem progenitor cells, aberrant activity implicated as oncogenic driver. Tazemetostat, potent, selective, oral inhibitor demonstrated clinical other malignancies;...
TPS4619 Background: BT8009 is a Bicycle toxin conjugate (BTC), comprising highly selective bicyclic peptide targeting nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via cleavable linker. Nectin-4 an adhesion molecule commonly expressed in many tumor types, including urothelial cancer (UC), and validated therapeutic target (Hoffman-Censits 2021). has low molecular weight short plasma half-life, with potential rapidly penetrate solid tumors reduce toxicity by minimizing...
TPS898 Background: Zelenectide pevedotin (zele; BT8009) is a Bicycle Toxin Conjugate (BTC), comprising highly selective bicyclic peptide targeting Nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via cleavable linker. an adhesion molecule commonly expressed in many tumor types, including la/mUC, and validated therapeutic target (Hoffman-Censits 2021). Zele has low molecular weight short plasma half-life, with potential rapidly penetrate solid tumors reduce toxicity by...
PURPOSE BT5528 is a Bicycle Toxin Conjugate, novel class of chemically synthesized molecules, comprising bicyclic peptide targeting EphA2 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]). overexpressed in many solid tumors and contributes oncogenesis, tumor-associated angiogenesis, metastasis. MATERIALS AND METHODS The primary objectives were investigate the safety tolerability define maximum-tolerated dose, if observed, recommended phase II dose (RP2D)/expansion dose....
Background CD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide ( Bicycle® ) technology. Nectin-4 overexpressed multiple human cancers that may benefit from agonism. To this end, we have developed BT7480, novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted cell agonist™ TICA™). Methods and co-expression analyses...
TPS3655 Background: BT5528 is a Bicycle Toxin Conjugate (BTC), comprising bicyclic peptide targeting the tumor antigen EphA2, linked to cytotoxin (monomethyl auristatin E [MMAE]) via microenvironment cleavable linker. Bicycles are novel class of chemically synthesized constrained peptides, developed by Therapeutics. EphA2 reported be overexpressed in range solid tumors, contributes oncogenesis, tumor-associated angiogenesis and metastasis. Intracellular signaling converges on pathways that...
TPS2668 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), novel class of chemically synthesized molecules, comprising bicyclic peptide targeting Nectin-4 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]) via valine-citrulline (val-cit) cleavable linker. Nectins (Nectin-1, -2, -3, and -4) nectin-like molecules (Necl) are Ca2+ independent immunoglobulin-like cell adhesion molecules. Recent studies have shown the importance in several human cancers, including lung,...
Abstract Introduction: Clinical studies in cancer patients have validated CD137 agonism as an activator of the immune system to enable tumor rejection. We demonstrated that small, chemically synthetic bicyclic peptides can drive tumor-localized and anti-tumor immunity mouse models. Here, we report next stage our work - delving into mechanism action these novel agents extending program serve whose tumors express EphA2. Experimental Procedures: MultiOmyx™ hyperplexed immunofluorescence assay...
Abstract Introduction: BT5528 is a Bicycle® Toxin Conjugate (BTC) which contains an EphA2 binding peptide (Bicycle) conjugated through molecular spacer and cleavable linker to the antimitotic toxin MMAE. attractive tumor target; overexpression has been reported in multiple types. Preclinical activity of described previously, demonstrating increased efficacy associated with high cell expression levels xenograft models. Enrollment Phase I dose escalation study (BT5528-100) started patients...
Abstract DOT1L inhibitor EPZ-5676 is currently under Phase 1 clinical trial investigation in relapsed/refractory patients with acute leukemia, including those an MLL-rearrangement (MLL-r). Early results, complete remissions, support ongoing development and preclinical into mechanisms precipitating treatment induced resistance. MLL-r cell lines KOPN-8 (MLL-ENL) NOMO-1 (MLL-AF9) were exposed to concentration above the pre-determined 14 day proliferation assay IC90. Initial of led expected...
Abstract Introduction: Bicycles® are a novel class of fully synthetic, short, constrained peptides. BT8009 consists bicyclic peptide targeting the tumor antigen Nectin-4, linked to cytotoxin monomethyl auristatin E (MMAE) via molecular spacer and cleavable linker. Nectin-4 is validated target highly expressed in wide range tumors. A Phase I/II dose escalation/expansion study, BT8009-100 (NCT04561362), enrolling patients with advanced solid tumors associated expression ongoing US. Here we...
<h3>Background</h3> <i>Bicycles</i> are fully synthetic constrained peptides with antibody-like affinities that target selectively, readily penetrate tumor tissue, have relatively short half-lives, and can be chemically linked together to generate multifunctional molecules. BT7480 is a <i>Bicycle</i> TICA™ binds both CD137 on immune cells Nectin-4 cancer deliver potent anti-tumor signal in expressing tumors. has been reported highly expressed wide range of human solid tumors, however the...
Abstract Tazemetostat is a small molecule inhibitor of the histone methyltransferase EZH2 and currently in phase 2 clinical trials including relapsed refractory Non-Hodgkin Lymphomas (RR-NHL) Diffuse Large B Cell Lymphoma Follicular Lymphoma. In 1 trial RR-NHL patients demonstrated positive activity with favorable safety profile. Acquired mutations D1 domain (I109K, Y111D, Y111L) SET (Y661D) have recently been reported as mechanism resistance to non-tazemetostat inhibition. Given observed...
Abstract EPZ-5676 is a small molecule inhibitor of the histone methyltransferase DOT1L currently in clinical development and represents first class novel therapeutic agent for treatment MLL-rearranged (MLL-r) leukemia. In preclinical studies, selectively inhibited intracellular H3K79 methylation, downstream target gene expression demonstrated complete tumor regression MLL-r leukemia xenograft model. We previously reported synergistic durable anti-proliferative activity when was combined with...
<p>Contains supplemental methods, figures, and tables 1, 2, 3, 5</p>
<p>Contains all pathways altered in NOMO-1 resistance identified by analysis with KEGG, GO - Biological Process, and MSigDB databases.</p>
<p>Contains the mechanism footprint gene list referenced by supplemental Table S3.</p>
<p>Contains supplemental methods, figures, and tables 1, 2, 3, 5</p>
<p>Contains all pathways altered in NOMO-1 resistance identified by analysis with KEGG, GO - Biological Process, and MSigDB databases.</p>