A5065799733- Melanoma and MAPK Pathways
- Monoclonal and Polyclonal Antibodies Research
- Caveolin-1 and cellular processes
- CAR-T cell therapy research
- Cancer Cells and Metastasis
- Viral Infectious Diseases and Gene Expression in Insects
- Immune cells in cancer
- Colorectal Cancer Treatments and Studies
- HER2/EGFR in Cancer Research
- Cancer Research and Treatments
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Advanced Fluorescence Microscopy Techniques
- Radiopharmaceutical Chemistry and Applications
- Protein Tyrosine Phosphatases
- Computational Drug Discovery Methods
- Immunotherapy and Immune Responses
- Cutaneous Melanoma Detection and Management
- CRISPR and Genetic Engineering
- Cancer Immunotherapy and Biomarkers
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Cytokine Signaling Pathways and Interactions
- Cancer Mechanisms and Therapy
Century Therapeutics (United States)
2021-2024
The Wistar Institute
2014-2021
Janssen (United States)
2020
Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this resistance still lacking. Here we generate humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas treated anti-PD-1, which results restricted tumor growth not complete regression. Tumor RNA-seq, multiplexed imaging...
Abstract Small molecule inhibitors targeting mutant EGFR are standard of care in non–small cell lung cancer (NSCLC), but acquired resistance invariably develops through mutations or activation compensatory pathways such as cMet. Amivantamab (JNJ-61186372) is an anti-EGFR and anti-cMet bispecific low fucose antibody with enhanced Fc function designed to treat tumors driven by activated and/or cMet signaling. Potent vivo antitumor efficacy observed upon amivantamab treatment human tumor...
Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification this heterogeneous cancer, several targeted immune therapies were approved increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) live tissue samples from 384 patients representing the full spectrum clinical, therapeutic, mutational, heterogeneity melanoma. PDX been...
Abstract In melanoma, therapies with inhibitors to oncogenic BRAF V600E are highly effective but responses often short-lived due the emergence of drug-resistant tumor subpopulations. We describe here a mechanism acquired drug resistance through microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce growth factor FGF-2, activates tumor-infiltrating IGF-1. B-cell-derived IGF-1 critical for melanomas and MEK heterogeneous...
To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models.We established 12 PDXs from BRAF inhibitor-progressed melanoma patients. Following expansion, were analyzed using targeted sequencing reverse-phase protein arrays. By multi-arm preclinical trial designs, we identified efficacious precision approaches.We alterations previously described as drivers of resistance: NRAS mutations 3 PDXs, MAP2K1 (MEK1) 2,...
Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs), cell lines, and tumors to identify mutational copy number aberrations. Samples came from 371 unique individuals: 263 were naive treatment, treated with targeted therapy (34), immunotherapy (54), or both (20). Models all reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, WT/WT/WT)...
Resistance to BRAF inhibitors (BRAFi) is one of the major challenges for targeted therapies BRAF-mutant melanomas. However, little known about role microRNAs in conferring BRAFi resistance. Herein, we demonstrate that miR-200c expression significantly reduced whereas target genes including Bmi1, Zeb2, Tubb3, ABCG5, and MDR1 are increased melanomas acquired resistance compared pretreatment tumor biopsies. Similar changes were observed BRAFi-resistant melanoma cell lines. Overexpression or...
Abstract Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, relapse occurs most cases. Intrinsically resistant cells drive resistance and display molecular biologic properties akin neural crest-like stem (NCLSC) including invasiveness, plasticity, self-renewal capacity. The shared transcriptional programs vulnerabilities between NCLSCs cancer remains poorly understood. Here, we...
The upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although acts as a tumor suppressor in various human cancer types, little is known about its role melanoma. In this study, we investigated progression and regulatory mechanism. Analysis Cancer Genome Atlas datasets revealed that high expression tissues correlates improved patient survival. Moreover, downregulated...
Abstract Dual-targeting cell therapies to address CD19 antigen loss in heme malignancies are being explored by Century Therapeutics and others for unmet clinical need hematological malignancies. CD22 chimeric receptor (CAR) T-cell have shown promising efficacy relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) alone combination with CAR-T (1,2). is a multi-domain glycoprotein expressed on B-cells. Natural splice variants of can exclude domains near the N-terminus, allowing...
<h3>Background</h3> CAR-T cell therapies have proven safe and efficacious for hematologic malignancies, but there remains a significant unmet need effective therapy options solid tumors. CAR-engineered induced pluripotent stem (iPSC)-derived effector cells allow the treatment of cancer as an off-the-shelf allogeneic therapy. Gamma delta (γδ) T exhibit cytolytic features conventional alpha beta (αβ) CD8<sup>+</sup> with additional capabilities innate recognition For example, expression CD16...
Abstract The approval of three drugs targeting the MAPK pathway has led to new standard therapies for melanoma with BRAFV600E mutations. excitement about these therapeutic successes is somewhat dampened by relapse most if not all treated patients due development acquired (secondary) resistance. Early clinical trial results indicate that combining BRAF and MEK inhibitors can improve survival delay onset Currently, there a lack good translational models study resistance pathways found in...
Abstract Introduction: Treatment for cancer is moving from a “one size fits all” to personalized and targeted approach addressing the unique biology of each patients' tumor. Preclinical research in ovarian (OVCA) has relied on established cell lines that have recently been shown marked differences molecular profiles when compared tumors TCGA. Patient derived xenografts (PDXs) are emerging as reliable preclinical model can recapitulate principal characteristics original tumor while remaining...
Abstract Despite the prevalence of recurrent, high activating BRAF V600 mutations in 45% tumors, cutaneous melanoma (CM) is a heterogeneous malignancy resulting from aberrant signaling multiple pathways. It has been traditionally characterized by activation MAPK and PI3K pathways, as well cell cycle disruption. In recent years, whole-genome exome sequencing studies have identified several new genes associated with melanomagenesis. However, comprehensive understanding concurrent, mutually...
Abstract Melanoma has seen a remarkable improvement in the treatment of advanced disease. However, majority patients still relapse with emergence resistant This is especially true for BRAF inhibitors, were multiple mechanisms resistance have been uncovered. lack dependable models to develop approaches overcome resistance, poses real challenge clinical decisions on second line therapies. In addition, combination therapies necessary achieve long term responses increase number possibilities be...
Abstract Introduction: To create a personalized, targeted approach to high grade serous ovarian cancers (HGSOC), reliable preclinical models are essential. About ~50% of HGSOC have defects in genes involved homologous recombination (HR) such as BRCA. PARP inhibitors (PARPi) capitalize on synthetic lethality HR-deficient tumors, however, clinical efficacy is limited (response rate only ~40%). Patient derived xenografts (PDXs) emerging model that recapitulates principal characteristics the...
Abstract Advanced melanoma has seen dramatic changes in standard of care the last years and many novel targeted small molecules immune checkpoint inhibitors are development. More than 200 clinical trials currently ongoing for metastatic melanoma. Thus, accurate pre-clinical models to predict responses urgently needed. We have established a large bank live tumor tissue (n=500) with more 300 expanded as PDX. Melanoma is uniquely suited establish patient-derived xenograft (PDX) models, since...
Abstract Melanoma patients develop resistance to both chemo- and targeted-therapy drugs. Promising pre-clinical clinical results with immune checkpoint inhibitors using antibodies directed against CTLA4 PD1 have re-energized the field of immune-based therapies in melanoma. However, similar or targeted-therapies only subsets melanoma respond blockade. Currently available immunodeficient mouse xenograft transgenic models a number short comings are unable address basis drug non-responsiveness...