A5021941727- Melanoma and MAPK Pathways
- Cancer, Hypoxia, and Metabolism
- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- interferon and immune responses
- Protein Degradation and Inhibitors
- Metabolism, Diabetes, and Cancer
- Cancer Mechanisms and Therapy
- Cancer Genomics and Diagnostics
- Cancer Immunotherapy and Biomarkers
- RNA modifications and cancer
- Chromatin Remodeling and Cancer
- Synthesis and biological activity
- Immunotherapy and Immune Responses
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Advanced Breast Cancer Therapies
- Bioinformatics and Genomic Networks
- Lung Cancer Treatments and Mutations
- Monoclonal and Polyclonal Antibodies Research
- Mitochondrial Function and Pathology
- Enzyme Structure and Function
- Histone Deacetylase Inhibitors Research
Translational Genomics Research Institute
2018-2025
City of Hope
2020-2025
University of Utah
2005-2021
Huntsman Cancer Institute
2006-2021
University of Nebraska Medical Center
2021
The University of Texas MD Anderson Cancer Center
2021
Banyan Biomarkers (United States)
2016
Millennium Institute
2014
Royal Prince Alfred Hospital
2014
The University of Sydney
2014
Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in uptake a strong clinical benefit BRAF-mutant melanoma, we examined role energy responses to inhibition. We observed pronounced consistent decreases glycolytic activity melanoma cells. Moreover, identified network BRAF-regulated transcription factors that control glycolysis Remarkably, this factors,...
Significance Triple-negative breast cancers (TNBCs) are aggressive with poor clinical outcomes. Understanding the pathways that control their growth may reveal new targets for therapeutic intervention. TNBCs highly glycolytic, providing fuel promoting biosynthetic pathways. We establish c-Myc transcription factor drives this metabolic phenotype. Classically, proto-oncogene glycolysis by activating target genes encoding glycolytic enzymes and glucose transporters; however, we show here...
Glucose and glutamine are abundant nutrients required for cell growth, yet how cells sense adapt to changes in their levels is not well understood. The MondoA transcription factor forms a heterocomplex with its obligate partner Mlx regulate ≈75% of glucose-dependent transcription. By mediating glucose-induced activation thioredoxin-interacting protein (TXNIP), MondoA:Mlx complexes directly repress glucose uptake. We show here that inhibits transcriptional TXNIP by triggering the recruitment...
Mutations of the SWI/SNF chromatin remodeling complex occur in 20% all human cancers, including ovarian cancer. Approximately half clear cell carcinomas (OCCC) carry mutations subunit ARID1A, while small carcinoma ovary hypercalcemic type (SCCOHT) presents with inactivating ATPase SMARCA4 alongside epigenetic silencing SMARCA2. Loss these ATPases disrupts activity and may also interfere function other histone-modifying enzymes that associate or are dependent on activity. One such enzyme is...
Glucose is required for cell growth and proliferation. The MondoA·Mlx transcription factor glucose-responsive accumulates in the nucleus by sensing glucose 6-phosphate. One direct glucose-induced target of complexes thioredoxin-interacting protein (TXNIP). TXNIP a potent negative regulator uptake, hence its regulation triggers feedback loop that restricts uptake. This similar to "hexose transport curb" first described almost 30 years ago. We show here MondoA responds non-glucose hexoses,...
The plant homeodomain (PHD) zinc finger is one of 14 known zinc-binding domains. PHD domains have been found in more than 400 eukaryotic proteins and are characterized by a Cys(4)-His-Cys(3) motif that spans 50-80 residues. precise function currently unknown; however, the ING1 ING2 tumor suppressors shown recently to bind phosphoinositides (PIs). We identified novel PHD-containing protein, Pf1, as binding partner for abundant ubiquitous transcriptional corepressor mSin3A. Pf1 contains two...
Abstract Background: RAS mutations, particularly KRASG12X, are critical oncogenic drivers in pancreatic cancer, with existing KRASG12C inhibitors unable to target other mutations and often leading resistance. RMC-6236, a multi-selective RAS(ON) inhibitor, demonstrates potent activity KRASG12X models, but resistance mechanisms that increase mutant may reduce its effectiveness. The fibrotic tumor microenvironment cancer exacerbates therapy resistance, combining RMC-6236 therapies could...
Mammalian target of rapamycin (mTOR) integrates multiple signals, including nutrient status, growth factor availability, and stress, to regulate cellular organismal growth.How mTOR regulates transcriptional programs in response these diverse stimuli is poorly understood.MondoA its obligate transcription partner Mlx are basic helix-loop-helix leucine zipper (bHLHZip) factors that sense execute a glucose-responsive program.MondoA-Mlx complexes activate expression thioredoxin-interacting...
Abstract Background: The five-year survival rate for colorectal cancer (CRC) remains at 14% despite improvements in early detection and the development of novel treatments, underscoring need new therapeutic strategies. immune landscape CRC is heterogeneous complex, posing challenges treatment decision-making. For example, tumors presenting with high microsatellite instability (MSI) or mismatch repair deficiency (MMRD) represent 15 - 20% all cases, are heavily infiltrated by cells, have a...
Abstract Hepatitis B virus has infected a third of the world’s population, and 296 million people are living with chronic infection. Chronic infection leads to progressive liver disease, including hepatocellular carcinoma failure, there remains no reliable curative therapy. These gaps in our understanding due, large part, paucity animal models HBV Here, we show that rhesus macaques regularly clear acute infection, similar adult humans, but can develop long-term if immunosuppressed. Similar...
Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible specific LSD1 inhibition HCI-2509 in cell lines particularly effect on transcriptomic profile MYCN amplified NGP cells. Cell survival assays show that is cytotoxic to low micromole or lower doses. Transcriptional profiling cells treated shows a significant p53, cycle, hypoxia pathway gene...
Glucose and glutamine are the most abundant circulating nutrients support growth proliferation of all cells, in particular rapidly growing dividing cancer cells. Several recent studies implicate an expanded Myc network how cells sense utilize both glucose glutamine. These reveal unappreciated coordination between glycolysis glutaminolysis, potentially providing new targets for therapeutic intervention cancer.
An open-label, randomized, exploratory study of 44 healthy overweight subjects with cardio-metabolic syndrome (CMS) risk factors was conducted to assess the safety, tolerability, and efficacy a proprietary lifestyle modification program without (DIET) (PROG) targeted nutraceutical supplementation, including phytosterols, antioxidants, probiotics, fish oil, berberine, soy, pea, whey proteins over 13 weeks. Key metrics were recorded at baseline weeks 9 13. For DIET PROG groups, compliance 85%...
We examined the clinical safety and efficacy of F105 in 11 subjects with moderate dyslipidemia. is a combination bergamot fruit extract (Citrus bergamia, BFE) 9 phytoextracts selected for their ability to improve antioxidant anti-inflammatory activity BFE. In vitro exhibited synergistic inhibition oxygen radical absorbing capacity, peroxynitrite formation, myeloperoxidase activity. Following 12 weeks daily, no treatment-related adverse events or changes body mass were seen. Statistically...
Abstract Purpose: STING (stimulator of interferon genes) plays an important role in innate immunity by activating type I interferons response to cytosolic nucleic acid ligands such as cyclic dinucleotides (CDNs). In recent years, has become attractive therapeutic target for cancer immune therapy and hydrolysis resistant CDNs have been developed a new class therapeutics. These shown possess potent preclinical efficacy but early results from phase trials disappointing. Ectonucleotide...
Abstract Chromatin remodeling SWItch/Sucrose-NonFermentable (SWI/SNF) complexes, initially identified in yeast 20 years ago, are evolutionarily conserved multi-subunit protein complexes that use the energy from hydrolysis of adenosine triphosphate (ATP) to remodel nucleosome structure and modulate transcription. Mutations proteins SWI/SNF occur 20% human cancers including ovarian cancer (OC). Approximately 50% clear cell carcinoma (OCCC) carries mutations subunit ARID1A while small ovary...
Protein synthesis is regulated by the availability of amino acids, engagement growth factor signaling pathways, and adenosine triphosphate (ATP) levels sufficient to support translation. Crosstalk between these inputs extensive, yet other regulatory mechanisms remain be characterized. For example, translation initiation inhibitor rocaglamide A (RocA) induces thioredoxin-interacting protein (TXNIP). TXNIP a negative regulator glucose uptake; thus, its induction RocA links glucose. MondoA...
The central role of β -catenin in the Wnt pathway makes it an attractive therapeutic target for cancers driven by aberrant signaling. We recently developed a small-molecule inhibitor, BC-2059, that promotes apoptosis disrupting -catenin/transducin -like 1 (TBL1) complex through unknown mechanism action. In this study, we show BC-2059 directly interacts with high affinity TBL1 when -catenin. identified two amino acids hydrophobic pocket are required binding -catenin, and computational...
Abstract Purpose: Compelling evidence suggests that careful and therapeutically relevant activation of the STING (STimulator INterferon Genes) pathway is vital to elicit potent anti-cancer innate immune responses. widely expressed targeting it directly poses many challenges, including systemic interferon. Therefore, alternative approaches activate in a controlled manner may generate better therapeutic response cancer patients. Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) direct...
Ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1/NPP1) is a membrane-bound nucleotide metabolizing enzyme that implicated in variety of physiological and pathological conditions.Recently, ENPP1 was discovered as the dominant 2'3'-cGAMP hydrolyzing enzyme.2'3'-cGAMP endogenous STING agonist, generated from breakdown cytosolic DNA by cGAS.Hydrolysis resistant 2'3'-cGAMP's have been demonstrated to be potent activators STING-dependent innate immunity these are currently undergoing...
Abstract Purpose: In recent years, programs targeting the innate immune pathways alone and alongside adaptive have become increasingly popular. A main area of interest in immunity is STING (STimulator INterferon Genes) pathway. plays an integral role by activating type 1 interferons response to detection cytosolic nucleic acid cGAS (Cyclic GMP-AMP Synthase). detects DNA converts it into 2′3′ cGAMP, which direct ligand STING. Targeting activation this pathway using synthetic, non-hydrolyzable...
Abstract Purpose: It has become increasingly clear that the activation of both innate and adaptive immune systems is vital to provide best outcomes with immunotherapies. As part response, checkpoint inhibitors (CIs) have shown promise in clinic, but seem only work a small subset cancers response rates below 20%. anticipated may help sensitize multiple cancer types therapies. cGAS-STING pathway, which activated cytosolic DNA, emerged as key mechanism activate immunity, primarily through type...