A5083302662- Protein Degradation and Inhibitors
- PARP inhibition in cancer therapy
- Prostate Cancer Treatment and Research
- Estrogen and related hormone effects
- Multiple Myeloma Research and Treatments
- FOXO transcription factor regulation
- DNA Repair Mechanisms
- Glioma Diagnosis and Treatment
- Circular RNAs in diseases
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Breast Cancer Treatment Studies
- Biochemical and Molecular Research
- Click Chemistry and Applications
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Cancer Research and Treatments
- Molecular Biology Techniques and Applications
- Effects of Radiation Exposure
- BRCA gene mutations in cancer
- MicroRNA in disease regulation
- Cancer-related gene regulation
- Vitamin C and Antioxidants Research
- Cancer, Lipids, and Metabolism
University of Michigan
2016-2025
Innocrin Pharmaceuticals (United States)
2018
University of California, San Francisco
2018
Michigan Medicine
2013-2017
Michigan United
2015
Howard Hughes Medical Institute
2014
University of Trento
2014
Michigan Center for Translational Pathology
2014
Cornell University
2014
The University of Texas MD Anderson Cancer Center
2014
Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB proteins are common hereditary cancers, mechanisms impaired sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) prostate cancer. We identify PCAT-1, cancer outlier lncRNA, which regulates cell response genotoxic stress. PCAT-1 expression produces functional deficiency homologous recombination through its...
Abstract Molecular classification of cancers into subtypes has resulted in an advance our understanding tumour biology and treatment response across multiple types. However, to date, cancer profiling largely focused on protein-coding genes, which comprise <1% the genome. Here we leverage a compendium 58,648 long noncoding RNAs (lncRNAs) subtype 947 breast samples. We show that lncRNA-based categorizes tumours by their known molecular cancer. identify cohort cancer-associated...
Abstract Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens genomically-distinct models GBM, we find purine metabolites, especially guanylates, strongly correlate Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise,...
Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, series clonal cell lines were developed from enzalutamide-resistant tumor xenografts study molecular mechanism test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in lines,...
Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with advent AR antagonist therapies, patients continue to develop resistance, and new strategies combat continued signalling are needed. Here, we degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order determine whether depletion protein can overcome mechanisms resistance commonly associated current...
While effective targeted therapies exist for estrogen receptor-positive and HER2-positive breast cancer, no such triple-negative cancer (TNBC); thus, it is clear that additional targets radiosensitization treatment are critically needed.Expression microarrays, qRT-PCR, Western blotting were used to assess MELK RNA protein expression levels. Clonogenic survival assays quantitate the radiosensitivity of cell lines at baseline after inhibition. The effect knockdown on DNA damage repair kinetics...
Abstract NADPH is a critical reductant needed in cancer cells to fuel the biosynthesis of deoxynucleotides and antioxidants sustain stress-survival responses after radiation-induced DNA damage. Thus, one rational strategy attack target their heavy reliance on NADPH. Here, we report that isocitrate dehydrogenase IDH1 most strongly upregulated NADPH-producing enzyme glioblastoma (GBM). silencing GBM reduced levels NADPH, deoxynucleotides, glutathione increased sensitivity senescence. Rescuing...
Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use radiation therapy (RT); therefore, approaches that result radiosensitization BC critically needed. Using patients' tumor gene expression data from 4 independent sets, we correlated to find genes significantly early after RT. The highest-ranked gene, TTK, was most highly expressed across multiple sets. Inhibition TTK by both genetic and pharmacologic methods enhanced...
Abstract The EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic program. Therapeutic targeting of has been unsuccessful; however, identifying mediators the function could offer new therapeutic options. Here, we describe dependency EWS/ETS-driven upon chromatin reader BET bromdomain proteins and investigate potential inhibitors in treating EWS. EWS/FLI1 EWS/ERG were found a transcriptional complex with BRD4, knockdown BRD2/3/4 significantly impaired...
Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization are critically needed. We characterized the therapy response 21 cell lines paired this data with high-throughput drug screen to identify androgen receptor as a top target radiosensitization. Our radiosensitizer nominated bicalutamide most effective treating therapy-resistant lines....
Abstract Sustained locoregional control of disease is a significant issue in patients with inflammatory breast cancer (IBC), local rates 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there clear need intensification therapy, including radiation. Inhibition DNA repair protein PARP1 has had little efficacy as single agent outside studies restricted to BRCA mutations; however, inhibition (PARPi) may lead radiosensitization aggressive tumor types. Thus, this study...
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have improved progression-free survival for metastatic, estrogen receptor-positive (ER+) breast cancers, but their role in the nonmetastatic setting remains unclear. We sought to understand effects of CDK4/6 inhibition (CDK4/6i) and radiotherapy multiple preclinical cancer models.Transcriptomic proteomic analyses were used identify significantly altered pathways after CDK4/6i. Clonogenic assays quantify enhancement ratio (rER). DNA damage was...
ETS gene fusions, which result in overexpression of an transcription factor, are considered driving mutations approximately half all prostate cancers. Dysregulation factors is also known to exist Ewing's sarcoma, breast cancer, and acute lymphoblastic leukemia. We previously discovered that ERG, the predominant family member interacts with DNA damage response protein poly (ADP-ribose) polymerase 1 (PARP1) human cancer specimens. Therefore, we hypothesized ERG-PARP1 interaction may confer...
Abstract Background Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Methods utilized doxycycline-inducible shRNA-mediated strategy knockdown GOT1 PDA colorectal (CRC) cell lines tumor models similar genotype. These were analyzed for ability form...
How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links to and has significant therapeutic implications. GTP, but not other nucleotides, the activity of Rac1, guanine nucleotide-binding protein, which promotes dephosphorylation serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, previously known activate repair, nonhomologous end joining. In patients mouse models glioblastoma,...
Abstract Background Diffuse midline gliomas (DMG), including diffuse intrinsic pontine (DIPGs), are a fatal form of brain cancer. These tumors often carry driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M characterized by altered metabolism and resistance standard care radiation (RT) but how the H3K27M mediates metabolic response consequent treatment is uncertain. Methods We performed metabolomics irradiated untreated isogenic DMG cell lines observed an...
Abstract Background: Breast cancer (BC), the most common globally and a leading cause of death in women, often utilizes radiation therapy (RT) as part treatment, with over 85% patients receiving RT after breast-conserving surgery. Still, 15% women experience local recurrence despite RT, underscoring need to better understand molecular mechanisms driving response resistance. We hypothesized that transcriptomic changes occur ionizing intrinsically radiosensitive resistant BC models would offer...
Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and known to harbor divergent highly oncogenic functions in human cancer. While induced during disease progression many cancer types, mechanisms underlying function remain poorly understood. Herein, tumor xenograft models prostate were utilized resolve downstream pathways that are required for protumorigenic D1b. Specifically, was found modulate expression large transcriptional network cooperates with androgen receptor (AR)...
Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed 15-35% TNBC tumors. The aim this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor antagonist, able radiosensitize AR-positive (AR+) models. In cell viability assays,...
Histone H3.3G34R/V mutant gliomas demonstrate LIF/STAT pathway activation that can be disrupted for therapeutic benefit.
RADIOTHERAPY IS USED IN THE MANAGEMENT OF PANCREATIC CANCER BECAUSE ITS HIGH PROPENSITY FOR LOCOREGIONAL RELAPSE: one third of patients succumb to localized disease. Thus, strategies improve the efficacy radiotherapy in pancreatic cancer are important pursue. We used naturally serum-free, selectively permeable basement membranes and confocal microscopy fluorescent antibody-stained human Panc-1, MiaPaCa-2, BxPC-3 cell lines investigate effects ionizing radiation on α(5)β(1) integrin...
Abstract Purpose: The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise treatment of metastatic castration-resistant (mCRPC), been to function even in the context resistance next-generation AR-targeted therapies such as enzalutamide abiraterone. Their clinical translation, however, has limited by off-target effects, toxicity, rapid resistance. Experimental Design: We developed...
A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation by AR signaling, we hypothesized that signaling may limited efficacy some these patients. To assess role on inhibition, first performed an silico analysis human tissue samples stratified status (+ or −), which...