A5102774768- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Prostate Cancer Treatment and Research
- Peptidase Inhibition and Analysis
- Cancer Immunotherapy and Biomarkers
- Cancer-related Molecular Pathways
- Cancer, Lipids, and Metabolism
- PARP inhibition in cancer therapy
- Pancreatic and Hepatic Oncology Research
- Autophagy in Disease and Therapy
- Gastric Cancer Management and Outcomes
- Multiple Myeloma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer Genomics and Diagnostics
- DNA Repair Mechanisms
- Colorectal Cancer Screening and Detection
- Immune Cell Function and Interaction
- Pancreatic function and diabetes
- Mycobacterium research and diagnosis
- Immunotherapy and Immune Responses
- Neuroblastoma Research and Treatments
- Contact Dermatitis and Allergies
- Endoplasmic Reticulum Stress and Disease
- Histone Deacetylase Inhibitors Research
- Trauma, Hemostasis, Coagulopathy, Resuscitation
Michigan Center for Translational Pathology
2023-2025
University of Michigan
2018-2025
U-M Rogel Cancer Center
2024
University of California, Irvine
2021
Cedars-Sinai Medical Center
2020
Office of Academic Affiliations
2019
Northwestern University
2016
University of Illinois Chicago
2013
Jefferson College
2008
Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) PBRM1. AU-24118 demonstrated tumor regression a model castration-resistant prostate cancer (CRPC) which was further enhanced with combination...
Highlights d Cdk12 ablation induces preneoplastic prostate lesions with T cell infiltration loss mediates genomic instability through
Despite the remarkable clinical success of immunotherapies in a subset cancer patients, many fail to respond treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition lipid kinase PIKfyve, regulator autophagic flux lysosomal biogenesis, upregulated surface expression major histocompatibility complex class I (MHC-I) cells via impairing flux, resulting enhanced cell killing mediated by CD8
Abstract Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy other lysosomal processes. Although targeting these pathways has shown potential preclinical studies, progress been hampered by the challenge identifying characterizing favorable targets for drug development. Here, we characterize...
Background & Objective: Treating pancreatic ductal adenocarcinoma (PDAC) remains exceptionally difficult, with scant advancements in clinical management over the last thirty years. Aptly dubbed "graveyard of chemotherapy," PDAC poses formidable challenges. Even most effective first-line chemotherapy regimens merely extend median survival for patients metastatic disease beyond 12 months. Due to its poorly vascularized and fibrotic environment, tumor cells encounter hypoxia nutrient...
Abstract PIKfyve plays a key role in autophagy and lysosomal functions, which are critical for pancreatic ductal adenocarcinoma (PDAC) cell metabolism survival. Consistent with this, we found that perturbation suppresses reduces PDAC viability. Prior studies show processes maintaining iron homeostasis mitochondrial respiration PDAC. However, inhibition did not seem to significantly affect oxygen consumption rate (OCR) compared other inhibitors such as chloroquine bafilomycin, suggesting also...
Abstract Background: Pancreatic Ductal Adenocarcinoma (PDAC) exists within a harsh, nutrient-depleted microenvironment, and is known to use lysosomal processes, such as autophagy, for maintenance of metabolic function. PIKfyve lipid kinase that serves the single source PI(3, 5)P2, molecule critical process autophagy. Considering role in we hypothesized it be crucial PDAC pathophysiology. Methods & Results: To evaluate significance PDAC, employed RNA-ISH found was significantly higher...
Abstract Adenocarcinoma of the ovary is fifth leading cause cancer death among American women. Most mortality results from high-grade serous ovarian carcinoma (HGS-OvCa)—a disease type resistant to conventional chemotherapy, and therein requiring urgent preclinical modeling for pharmaceutical testing. We generated a novel model by employing Ovgp1-driven Cre recombinase catalyze CRISPR-Cas9-medicated ablation Trp53, Rb1 Nf1 tumor suppressor genes in mouse (sgPRN mice). The gene encoding...
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown a significant global increase over the past decade. The mTOR signaling pathway is positive regulator of cell cycle progression, with its activation playing key role in pathogenesis NETs. Since 2011, FDA-approved inhibitor everolimus has been used as an anti-tumor agent for treating progressive NETs, and clinical efficacy limited due to rapid disease relapse progression. In this study, we investigated autophagy, specifically...
Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism
The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. However, limited clinical progress been achieved with inhibitors. Here, we report the discovery of first-in-class degrader 12d (PIK5-12d) by employing proteolysis-targeting chimera approach. PIK5-12d potently degraded protein DC50 value 1.48 nM and Dmax 97.7% prostate cancer VCaP cells. Mechanistic studies revealed that it selectively induced degradation VHL- proteasome-dependent manner....
Patients on mechanical circulatory support (MCS) devices are placed aspirin and may require platelet function testing (PFT) to monitor the adequacy of therapy. Routine laboratory PFT is performed using whole blood aggregation (WBA) which typically has a long turnaround time (4–5 hours) not be readily available. By contrast, mapping by thromboelastography (TPM) can provide results within 45 minutes. The objective this study was compare TPM with WBA. We compared maximal amplitude (MA) that...
Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and androgen deprivation therapy might be associated with protection. Combined fact
Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) PBRM1. AU-24118 demonstrated tumor regression model castration-resistant prostate cancer (CRPC) which was further enhanced with...
Biallelic loss of cyclin-dependent kinase 12 (
Colorectal cancer (CRC) screening decreases CRC incidence; however, many patients are not successfully screened.To improve rates at our institution by decreasing the rate of rejected fecal immunochemical tests (FITs), a means screening, from 28.6% to <10% December 2017.Specimens were for following reasons: expired specimen, lack recorded collection date/time, physician orders, incomplete patient information, and illegible handwriting. Multidisciplinary teams devised interventions: FIT...
Abstract Background: PIKfyve is a lipid kinase that serves as the single source for PI(3,5)P2, critical molecule lysosome functions, including autophagy. Pancreatic Ductal Adenocarcinoma (PDAC) known to utilize autophagy well other functions survive in its harsh microenvironment. Considering role of autophagy, we hypothesized important PDAC pathophysiology. Indeed, screened multiple cell lines different cancer lineages and found were highly sensitive inhibitors apilimod ESK981. Given these...
Abstract Background PIKfyve is a lipid kinase that serves as the sole source of cellular PI(3,5)P2 and PI5P, critical phosphatidylinositols for autophagy lysosome function. Pancreatic ductal adenocarcinoma (PDAC) known to upregulate depend on lysosomal functions such exist in its harsh, nutrient-disrupted microenvironment. Thus, we aimed establish therapeutic target PDAC. Using PIKfyve-knockout genetically engineered mouse model pancreatic cancer (KC KPC), determined was necessary PDAC...
Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) accounts for 95% of all pancreatic cancers and, as one the most lethal cancers, has a five-year survival rate approximately 6%. Autophagic processes have been reportedly elevated in PDAC; thus, inhibition autophagy leads to decreased tumor growth. are catabolic mechanisms that recycle cellular components. Cells stressful conditions, such starvation, redistribute energy sustain cell survival; however, this can also lead death when...
Abstract Therapies targeting the androgen receptor (AR) as main driver of prostate cancer (PCa) can lead to various mechanisms resistance and promote progression castration-resistant PCa (CRPC), which has a median survival only 13-23 months. Amongst recurrent CRPC, 17%-30% patients develop neuroendocrine (NEPC), is subtype characterized by unique histology. NEPC exhibits loss AR signaling during transdifferentiation results in AR-targeted therapies gain cell characteristics resembling poorly...
Abstract The widespread success of cancer immunotherapies suggests a promising future - but has been subverted by unresponsiveness and resistance. Current research furthered the understanding immunotherapy resistance through findings “hot” (responsive) “cold” (unresponsive) tumors. Here, we focus on genetic pharmacological inhibition PIKfyve, lipid kinase regulator autophagic flux lysosomal biogenesis. We find that PIKfyve results in upregulation major histocompatibility complex class I...
Abstract Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 per se is sufficient to drive development—either alone, or in the context other genetic alterations—and CDK12-mutant tumors exhibit sensitivity specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation induce preneoplastic lesions and robust T cell infiltration mouse...
Abstract Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy other lysosomal processes including macropinocytosis. Although targeting these pathways has shown potential preclinical studies, progress been hampered by the challenge identifying characterizing favorable targets for drug...