A5063149358- Estrogen and related hormone effects
- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- Lung Cancer Treatments and Mutations
- Chromatin Remodeling and Cancer
- Cancer Mechanisms and Therapy
- CRISPR and Genetic Engineering
- Glioma Diagnosis and Treatment
- PI3K/AKT/mTOR signaling in cancer
- Advanced Breast Cancer Therapies
- Pluripotent Stem Cells Research
- Mechanisms of cancer metastasis
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Cancer Treatment and Pharmacology
- Computational Drug Discovery Methods
- Single-cell and spatial transcriptomics
- HER2/EGFR in Cancer Research
- Synthesis and biological activity
- Brain Metastases and Treatment
- Histone Deacetylase Inhibitors Research
- RNA Research and Splicing
- Cancer therapeutics and mechanisms
- Genomics and Chromatin Dynamics
University of California, San Diego
2016-2024
Olema Pharmaceuticals (United States)
2021-2023
Ludwig Cancer Research
2015-2022
Institute of Biomedical Science
2022
UC San Diego Health System
2019
Many cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of that underlies treatment resistance. Here we introduce a modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) captures authentic pathobiology. Orthotopic engraftment the neural progenitor derived from hiPSCs have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas...
Ciro Zanca1, Genaro R. Villa1,2,3, Jorge A. Benitez1, Amy Haseley Thorne1, Tomoyuki Koga1, Matteo D'Antonio4, Shiro Ikegami1, Jianhui Ma1, Antonia D. Boyer1, Afsheen Banisadr1, Nathan M. Jameson1, Alison Parisian1, Olesja V. Eliseeva5, Gabriela F. Barnabe1, Feng Liu1,6,7,8, Sihan Wu1, Huijun Yang1, Jill Wykosky1, Kelly Frazer4,9,10, Vladislav Verkhusha11, Maria G. Isaguliants5,12,13, William Weiss14,15,16, Timothy C. Gahman1, Andrew K. Shiau1, Clark Chen4, Paul S. Mischel1,4,17, Webster...
Significance EGFR cancer mutations display an astonishing tissue-specific asymmetry: in lung cancer, target the intracellular kinase (KD), while glioblastomas (GBMs), a variety of missense clusters and deletions concentrate at ectodomain (ECD). Intriguingly, GBM-activating share paradoxical preference for inhibitors that bind inactive kinase. By integrating simulations, small-angle X-ray scattering, GBM models, we demonstrate ECD mutants converge to transition state characterized by cryptic...
Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of approximately 15 months; therefore, more effective treatment options for GBM are required. To identify new drugs targeting GBMs, we performed high-throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype.High-throughput screening was on GSCs followed by dose-response assay 5 identified original "hits." A PI3K/mTOR...
Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that predominantly associated with inactivation of the gene
The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with majority patients presenting as ER-positive (ER+). Endocrine therapy mainstay cancer but development resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties fulvestrant, agonist activity tamoxifen, and limited benefit elacestrant leave unmet needs or without ESR1, gene that encodes ER protein. Here we describe palazestrant (OP-1250), novel, orally bioavailable...
Heterozygous TERT (telomerase reverse transcriptase) promoter mutations (TPMs) facilitate expression and are the most frequent mutation in glioblastoma (GBM). A recent analysis revealed this is one of earliest events gliomagenesis. However, no appropriate human models have been engineered to study role initiation these tumors.
Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability MLN4924 or pevonedistat (a neddylation inhibitor) in subset of glioblastoma (GBM) preclinical models identify biomarkers, mechanisms, signatures differential response.
Abstract The epidermal growth factor receptor (EGFR) is overexpressed in numerous solid tumors and the subject of extensive therapeutic efforts. Much research on EGFR focused protein dynamics downstream signaling; however, few studies have explored its transcriptional regulation. Here, we identified two enhancers (CE1 CE2) present within first intron gene models glioblastoma (GBM) head neck squamous cell carcinoma (HNSCC). CE1 CE2 contain open chromatin H3K27Ac histone marks, enhance...
Neddylation (NAE) inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report the cytotoxic vulnerability NAE inhibitors in subset of glioblastoma (GBM) preclinical models identify genetic alterations biological processes underlying differential response.
A lack of biological markers has limited our ability to identify the invasive cells responsible for glioblastoma multiforme (GBM). To become migratory and invasive, must downregulate matrix adhesions, which could be a physical marker potential. We engineered murine astrocytes with common GBM mutations, e.g.
Abstract OP-1250, a complete estrogen receptor antagonist (CERAN) and selective degrader (SERD), is currently in Phase I/II clinical trials for the treatment of positive (ER+)/human epidermal growth factor 2 negative (HER2-) breast cancer. OP-1250 has previously demonstrated efficacy both 1 (ESR1) wild-type Y537S mutant cancer xenograft models. Inhibitors cyclin-dependent kinases 4 6 (CDK4/6) are standard first-line ER+ advanced or metastatic combination with endocrine therapy. To...
Abstract Estrogen receptor-positive (ER+) breast cancer can undergo metastatic spread to the brain, which occurs in up 15% of HER2-/ER+ patients. Although endocrine therapy is not explicitly approved for brain metastasis and clinical trials are lacking, anecdotal reports responses by agents motivate further investigation. One such agent ER antagonist tamoxifen, has previously been shown reach high levels tissue ER+ metastases patients with cancer*. We reported that OP-1250, a novel, oral...
<p>Supplementary text including supplementary materials and methods references.</p>
<div>Abstract<p>The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with majority patients presenting as ER-positive (ER<sup>+</sup>). Endocrine therapy mainstay cancer but development resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties fulvestrant, agonist activity tamoxifen, and limited benefit elacestrant leave unmet needs or without <i>ESR1</i>, gene that encodes ER protein....
<p>OP-1250 demonstrates potent activity in an ER+ breast cancer intracranial xenograft and outperforms ribociclib. A, Schematic of experiment with data shown B–D. B, Mean SEM tumor volume over time listed treatments as assessed by MRI ESR1Y537S ST941 PDX model. C, Percent change individual animals treatment groups at day 101 or the last recorded timepoint study, normalized to 1 volume. D, Kaplan–Meier graphs animal survival mice implanted intracranially xenograft. Dosing ended on 100...
<div>Abstract<p>The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with majority patients presenting as ER-positive (ER<sup>+</sup>). Endocrine therapy mainstay cancer but development resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties fulvestrant, agonist activity tamoxifen, and limited benefit elacestrant leave unmet needs or without <i>ESR1</i>, gene that encodes ER protein....
<p>Combination of OP-1250 with palbociclib or ribociclib enhances suppression cell cycle-related gene expression. A, t-SNE plot MCF7 xenograft samples from vehicle, low-dose OP-1250, and monotherapy combination treatment groups. B, C, Heatmap showing expression genes associated the E2 late signature E2F n = 3 tumors low dose therapy Red indicates high relative to vehicle blue D, Comparison log2-fold change values for 14 between (pink) monotherapies (blue purple 1 mg/kg 25 palbociclib,...
<p>OP-1250 demonstrates potent in vivo activity and outperforms competitor compounds ESR1 mutant xenograft studies. A, Percent change tumor volume of individual animals listed treatment groups at day 29 the ESR1Y537S HCI-013 PDX study, normalized to 1 volume. B, Mean SEM over time with treatments HCI-013EI breast cancer model conducted absence estrogen supplementation. The dotted line represents stasis. C, study supplementation, D, ST941 E, Representative immunostained images Ki67 ER⍺...
<p>OP-1250 acts as a selective ER degrader (SERD) in wild-type and ESR1 mutant cell lines. A, B, Representative blot images from the simple western assay shown Figure 3 (see main article) after 24-h treatment with 300 nM compound or 1 E2 indicated treatments C, D, of MCF7 cells treated for 2 h, 4 8 h listed concentrations compounds presence absence MG-132 analysis ERα protein levels compounds. Samples were normalized to untreated control, mean SD across at least three independent...
<p>Effects of E2 and antiestrogens on transcriptional activity cellular proliferation in E2-depleted media. A, Volcano plot genes differentially expressed by 15-min treatment relative to vehicle PRO-seq experiment. Each dot represents a gene the annotation set. Adjusted p-value is plotted y-axis fold-change time-matched x-axis. The number top right-hand corner changed, red dots indicate with observed change expression. B, read distribution at estrogen target CCND1 MYC after 15 min...