Eric J. Brown
VerifiedUniversity of Pennsylvania · Rehabilitation Medicine
Active 1913–2025
About
Eric J. Brown, Ph.D., is an Associate Professor of Cancer Biology at the University of Pennsylvania Perelman School of Medicine. He is a member of the Abramson Cancer Center, the Penn Skin Disease Research Center, the Penn Institute for Regenerative Medicine, and the Institute for Translational Medicine and Therapeutics. His research focuses on mechanisms that maintain genome stability during DNA replication and their importance in cancer treatment and aging. Dr. Brown's laboratory studies how genome integrity is preserved during DNA replication and investigates how defects in these mechanisms impact age-associated diseases and cancer risk and treatment. His work emphasizes the role of the ATR protein kinase as an essential sensor during DNA replication, regulating a signal transduction cascade that preserves troubled DNA replication forks and prevents their collapse into DNA double strand breaks. The research explores how the ATR pathway is activated under conditions such as oncogenic stress, replisome dysfunction, and encounters with difficult-to-replicate DNA sequences or DNA damage, which are common in cancers. Using proteomic and genomic approaches, Dr. Brown's lab investigates how the ATR pathway counters replicative stress and explores the potential of ATR inhibitors as cancer treatments by identifying biomarkers of sensitivity and targets for combination therapies. His educational background includes a B.A. in Genetics from the University of California at Berkeley and a Ph.D. in Immunology from Harvard University.
Research topics
- Internal medicine
- Medicine
Selected publications
DNA damage response regulator ATR licenses PINK1-mediated mitophagy
Nucleic Acids Research · 2025-02-27 · 5 citations
articleOpen accessDefective DNA damage response (DDR) and mitochondrial dysfunction are a major etiology of tissue impairment and aging. Mitochondrial autophagy (mitophagy) is a mitochondrial quality control (MQC) mechanism to selectively eliminate dysfunctional mitochondria. ATR (ataxia-telangiectasia and Rad3-related) is a key DDR regulator playing a pivotal role in DNA replication stress response and genomic stability. Paradoxically, the human Seckel syndrome caused by ATR mutations exhibits premature aging and neuropathies, suggesting a role of ATR in nonreplicating tissues. Here, we report a previously unknown yet direct role of ATR at mitochondria. We find that ATR and PINK1 (PTEN-induced kinase 1) dock at the mitochondrial translocase TOM/TIM complex, where ATR interacts directly with and thereby stabilizes PINK1. ATR deletion silences mitophagy initiation thereby altering oxidative phosphorylation functionality resulting in reactive oxygen species overproduction that attack cytosolic macromolecules, in both cells and brain tissues, prior to nuclear DNA. This study discloses ATR as an integrated component of the PINK1-mediated MQC program to ensure mitochondrial fitness. Together with its DDR function, ATR safeguards mitochondrial and genomic integrity under physiological and genotoxic conditions.
Gynecologic Oncology · 2025-09-01
article2025-11-25
articleOpen access<p>Trial schema</p>
Cancer Research · 2025-04-21
articleMetastatic prostate cancer (PCa) is incurable and the second leading cause of cancer death among men in the Western world. Although patients initially respond to androgen deprivation therapy (ADT), most eventually develop castration-resistant prostate cancer (CRPC) and metastasize to bone. Second-generation AR signaling inhibitors, such as abiraterone acetate and enzalutamide, have been shown to provide a median survival benefit of 6 to 24 months for metastatic CRPC patients. Therefore, more effective therapies are needed, including novel and innovative therapeutic combination approaches. PARP inhibitors are used primarily in treating patients with DNA damage response (DDR) pathway (e.g. BRCA1/2) mutated cancers because these mutations cause a deficit in homology-directed DNA repair (HDR) that confers sensitivity to these agents. Though BRCA1/2 mutations are relatively rare, genomic defects in other DNA repair genes account for approximately 20% of advanced CRPC. Therefore, PARP inhibitor was recently FDA-approved for metastatic PCa carrying these mutations. However, the rest of the 80% HR-proficient CRPC patients do not benefit from PARPi. Apart from that, prostate tumors are immunologically cold tumors and only 5% of PCa patients respond to immune checkpoint blockers. Using next generation genomics approaches, we have found that inhibiting transcriptional kinase CDK7 in PCa cells creates a BRCA-deficient state (BRCAness) that sensitizes these HR-proficient tumor cells to PARP inhibitors in vitro and in vivo. Mechanistically, knockdown or inhibition of CDK7 led to transcriptional downregulation of DDR genes through loss of Mediator activity along with accumulation of R-loops resulting in the induction of DNA damage, micronuclei formation with consequent activation of cGAS-STING mediated inflammatory signaling, and synergy with anti-PD1 therapy in a syngeneic PCa model in vivo without toxicity. These findings suggest that CDK7 inhibition synergizes with PARP inhibitors and immune checkpoint blockers, offering a promising therapeutic strategy for both HR-proficient and HR-deficient metastatic PCa. This approach has the potential to overcome current limitations of immune checkpoint inhibitors and provides new avenues for targeted combination therapies in advanced PCa treatment. Citation Format: Chandan Kanta Das, Hesham Mohei, Brijesh Kumar Verma, Muzaffer Kassab, Phillip Wulfridge, Sharan Venkatesh, Mohammed Alhusayan, Reyaz ur Rasool, Kavitha Sarma, Roger A. Greenberg, Eric J. Brown, Malay Haldar, Irfan A. Asangani. Transcriptional regulation of DNA damage response and associated inflammatory signaling by CDK7 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6159.
2025-11-25
articleOpen access<p>Representativeness of Study Participants</p>
Abstract 2907: A first-in-class series of potent and selective macrocyclic ATR inhibitors
Cancer Research · 2025-04-21
articleAbstract ATR, a phosphatidyl-inositol kinase-related kinase (PIKK), is a promising target for cancer treatment. Although ATR inhibitor (ATRi)-based therapies show increased activity in tumors that harbor various cancer-associated alterations, the therapeutic index of this drug class has remained a challenge. One potential risk factor in causing drug-related adverse is limited selectivity for the drug target (i.e. off-targeting). In small molecule drugs, macrocyclic structures can reduce the number of conformations possible and, thus, promote selectivity for their targets. Therefore, to increase the selectivity of ATRi and potentially reduce adverse effects of treatment, Aprea Therapeutics developed a first-in-class series of macrocyclic ATRi to potentially increase the tolerability of treatment while maintaining biomarker-driven efficacy. These macrocyclic ATRi are highly potent, with IC50s below 20 nM based on in vitro biochemical kinase assays and cellular inhibition of phosphorylation on S345 of CHK1, a direct ATR substrate. Notably, members of the Aprea series of macrocyclic ATRi demonstrate minimally off-target other PIKKs both in in vitro kinase assays and in cultured cells, with off-targeting of other PIKKs (ATM, PRKDC, MTOR, and SMG1) occurring at concentrations that are hundreds of fold greater than that required to inhibit ATR. Cell proliferation and replication fork stability assays confirm low nanomolar EC50s as single agents at levels that correlate with their ability to inhibit ATR. As expected based on ATR’s role in the replication stress and DNA damage responses, the antiproliferative effects of members of this macrocyclic ATRi series were amplified by co-treatment with DNA-damaging chemotherapies, such as topoisomerase inhibitors, PARP inhibitors, and platinum agents. Mouse xenograft tumor studies with one of the macrocyclic series members, ATRN-119, indicate single-agent activity in colon and prostate cancer models. Moreover, the growth of orthotopically transplanted BRCA2-deficient ovarian cancer PDX tumors is significantly impeded by ATRN-119 single agent treatment, and the combination of ATRN-119 with PARP inhibitor treatment in this model synergistically suppresses tumor growth and causes tumor regression. Overall, Aprea’s new class of macrocyclic ATRi represents a new class of ATRi with selectivity for inhibiting ATR over other PIKKs, has cellular activities that match biochemical and cellular inhibition of ATR, and exhibits tumor suppressive effects and a single agent and in combination with PARP inhibition. ATRN-119 is now progressing through Phase I clinical dose escalation studies. Citation Format: Molly M. Hansbarger, Stephen J. Rocca, Tina Gill, Hank Breslin, Lanqi Jia, Erin M. George, Inna Rom, Teresa Lee, Jonathan Weinstein, Fiona Simpkins, Eric J. Brown, Oren Gilad. A first-in-class series of potent and selective macrocyclic ATR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2907.
Molecular Cancer Therapeutics · 2025-10-22
articleAbstract Background: Clear cell ovarian cancer (CCOC) is often resistant to standard chemotherapy and has limited treatment options in the advanced or recurrent setting. ARID1A is the most prevalent mutation, with approximately 50% of all CCOC harboring this mutation. ARID1A, a member of the SWI/SNF family, regulates transcription and has a major role in the repair of DNA lesions, directly facilitating DNA accessibility on the chromatin or indirectly by facilitating the functions of DNA repair proteins. We propose that CCOCs unique genomic alterations (e.g., ARID1A frameshift or nonsense mutations) will increase dependency on chromatin remodeling and DNA repair (e.g., ATR/CHK1/WEE1) pathways for survival. We hypothesize that combination of low-dose small-molecule inhibitors of the BET family (BRD4i) and the DNA damage repair pathway (ATR/CHK1/WEE1), will especially target ARID1A mutant cancer cells promoting mitotic catastrophe, apoptosis, and tumor regression, sparing normal cells. Method: Use a small size drug screen, we tested and compared drugs’ efficacy in ARID1A mutant cells with wildtype lines. The efficacy of BRD4i combination with either ATRi or WEE1i were evaluated in ARID1A mutant/wildtype lines, and also knockdown or knockout cells compared with isogenic parental lines. The drugs combination affecting the transcription regulation, cell cycle, homologous recombination, apoptosis, and DNA damage were investigated. A CCOC preclinical drug development patient-derived xenograft (PDX) platform was established and drugs’ combinations were evaluated in ARID1A mutant and ARID1A wild-type (ARID1A MUT and ARID1A WT) PDX models. Results: Through the small size of drug screen, we identified that BRD4i, ATRi and WEE1i are more effective in ARID1A mutant cells comparing to that in wildtype lines. Low-dose combination of BRD4i with DNA damage repair inhibitors, ATRi/WEE1i (BDR4i-ATRi or BRD4i-WEE1i), were synergistic in decreasing survival and colony formation in ARID1A MUT cells compared to ARID1A WT. Both combinations showed significant tumor regression and increased overall survival compared to standard chemotherapy or monotherapy in several ARID1A MUT PDX models but minimal in an ARID1A WT PDXs. Among BRD4i-DDRi combinations, BRD4i-ATRi is superior to BRD4i-WEE1i in terms of antitumor effect and drug tolerability. BRD4i-ATRi caused a robust G1 arrest. The BRD4i-ATRi treatment defects homologous recombination and leads to an increase in DNA double-strand breaks and cell apoptosis in the ARID1A MUT or knockout cells. Conclusion: Our studies identify a novel drug combination targeting a genetic alteration (e.g., ARID1A) common in CCOC that is highly effective and tolerable. BRD4i in combination with ATRi or WEE1i was synergistic in vitro in ARID1A MUT models. Using our novel CCOC drug development PDX platform, we demonstrated that BRD4i-ATRi combination therapy is more effective than standard chemotherapy or monotherapy alone with acceptable toxicity in ARID1A MUTPDXs. Citation Format: Yasuto Kinose, Haineng Xu, Hyoung Kim, Xiaolei Wang, Sushil Kumar, Xiaoyin Shan, Erin George, Sergey Medvedev, Amaryllis Ortiz, Sarah Gitto, Margaret Whicker, Kurt D'Andrea, Bradley Wubbenhorst, Dorothy Hallberg, Mark O'Connor, Lauren Schwartz, Wei-Ting Hwang, Katherine L. Nathanson, Gordon Mills, Victor E. Velculescu, Tian-Li Wang, Eric Brown, Ronny Drapkin, Fiona Simpkins. Target clear cell ovarian cancers with ARID1A loss by combination inhibition of BRD4 and ATR [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A133.
2025-11-25
articleOpen access<p>Trial protocol</p>
2024-09-16
supplementary-materialsOpen access<p>Representativeness of Study Participants</p>
European Journal of Cancer · 2024-10-01 · 1 citations
article
Recent grants
NIH · $5.9M · 2007
NIH · $3.3M · 2010
NIH · $3.8M · 2010
Infectious Disease/Basic Microbial Pathogenic Mechanisms
NIH · $17.1M · 1980–2026
NIH · $3.2M · 2017
Frequent coauthors
- 102 shared
Fiona Simpkins
University of Pennsylvania Health System
- 62 shared
Ryan L. Ragland
University of Pennsylvania
- 57 shared
Hyoung Kim
- 56 shared
Oren Gilad
- 49 shared
Clayton R. Cook
University of Minnesota
- 49 shared
Haineng Xu
- 49 shared
Lindsay M. Fallon
University of Massachusetts Boston
- 49 shared
Sarah B. Gitto
Cancer Research Center
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