A5102707386- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Advanced Proteomics Techniques and Applications
- PARP inhibition in cancer therapy
- Advanced Breast Cancer Therapies
- Cancer Genomics and Diagnostics
- Cancer Immunotherapy and Biomarkers
- Melanoma and MAPK Pathways
- Neuroendocrine Tumor Research Advances
- Lung Cancer Research Studies
- Science, Research, and Medicine
- Neuroblastoma Research and Treatments
- Cancer-related Molecular Pathways
- FOXO transcription factor regulation
- Molecular Biology Techniques and Applications
- Chromatin Remodeling and Cancer
- Mechanisms of cancer metastasis
- Cancer Mechanisms and Therapy
- Immunotherapy and Immune Responses
- Radiopharmaceutical Chemistry and Applications
- Colorectal Cancer Treatments and Studies
- Computational Drug Discovery Methods
- Protein Degradation and Inhibitors
- Glutathione Transferases and Polymorphisms
- Epigenetics and DNA Methylation
University of Minnesota System
2023-2025
University of Minnesota
2020-2025
Twin Cities Orthopedics
2020-2025
University of Minnesota Medical Center
2021-2025
Seoul National University
2025
Cedars-Sinai Medical Center
2024
University of Washington
2023
Broad Institute
2017-2022
Dana-Farber Cancer Institute
2006-2022
Levine Cancer Institute
2016-2021
Abstract The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge 1,2 . Recent advances interpretability machine learning models as applied to biomedical problems may enable discovery prediction genomics 3–5 Here we developed P-NET—a biologically informed deep model—to stratify patients with by treatment-resistance state evaluate drivers treatment resistance for therapeutic targeting through...
Abstract Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism adaptive resistance targeted therapy in cancer. An archetypal example development neuroendocrine prostate cancer (NEPC) after treatment adenocarcinoma (PRAD) with inhibitors androgen signaling. NEPC aggressive variant that aberrantly expresses genes characteristic (NE) tissues and no longer depends on androgens. Here, we investigate epigenomic basis this by profiling histone...
Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation distinct protein products with diverse functions. In genome-scale screen for inducers epithelial-to-mesenchymal transition (EMT), we found striking enrichment RNA-binding proteins. We validated that QKI RBFOX1 were necessary sufficient to induce an intermediate mesenchymal cell state increased tumorigenicity. Using RNA-seq eCLIP analysis, coordinately regulated function...
Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies enhance NK survival function are needed improve clinical efficacy. Here, we demonstrated that cells cultured ex vivo with interleukin-15 (IL-15) nicotinamide (NAM) exhibited stable induction of l -selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies CD62L were associated elevated...
Abstract Background Natural killer (NK) cells are non-antigen specific innate immune that can be redirected to targets of interest using multiple strategies, although none currently FDA-approved. We sought evaluate NK cell infiltration into tumors develop an improved understanding which histologies may most amenable cell-based therapies in the developmental pipeline. Methods DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from 45 cancer types ( N = 90,916...
Abstract While the effect of amplification-induced oncogene expression in cancer is known, impact copy-number gains on “bystander” genes less understood. We create a comprehensive map dosage compensation by integrating and copy number profiles from over 8000 tumors The Cancer Genome Atlas cell lines Cell Line Encyclopedia. Additionally, we analyze 17 open reading frame screens to identify toxic cells when overexpressed. Combining these approaches, propose class ‘Amplification-Related Gain Of...
202 Background: While several PARP inhibitors are approved in combination with hormonal therapies for metastatic castrate resistant prostate cancer (CRPC), their use sensitive (CSPC) is understudied. We previously reported that olaparib monotherapy (without ADT) shows significant clinical activity BRCA2 -altered patients biochemically recurrent (BCR) cancer. Here, we explored prognostic and predictive PARP-related mRNA biomarkers derived from primary tumors. Methods: characterized the...
Abstract Background: Germline alterations in homologous recombination repair (gHRR) genes impact the pathogenesis, treatment options, and survival of cancer patients. However, distinct gHRR gene may differentially response oncogenic signaling. Here we interrogated genomic transcriptomic data assessed clinical outcomes patients with mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, prostate cancers) to identify therapeutic vulnerabilities. Methods: We 24,309...
The use of serial serum measurements the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate for survival time failure (TTF) cohort 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine three separate studies. Statistically significant correlations between percentage both overall TTF were found, median...
Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide in an open reading frame (ORF) expression screen and tumor xenografts. overexpression is essential enzalutamide-resistant patient-derived organoid. In AR-expressing cancer cells, interactions enhance AR activity at a subset...
Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries identify potential drug targets specific for these cancers. We discovered MDM2 MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) ATSP-7041 (MDM2/4-dual),...
Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) effective in initial treatment cancer, resistance to ADT or next-generation pathway inhibitors invariably arises, most commonly through re-activation AR axis. Thus, orthogonal approaches inhibit advanced are essential. Here, via genome-scale CRISPR-Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator expression...
Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing endothelial growth factor (VEGF) as well VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial axitinib 5mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were...
Metastasis is a complex and poorly understood process. In pancreatic cancer, loss of the transforming growth factor (TGF)-β/BMP effector SMAD4 correlated with changes in altered histopathological transitions, metastatic disease, poor prognosis. this study, we use isogenic cancer cell lines to identify regulated genes that contribute development colonization. We perform an vivo screen identifying FOSL1 as both target sufficient drive colonization lung. The targeting these early treatment may...
Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cell lines, we found that cancers nervous system lineage, including adult and pediatric gliomas neuroblastomas, required the nuclear kinase vaccinia-related 1 (VRK1) for their survival vivo. VRK1 dependency was inversely correlated expression paralog VRK2. VRK2 knockout sensitized to loss,...
B7-H3 (CD276) is a transmembrane glycoprotein of the B7 immune checkpoint superfamily that has emerged as promising therapeutic target. To better understand applicability B7-H3-directed therapies, we analyzed 156,791 samples comprising 50 cancer types to interrogate clinical, genomic, transcriptomic, and immunologic correlates mRNA expression. DNA (592-gene/whole-exome) RNA (whole-transcriptome) sequencing was performed from submitted Caris Life Sciences. high versus low expression based on...
Abstract The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided a greater incidence lethal, aggressive variant (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent may also transdifferentiate to express neuroendocrine lineage markers and are termed (NEPC). Recent evidence suggests kinase signaling be an important driver NEPC. To identify targetable...
Abstract B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression normal tissues and associated poor prognosis, making it excellent therapy target. We interrogated its regulation metastatic castration-resistant (mCRPC). found greater of transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including tumors that lacked prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts B7-H3, this...
Abstract Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified patient who presented high-grade primary two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had high burden (TMB), demonstrated microsatellite instability (MSI), they markedly...
Abstract Resistance to androgen-deprivation therapies leads metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform into emergent aggressive variant (AVPC), which has neuroendocrine (NE)-like features. In this work, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models reflect and retain key features the tumor from advanced patients. Here performed proteome phosphoproteome characterization 48 PDX tumors identified...
236 Background: Several aggressive tumor variants have emerged since the broad use of 2nd generation androgen therapies for metastatic prostate cancers (mPCs). Close to 20% mPCs are double negative (DNPC) that lack receptor (AR) and do not exhibit histopathological features neuroendocrine cancer (NEPC). Our study focused on R-spondin family genes ( RSPO1/2/3/4 ), which secreted proteins classified as WNT regulators. In mPCs, we examined their genomic alterations, impact clinical outcomes,...
Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt and exploit their microenvironment for sustained growth. The liver common site metastasis, but the interactions between hepatocytes remain poorly understood. In context these play crucial role in promoting survival progression. This study leverages multiomics coverage via liquid chromatography high-resolution, high-mass-accuracy mass spectrometry-based untargeted metabolomics, 13C-stable isotope tracing, RNA...