A5046060433- PARP inhibition in cancer therapy
- Cancer-related Molecular Pathways
- DNA Repair Mechanisms
- Genetic factors in colorectal cancer
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- BRCA gene mutations in cancer
- Monoclonal and Polyclonal Antibodies Research
- Thyroid Cancer Diagnosis and Treatment
- Molecular Biology Techniques and Applications
- RNA Research and Splicing
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
- Synthesis and Biological Evaluation
- Lung Cancer Diagnosis and Treatment
- Cancer Research and Treatments
- Wnt/β-catenin signaling in development and cancer
- Ovarian cancer diagnosis and treatment
- Histone Deacetylase Inhibitors Research
- 14-3-3 protein interactions
- HER2/EGFR in Cancer Research
- Cancer, Hypoxia, and Metabolism
- Protein Degradation and Inhibitors
- Nuclear Structure and Function
Almac (United Kingdom)
2017-2025
GW Pharmaceuticals (United Kingdom)
2005-2023
Mission Therapeutics (United Kingdom)
2015-2016
AstraZeneca (United Kingdom)
2010-2012
Molecular Oncology (United States)
2012
National Cancer Institute
1998-2012
Rutgers Cancer Institute of New Jersey
2012
Cancer Institute of Florida
2012
Target (United States)
2012
University of British Columbia
2010
Whereas target-specific drugs are available for treating ERBB2-overexpressing and hormone receptor-positive breast cancers, no tailored therapy exists receptor- ERBB2-negative ("triple-negative") mammary carcinomas. Triple-negative tumors account 15% of all cancers frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. The DNA-repair characteristic BRCA1-deficient cells confer sensitivity to poly(ADP-ribose) polymerase 1...
Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme potency both PARP-1 PARP-2. Optimized compounds from the also demonstrate good pharmacokinetic profiles, oral bioavailability, activity in vivo SW620 colorectal xenograft model....
Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical inhibitor (PARPi) olaparib through activation P-glycoprotein drug efflux transporter. Here, we show tumor-specific genetic inactivation increases long-term response olaparib, but these eventually developed PARPi resistance. In fraction cases, this caused...
Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations likely generated an error-prone DNA polymerase, and the mismatch repair pathway may process mispairs. To examine role MSH2 protein in hypermutation, Msh2−/− mice were immunized with oxazolone, cells analyzed for mutation their VκOx1 light chain genes. The frequency repair-deficient was similar to that Msh2+/+ mice, showing MSH2-dependent does not cause hypermutation....
Abstract Germ-line heterozygosity of the BRCA2 gene in women predisposes to breast and ovarian cancers. Successful therapies targeted specifically at these neoplasms have thus far remained elusive. Recent studies mice shown that inhibition poly(ADP-ribose) polymerase-1 (PARP-1) targets cells lacking Brca2 xenografts derived from BRCA2-deficient ES or Chinese hamster ovary cells. We set out develop a more relevant preclinical model will inform accelerate translation into clinic. As such, we...
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so poor substrate drug transporters. Here we demonstrate efficacy this compound against olaparib-resistant tumors that overexpress P-glycoprotein. addition, better tolerated in combination with chemotherapy than mice, which suggests could have significant...
Most patients with ovarian carcinomas succumb to their disease and there is a critical need for improved therapeutic approaches. Carcinomas arising in BRCA mutation carriers display defective DNA double-strand break repair that can be therapeutically exploited by inhibition of PARP-1, key enzyme the single-strand breaks, creating synthetic lethality tumor cells.To investigate vivo, we established BRCA2 germline-mutated xenograft model was developed directly from human cancer tissue, treated...
Abstract Background Understanding how to modulate the microenvironment of tumors that are resistant immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate ability USP7 reprogram tumor (TME) by inhibiting secretion vascular endothelial growth factor (VEGF) from fibroblasts. Methods To understand role played TME, systematically evaluated effects potent, selective on co‐cultures comprising components using human primary cells. We also inhibition syngeneic...
Constitutive activation of the RET receptor tyrosine kinase underlies genesis and progression multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer predisposition. Importantly, although represents common theme in neoplasias, not all activating mutations are functionally equivalent. Consistent with this, we ascertained patient classical features MEN 2B, but lacking either (M918T or A883F). Instead, harbors novel pair germ line missense cis at codons 804 805. We evaluated...
Recently, results obtained from mice with targeted inactivations of postreplication DNA mismatch repair (MMR) genes have been interpreted to demonstrate a direct role for MMR in antibody variable (V) gene hypermutation. Here we show that do not express the factor Msh2 wide-ranging defects antigen-driven B cell responses. These include lack progression germinal center (GC) reaction associated increased intra-GC apoptosis, severely diminished antigen-specific immunoglobulin G responses, and...
Background: Dominant-activating mutations in the RET protooncogene, a receptor tyrosine kinase, have been identified as cause of medullary thyroid carcinoma. Such oncogenic induce its ligand-independent constitutive trans-autophosphorylation. We investigated role endogenous autophosphorylation maintaining neoplastic phenotype carcinoma cells and orthotopic carcinomas transgenic mice. Methods: constructed adenoviral vectors expressing dominant-negative truncated form RET, termed ΔTK ,...
Abstract There is growing interest in exploiting bispecific approaches for the design of next generation ADCs to improve therapeutic efficacy, increase window and overcome drug resistance. ALM-401 a highly selective, engineered ADC (bsADC) Candidate Drug targeting tumor associated antigens ROR1 EGFR. designed deliver enhanced efficacy solid indications an improved toxicity profile versus canonical these clinically established targets. EGFR were identified as top target pairing bsADC using...
The effect of mutations at codon 804 in the RET protooncogene is disputed. Some studies have suggested that V804L mutation causes low penetrance multiple endocrine neoplasia type 2 syndrome, with late onset and relatively indolent course, whereas others reported V804M an aggressive potential. In this paper, we report three apparently unrelated medullary thyroid carcinoma cases homozygous for these mutations. To clarify phenotypic heterogeneity associated mutations, compare clinical data age...
Abstract Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide. Methods used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week unselected Results Twenty (8 male, 12 female) various tumours were treated (18 evaluable toxicity) over eight planned dose levels (10–300 mg). well-tolerated at all without CTCAE grade 4...
The efficient and specific introduction of genes into cancer cells in vivo remains a major challenge for current gene therapy modalities. Peptides possess appropriate properties to serve as tumor-targeting agents. Thus, finding new cancer-selective peptides directing transfer neoplastic by reducing transduction normal is central goal molecular targeting. We have previously reported identification peptide (HTFEPGV) that selectively binds human medullary thyroid carcinoma (MTC)-derived TT...
Three-dimensional (3D)
Abstract The placental alkaline phosphatases ALPP and ALPPL2 are attractive targets for antibody protein-drug conjugate (ADC PDC) approaches. These GPI-anchored cell-surface proteins, which share very high sequence identity, over-expressed in a number of different solid tumor indications including testicular, ovarian, endometrial, gastric, pancreatic non-small cell lung cancers but have little expression on normal adult tissues. Consequently, there is significant interest exploiting...
We report the finding of a novel missense mutation at codon 833 in tyrosine kinase RET proto-oncogene patient with carcinoma thyroid. In vitro experiments demonstrate that R833C induces transformed foci only when present long 3' splice isoform and, keeping model which receptor has to dimerize be completely activated, glial cell line-derived neurotrophic factor stimulation leads RET(R833C) higher level activation. Tyrosine assays show weak intrinsic activity and phosphorylation an exogenous...