A5049302160- PARP inhibition in cancer therapy
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Cancer Research and Treatments
- Statistical Methods in Clinical Trials
- Evolution and Genetic Dynamics
- Lung Cancer Treatments and Mutations
- Ovarian cancer diagnosis and treatment
- Antibiotic Resistance in Bacteria
- Protein Degradation and Inhibitors
- Colorectal Cancer Treatments and Studies
- Lymphoma Diagnosis and Treatment
- CRISPR and Genetic Engineering
- Pharmacogenetics and Drug Metabolism
- CAR-T cell therapy research
- Medical Imaging Techniques and Applications
- Chronic Lymphocytic Leukemia Research
- Antibiotics Pharmacokinetics and Efficacy
- RNA and protein synthesis mechanisms
- Advanced Breast Cancer Therapies
- Acute Myeloid Leukemia Research
- Cancer Mechanisms and Therapy
- Cancer-related Molecular Pathways
- Radiomics and Machine Learning in Medical Imaging
- Monoclonal and Polyclonal Antibodies Research
University of North Carolina at Chapel Hill
2020-2025
University of North Carolina Health Care
2024
UNC Lineberger Comprehensive Cancer Center
2024
Center for Systems Biology
2010-2022
Harvard University
2011-2022
UNSW Sydney
2016
The University of Adelaide
2004-2009
Predicting evolutionary paths to antibiotic resistance is key for understanding and controlling drug resistance. When considering a single final resistant genotype, epistatic contingencies among mutations restrict evolution small number of adaptive paths. Less attention has been given multi-peak landscapes, while specific peaks can be favoured, it unknown whether how early commitment fate made. Here we characterize multi-peaked landscape trimethoprim by constructing all combinatorial alleles...
Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for success of such has rarely been investigated detail, obscuring lessons learned. Here, we use isobologram analysis to score pharmacological interaction, clone tracing CRISPR screening measure cross-resistance among five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We...
Abstract Background Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets TCL lines, patient-derived xenografts (PDXs), primary patient samples depend on Bcl-xL for survival. However, small molecule inhibitors such as ABT263 failed during clinical development due to on-target dose-limiting thrombocytopenia. Methods We developed DT2216, a...
Abstract Purpose: Combinations of immune-checkpoint inhibitors (ICI) with other cancer therapies have been approved for advanced cancers in multiple indications, and numerous trials are under way to test new combinations. However, the mechanisms that account superiority ICI combinations relative their constituent monotherapies remain unknown. Experimental Design: We analyzed 13 phase III clinical testing ICIs each or drugs patients melanoma lung, breast, gastric, kidney, head neck cancers....
Abstract Combination therapy is an important part of cancer treatment and often employed to overcome or prevent drug resistance. Preclinical screening strategies prioritize synergistic combinations; however, studies antibiotic combinations show that interactions can accelerate the emergence resistance because one depletes effect both. In this study, we aimed determine whether synergy drives development in cell lines using live-cell imaging. Consistent with prior models tumor evolution, found...
Transcriptional interference is the in cis suppression of one transcriptional process by another. Mathematical modeling shows that promoter occlusion elongating RNA polymerases cannot produce strong interference. Interference may instead be generated (1) dislodgement slow-to-assemble pre-initiation complexes and transcription factors (2) prolonged paused polymerases.
Tyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship therapeutic mechanisms remain unclear; we therefore undertook a systems-level analysis of human cardiomyocytes (CMs) exposed four TKIs. CMs differentiated from induced pluripotent stem cells (hiPSCs) were sunitinib, sorafenib, lapatinib, or erlotinib, responses assessed by functional assays, microscopy, RNA sequencing, mass spectrometry...
Abstract Antibiotic-sensitive and -resistant bacteria coexist in natural environments with low, if detectable, antibiotic concentrations. Except possibly around localized sources, where resistance can provide a strong advantage, bacterial fitness is dominated by stresses unaffected to the antibiotic. How do such mixed heterogeneous conditions influence selective advantage or disadvantage of resistance? Here we find that sub-inhibitory levels tetracyclines potentiate selection for against...
Highlights•5-FU does not synergize with DNA-damaging agents such as oxaliplatin or irinotecan•5-FU incorporation into structured RNAs (primarily rRNA) causes cancer cell death•5-FU drives lysosomal degradation of rRNA and ubiquitylation ribosomal proteins•Upregulating transcription enhances tumor killing following 5-FU treatmentSummary5-fluorouracil (5-FU), a major anti-cancer therapeutic, is believed to function primarily by inhibiting thymidylate synthase, depleting deoxythymidine...
779 Background: Immune checkpoint blockade (ICB)-based combination regimens have transformed the treatment landscape of advanced solid tumors including urothelial cancer. Understanding whether such combinations are synergistic, additive, or less than additive is crucial for (a) refining therapy in cancer, (b) dissecting role concurrent versus sequential treatment, and (c) identifying which cytotoxic agents combine most favorably with ICB. Here we analyzed phase III trials cancer to determine...
Abstract Models of tumor drug response have illuminated important concepts in oncology, but there remains a need for theory that combines intra-tumor and inter-patient heterogeneity to explain patient outcomes, especially curative treatments. We present mathematical model multi-drug therapy describes both cell-to-cell patient-to-patient as distributions sensitivity, apply it simulate combination therapies Diffuse Large B-Cell Lymphoma (DLBCL). Simulated trials reproduced Progression-Free...
Bacteria regulate genes to survive antibiotic stress, but regulation can be far from perfect. When is not optimal, mutations that change gene expression contribute resistance. It systematically understood what extent natural or optimal for distinct antibiotics, and how changes in of specific quantitatively affect Here we discover a simple quantitative relation between fitness, expression, potency, which rationalizes our observation multitude even innate defense mechanisms have critically...
Individual participant data (IPD) from oncology clinical trials is invaluable for identifying factors that influence trial success and failure, improving design interpretation, comparing pre-clinical studies to outcomes. However, the IPD used generate published survival curves are not generally publicly available. We impute ~500 arms of Phase 3 (representing ~220,000 events) find they well fit by a two-parameter Weibull distribution. Use functions with overall significantly increases...