About

Ronald Evans, PhD, is a Professor and Director of the Gene Expression Laboratory at the Salk Institute for Biological Studies. He is an authority on hormones, their normal activities, and their roles in disease. His major achievement includes the discovery of a large family of molecules called nuclear hormone receptors, which respond to steroid hormones, vitamin A, and thyroid hormones. These receptors are key in controlling metabolism of sugar, salt, calcium, and fat, impacting daily health and disease treatment. Evans' research has led to the development of targeted therapies for breast cancer, prostate cancer, pancreatic cancer, leukemia, osteoporosis, and asthma. He also developed a new class of drugs called exercise mimetics that promote fitness benefits without training, addressing issues related to obesity and metabolic disorders. His team identified the role of fibroblast growth factor 1 (FGF1) in insulin regulation and created a diet pill that tricks the body into burning fat, which has shown effectiveness in mice. Additionally, Evans' research uncovered the importance of REV-ERB-α and REV-ERB-β receptors in synchronizing sleep and metabolic cycles, linking circadian rhythms to metabolic health. His work on vitamin D derivatives has opened new avenues for pancreatic cancer treatment, with clinical trials underway to evaluate their efficacy.

Research topics

• Biology
• Medicine
• Internal medicine
• Biochemistry
• Endocrinology
• Pharmacology
• Immunology
• Chemistry
• Cancer research
• Genetics
• Cell biology
• Computational biology
• Bioinformatics
• Physiology
• Pathology
• Neuroscience

Selected publications

• HDAC Inhibition Sensitizes Pancreatic Tumors to DNA Damage by Global Redistribution of the Transcriptional Machinery

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-19

  articleOpen accessSenior authorCorresponding

  ABSTRACT The DNA damage response (DDR) is critical for pancreatic ductal adenocarcinoma (PDAC) development and therapeutic responses, including to genotoxic agents. While epigenetic modulators have been shown to contribute to the DDR, how chromatin regulation dictates responses to DNA damage in PDAC remains incompletely understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR. HDAC1/2 directs the genomic distribution of H3K27ac, ensuring sufficient BRD4 and RNA polymerase II (Pol II) occupancy at DDR gene promoters. HDAC inhibition by entinostat shifts the balance of H3K27 acetylation preferentially towards intergenic regions, diverting BRD4 and Pol II from promoters, thereby suppressing DDR gene expression. In line with this, HDAC inhibition heightens DNA damage and sensitizes PDAC to diverse DNA-damaging and DDR-targeting agents. Since the clinical development of HDAC inhibitors has been limited by systemic toxicity, we developed bottlebrush prodrug (BPD) nanoparticles for tumor-selective entinostat delivery. Entinostat-BPD achieved tumor-specific HDAC inhibition while displaying potent efficacy and reduced systemic toxicity. These findings reveal an HDAC-dependent DDR vulnerability and offer combinational and precision targeting strategies to facilitate clinical translation and improve PDAC patient outcomes. SIGNIFICANCE STATEMENT The ability of tumor cells to tolerate DNA damage limits the efficacy of many anticancer therapies. Our study reveals that pancreatic cancer cells enforce this resistance by sustaining expression of DNA damage response (DDR) genes through Class I histone deacetylases (HDACs). HDACs maintain genome-wide acetylation patterns required for efficient recruitment of the transcriptional machinery to DDR genes. Pharmacological HDAC inhibition disrupts this process and sensitizes pancreatic cancer cells to diverse DNA-damaging agents. To overcome systemic toxicity that limits translational potential, we further establish a bottlebrush prodrug nanoparticle platform that enables tumor-selective HDAC inhibition. Given the central role of the DDR in cancer, targeting HDAC-mediated DDR regulation through drug combinations and precision delivery may have broad therapeutic relevance across cancer types.

  PublisherDOI

• Targeting Wnt/β-catenin and circadian regulator restores PRC2/EZH2-controlled chromatin bivalency and suppresses cell state diversity

  Journal of Clinical Investigation · 2026-03-17

  articleOpen access

  PRC2/EZH2 inhibitors (PRC2i/EZH2i) are promising for the treatment of advanced cancers including metastatic prostate cancer. Here, we show that PRC2i/EZH2i alone or in combination with androgen receptor (AR) inhibitors induced diverse cell state programs (CSPs) (e.g., response to stress or IFN, MYC targets, stem cells, EMT lineage plasticity, and multiple developmental programs), which led to increased tumor cell invasion, metastasis, and resistance to other drugs, in addition to modest suppression of tumor growth. In contrast to the current perception, our comprehensive, integrated genomics and epigenomics profiling of patient-derived xenografts (PDXs) and clinical tumors revealed that PRC2/EZH2 suppressed CSP genes by maintaining chromatin bivalency. Hyperactive Wnt/β-catenin signaling and inhibitors of polycomb-repressive complex 2/enhancer of zeste homolog 2 (PRC2/EZH2) and the AR alter chromatin bivalency through antagonism of PRC2 and stimulation of MLL2/KMT2B in a feed-forward manner. The circadian rhythm regulator REV-ERBα unexpectedly reprogrammed β-catenin in promoting bivalency resolution and CSP gene expression. Dual targeting of Wnt/β-catenin and EZH2 diminished diverse cell states by restoring bivalency and effectively blocked tumor growth. Our findings provide unexpected insights into chromatin bivalency and dysregulated circadian rhythms in the control of cell state diversity and identify alternative therapeutic strategies that target PRC2/EZH2 for advanced malignancies.

  PublisherDOI

• A scalable embryonic stem cell–based platform for efficient generation of mitochondrial DNA mutant mice

  Proceedings of the National Academy of Sciences · 2026-04-08

  articleOpen accessSenior authorCorresponding

  Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.

  PublisherDOI

• Abstract LB097: HDAC inhibition sensitizes pancreatic cancer to DNA-damaging therapies via genome-wide redistribution of transcriptional machinery

  Cancer Research · 2026-04-17

  articleSenior author

  Abstract The ability of tumor cells to tolerate DNA damage through a robust DNA damage response (DDR) limits the efficacy of many anticancer therapies, including genotoxic agents; however, the epigenetic mechanisms that sustain DDR gene expression remain poorly understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR in pancreatic ductal adenocarcinoma (PDAC). HDAC1/2 maintain a proper genome-wide distribution of H3K27 acetylation, ensuring efficient recruitment of BRD4 and RNA polymerase II to DDR gene promoters. Pharmacological HDAC inhibition with entinostat preferentially enriches H3K27 acetylation at intergenic regions, diverting transcriptional machinery away from promoters and suppressing DDR gene expression. Consequently, HDAC inhibition increases DNA damage and sensitizes PDAC to diverse DNA-damaging (e.g., platinum agents, topoisomerase inhibitors) and DDR-targeting therapies (e.g., PARP inhibitors). To overcome the systemic toxicity that has limited the clinical translation of HDAC inhibitors, we developed a bottlebrush prodrug (BPD) nanoparticle platform for tumor-selective entinostat delivery. Entinostat-BPD enables tumor-specific HDAC inhibition, reduces system toxicity, and achieves tumor suppression comparable to free entinostat with only one-seventh of the cumulative drug exposure, demonstrating enhanced translational potential of this platform. Together, these findings uncover an HDAC-directed epigenetic mechanism that drives resistance to DNA damage-inducing agents and further establish combinatorial and precision-targeting strategies to improve PDAC outcomes. Given the central role of the DDR across cancer types and the widespread use of DNA-damaging therapies, this work may have broad therapeutic relevance beyond pancreatic cancer. Citation Format: Gaoyang Liang, Hung V. Nguyen, Jonathan Zhu, Hervé Tiriac, Hadiqa Zafar, Daniel Y. Cao, Gabriela Estepa, Dylan C. Nelson, Yang Dai, Tae Gyu Oh, Christopher Liddle, Ruth T. Yu, Andrew M. Lowy, Weiwei Fan, Morgan L. Truitt, Annette R. Atkins, Jeremiah A. Johnson, Michael Downes, Ronald M. Evans. HDAC inhibition sensitizes pancreatic cancer to DNA-damaging therapies via genome-wide redistribution of transcriptional machinery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB097.

  PublisherDOI

• CA19-9 promotes liver metastasis of pancreatic cancer through E-selectin mediated extravasation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-10

  articleOpen access

  Abstract Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, which drives patient mortality. CA19-9 is elevated in most PDAC tumors and is widely used as a clinical biomarker. Elevated serum levels are associated with poor outcomes. However, whether CA19-9 functionally contributes to metastatic progression has not been fully defined, in part because mice lack endogenous CA19-9 expression. Here, using syngeneic murine PDAC cells engineered to express CA19-9, we investigated its functional role in liver metastasis. In splenic injection models, CA19-9 expression markedly increased liver metastatic burden by promoting both metastatic seeding and subsequent metastatic outgrowth. In vitro , CA19-9 enhanced tumor cell adhesion to endothelial cells through interaction with E-selectin. Metastatic seeding of CA19-9-expressing cells was reduced by genetic deletion of E-selectin or antibody neutralization of either CA19-9 or E-selectin in vivo . Therapeutic targeting of CA19-9 with a neutralizing antibody markedly reduced liver metastatic burden after metastatic seeding. CA19-9 expression increased AKT signaling in PDAC cells and liver metastases, and CA19-9 levels correlated with AKT activation in human PDAC tissues. These findings show that CA19-9 promotes PDAC liver metastasis through E-selectin-dependent metastatic seeding and AKT-associated metastatic outgrowth, highlighting CA19-9 as a functional mediator of PDAC metastasis and a potential therapeutic target.

  PublisherDOI

• David John “Davo” Mangelsdorf (1958–2025): A life of science, friendship, and joy

  Proceedings of the National Academy of Sciences · 2025-12-17

  articleOpen access1st authorCorresponding

  David John "Davo" Mangelsdorf passed away on August 3, 2025, in Dallas, Texas at age 67 from an unexpected postsurgical complication. Davo made transformative contributions to nuclear receptor and metabolic biology. He discovered the retinoid X receptor (RXR) during his early years at Salk and, during his career and leadership at UT Southwestern, helped define the roles of orphan nuclear receptors, including LXR and FXR, as well as the metabolic hormones FGF19 and FGF21. This retrospective also reflects on the person behind the science. Davo brought curiosity, humor, and a sense of ease to every interaction. His legacy endures in his discoveries, in the colleagues and trainees he inspired, and in the kindness and laughter he shared throughout his life.

  PublisherOA PDFDOI

• Circadian regulator REV-ERBα is a master regulator of tumor lineage plasticity and an effective therapeutic target

  Proceedings of the National Academy of Sciences · 2025-11-13

  articleOpen accessCorresponding

  Epigenetic and transcriptional dysregulation plays a fundamental role in tumor lineage plasticity (LP). However, the underlying mechanisms, especially for the initial events of LP development, are still poorly understood. Here, we report that in progression of prostate cancer from adenocarcinoma to treatment-induced neuroendocrine prostate cancer (t-NEPC), anti-androgen receptor (AR) signaling inhibitors (ARSIs) reprogram the function of circadian regulator/nuclear receptor REV-ERBα by switching its target gene programs from kinase signaling and metabolic programs to programs of LP, which includes neurogenesis, stem cell, and epithelial-mesenchymal transition as well as over fifteen LP drivers including POU3F2/BRN2, ASCL1, FOXA2, ONECUT2, and MYCN. Unexpectedly, REV-ERBα facilitates the chromatin occupancy of BRN2, ASCL1, and FOXA1 in their activation of LP programs, thus functioning as a master regulator of ARSI-induced LP driver network. Mechanistically, REV-ERBα induces chromatin accessibility and H3K27ac modification at promoters of LP genes through its recruitment of BRD4 and p300. Overexpression of REV-ERBα alone is sufficient to induce LP and neuroendocrine phenotype and confers resistance to ARSI in adenocarcinoma cells. Loss of REV-ERBα potently inhibits NEPC cell growth and abolishes the expression of LP drivers and gene programs. Pharmacological inhibition of REV-ERBα exhibits high potency in blocking the growth of NEPC tumors including patient-derived xenografts. Our findings reveal that therapy-induced LP development entails a coordinated induction of a network of LP drivers and that REV-ERBα is an unexpected master regulator of the network and a promising therapeutic target for treatment of advanced prostate cancer such as NEPC.

  PublisherDOI

• Pembrolizumab ± paricalcitol in metastatic pancreatic cancer postmaximal cytoreduction

  The Oncologist · 2025-01-01 · 9 citations

  articleOpen access

  LESSONS LEARNED: Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life. BACKGROUND: Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade. METHODS: This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS). RESULTS: There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms. CONCLUSIONS AND RELEVANCE: Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity. TRIAL REGISTRATION: Clinicaltrials.gov, ID: NCT03331562.

  PublisherDOI

• Phase IB trial of high dose ascorbic acid + nab-paclitaxel + cisplatin + gemcitabine in patients with untreated metastatic pancreatic cancer

  Redox Biology · 2025-10-25

  articleOpen access

  Preclinical studies suggest that cancer cells take up oxidized vitamin C (dehydroascorbate, DHA) via the GLUT1 transporter, leading to oxidative stress and glutathione depletion. This mechanism may offer a therapeutic strategy for KRAS-mutated cancers. This Phase IB trial evaluated high-dose intravenous ascorbic acid (AA) combined with nab-paclitaxel, cisplatin, and gemcitabine (NABPLAGEM) in patients with untreated metastatic pancreatic ductal adenocarcinoma (PDAC). Eligible patients (≥18 years, ECOG 0–1, measurable PDAC, adequate organ function) received AA (25, 37.5, or 56.25 g/m 2 twice weekly) plus NABPLAGEM on Days 1 and 8 of 21-day cycles. The primary endpoint was determining the maximum tolerated dose (MTD) of AA. Seventeen patients were enrolled (median age 63.9; 70.6% female; 82.4% white). No MTD was reached; AA up to 56.25 g/m 2 twice weekly was feasible. Patients on the lowest AA dose remained on treatment longer. Grade ≥3 treatment-related adverse events (TRAEs) included thrombocytopenia (82.4%), anemia (35.3%), neutropenia (29.4%), hypokalemia (29.4%), diarrhea (11.8%), and colitis (11.8%), with no significant differences between dose groups. Peak AA levels >20 mM were achieved in 57% of patients at the highest dose. Median progression-free survival (PFS) and overall survival (OS) were 7.1 and 14.2 months, respectively, with no significant differences by AA dose. Textural imaging showed decreased liver fat in 3 of 4 patients with baseline steatosis. High-dose AA with NABPLAGEM was tolerable in patients with advanced PDAC but did not improve disease response compared to historical data for chemotherapy alone. A separate study suggests AA may enhance gemcitabine and nab-paclitaxel efficacy without cisplatin. AA and cisplatin may have overlapping DNA-damaging effects, or differences in AA dosing frequency and exposure may influence outcomes - variables to consider in future trials. NCT03410030 • Pancreatic ductal adenocarcinoma tumors carry mutations in KRAS • KRAS mutations are associated with overexpression of the GLUT1 receptor • GLUT1 facilitates the uptake of ascorbic acid which can generate free radicals • Clinical trial, advanced pancreatic cancer, high dose ascorbic acid + chemotherapy

  PublisherDOI

• Adipocyte heparan sulfate determines type 2 diabetes susceptibility in mice via FGF1-Mediated glucose regulation

  Molecular Metabolism · 2025-10-09

  articleOpen access

  Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS. • Adipocyte heparan sulfate does not impact diet-induced weight gain. • Adipocyte heparan sulfate sulfation compromises glucose regulation and insulin sensitivity under nutrient stress. • Mice with reduced HS sulfation show increased insulin resistance and fatty liver disease in a diet-induced obesity model. • Mechanistically HS sulfation is essential for the glucose-lowering effect of FGF1, a critical paracrine insulin sensitizer in adipose tissue.

  PublisherDOI

Recent grants

• Engineering human islet-like organoids for transplantation

  NIH · $3.4M · 2018–2022

• NIH Grant P01CA054418

  NIH · $29.0M · 2006

• NIH Grant R37GM026444

  NIH · $5.0M · 2000

• NIH Grant U19DK062434

  NIH · $51.6M · 2012

• NIH Grant R01GM026444

  NIH · $1.6M · 1990

Frequent coauthors

• Michael Downes

  Salk Institute for Biological Studies

  509 shared

• Christopher Liddle

  University of Sydney

  306 shared

• Ruth T. Yu

  Peking University Cancer Hospital

  225 shared

• David J. Mangelsdorf

  The University of Texas Southwestern Medical Center

  213 shared

• Michael G. Rosenfeld

  University of California, San Diego

  137 shared

• Pierre Chambon

  Institut de génétique et de biologie moléculaire et cellulaire

  130 shared

• Gregor Eichele

  Max Planck Institute for Multidisciplinary Sciences

  130 shared

• Mitchell A. Lazar

  University of Pennsylvania

  129 shared

Education

• PhD, Microbiology

  University of California Los Angeles

  1974

• BA, Bacteriology

  University of California Los Angeles

  1970

Awards & honors

• Kimberly Prize, 2025
• Rolf Luft Award, 2025
• Japan Prize in the field of Medical Science and Pharmaceutic…
• Asan Award in Basic Medicine, 2021
• NOMIS Distinguished Scientist and Scholar Award, 2020