Honors & Awards
Knight-Hennessy Scholar, Stanford
Education & Certifications
Bachelor of Science, University of Michigan Ann Arbor (2022)
MPhil, University of Cambridge, Medical Sciences (2023)
BS, University of Michigan, Biology and Business (2022)
Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.
2023; 13 (11): 2370-2393
Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction.SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.
View details for DOI 10.1158/2159-8290.CD-23-0131
View details for PubMedID 37584601
CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA
OXFORD UNIV PRESS INC. 2022: 86-87
View details for Web of Science ID 000888571000329
Expanding Access to CNS-TAP: Design, Development, and Initial Use of a Complex Precision Health Specialty Web App for Neuro-Oncology.
Studies in health technology and informatics
2022; 290: 804-808
This paper offers a case study to demonstrate how a complex scoring model tool called CNS-TAP, originally created by a neuro-oncology team at one institution, was upgraded and made accessible to a wider audience. In the Results and Discussion, many issues of web app design, development, and sustainability are covered. Overall, we chart a path to expand access to many unique software tools created and needed by today's medical specialists.
View details for DOI 10.3233/SHTI220190
View details for PubMedID 35673129
Predicting CNS penetration of precision medicine therapies in oncology: A comparison of the CNS TAP tool and the BOILED-Egg computational model
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300713
Cell-Free Tumor DNA (cf-tDNA) Liquid Biopsy: Current Methods and Use in Brain Tumor Immunotherapy
FRONTIERS IN IMMUNOLOGY
2022; 13: 882452
Gliomas are tumors derived from mutations in glial brain cells. Gliomas cause significant morbidity and mortality and development of precision diagnostics and novel targeted immunotherapies are critically important. Radiographic imaging is the most common technique to diagnose and track response to treatment, but is an imperfect tool. Imaging does not provide molecular information, which is becoming critically important for identifying targeted immunotherapies and monitoring tumor evolution. Furthermore, immunotherapy induced inflammation can masquerade as tumor progression in images (pseudoprogression) and confound clinical decision making. More recently, circulating cell free tumor DNA (cf-tDNA) has been investigated as a promising biomarker for minimally invasive glioma diagnosis and disease monitoring. cf-tDNA is shed by gliomas into surrounding biofluids (e.g. cerebrospinal fluid and plasma) and, if precisely quantified, might provide a quantitative measure of tumor burden to help resolve pseudoprogression. cf-tDNA can also identify tumor genetic mutations to help guide targeted therapies. However, due to low concentrations of cf-tDNA, recovery and analysis remains challenging. Plasma cf-tDNA typically represents <1% of total cf-DNA due to the blood-brain barrier, limiting their usefulness in practice and motivating the development and use of highly sensitive and specific detection methods. This mini review summarizes the current and future trends of various approaches for cf-tDNA detection and analysis, including new methods that promise more rapid, lower-cost, and accessible diagnostics. We also review the most recent clinical case studies for longitudinal disease monitoring and highlight focus areas, such as novel accurate detection methodologies, as critical research priorities to enable translation to clinic.
View details for DOI 10.3389/fimmu.2022.882452
View details for Web of Science ID 000789614600001
View details for PubMedID 35464472
View details for PubMedCentralID PMC9018987
Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma
2022; 24 (8): 1366-1374
Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis.We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI).Change in H3.3K27M VAF over time ("VAF delta") correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF "spikes" (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression.Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.
View details for DOI 10.1093/neuonc/noac030
View details for Web of Science ID 000764112000001
View details for PubMedID 35137228
View details for PubMedCentralID PMC9340643
Variability in endoscopic assessment of Nissen fundoplication wrap integrity and hiatus herniation
DISEASES OF THE ESOPHAGUS
2022; 35 (5)
Upper endoscopy (EGD) is frequently performed in patients with esophageal complaints following anti-reflux surgery such as fundoplication. Endoscopic evaluation of fundoplication wrap integrity can be challenging. Our primary aim in this pilot study was to evaluate the accuracy and confidence of assessing Nissen fundoplication integrity and hiatus herniation among gastroenterology (GI) fellows, subspecialists, and foregut surgeons.Five variations of post-Nissen fundoplication anatomy were included in a survey of 20 sets of EGD images that was completed by GI fellows, general GI attendings, esophagologists, and foregut surgeons. Accuracy, diagnostic confidence, and inter-rater agreement across providers were evaluated.There were 31 respondents in the final cohort. Confidence in pre-survey diagnostics significantly differed by provider type (mean confidence out of 5 was 1.8 for GI fellows, 2.7 for general GI attendings, 3.6 for esophagologists, and 3.6 for foregut surgeons, P = 0.01). The mean overall accuracy was 45.9%, which significantly differed by provider type with the lowest rate among GI fellows (37%) and highest among esophagologists (53%; P = 0.01). The accuracy was highest among esophagologists across all wrap integrity variations. Inter-rater agreement was low across wrap integrity variations (Krippendorf's alpha <0.30), indicating low to no agreement between providers.In this multi-center survey study, GI fellows had the lowest accuracy and confidence in assessing EGD images after Nissen fundoplication, whereas esophagologists had the highest. Diagnostic confidence varied considerably and inter-rater agreement was poor. These findings suggest experience may improve confidence, but highlight the need to improve the evaluation of fundoplication wraps.
View details for DOI 10.1093/dote/doab078
View details for Web of Science ID 000756741300001
View details for PubMedID 34963133
View details for PubMedCentralID PMC9118466
CNS-TAP TOOL RECOMMENDATIONS OF TARGETED ANTI-CANCER AGENTS COMPARED TO THOSE SELECTED BY A MULTIDISCIPLINARY TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL (PNOC003)
OXFORD UNIV PRESS INC. 2021: 108
View details for Web of Science ID 000757356200429
SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (CF-TDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201
OXFORD UNIV PRESS INC. 2021: 16-17
View details for Web of Science ID 000757356200061
Panobinostat penetrates the blood-brain barrier and achieves effective brain concentrations in a murine model
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2021; 88 (3): 555-562
Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with increased activity against H3K27M mutant cell lines. Given limited evidence regarding the CNS penetration of panobinostat, we sought to characterize its BBB penetration in a murine model.Panobinostat 15 mg/kg was administered IV to 12 CD-1 female mice. At specified time points, mice were euthanized, blood samples were collected, and brains were removed. LC-MS was performed to quantify panobinostat concentrations. Cmax and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines.Mean panobinostat plasma concentrations (ng/mL) were 27.3 ± 2.5 at 1 h, 7.56 ± 1.8 at 2 h, 1.48 ± 0.56 at 4 h, and 2.33 ± 1.18 at 7 h. Mean panobinostat brain concentrations (ng/g) were 60.5 ± 6.1 at 1 h, 42.9 ± 5.4 at 2 h, 33.2 ± 6.1 at 4 h, and 28.1 ± 4.3 at 7 h. Brain-to-plasma ratio at 1 h was 2.22 and the brain to plasma AUC ratio was 2.63. Based on the published human pharmacokinetic data, the anticipated Cmax in humans is expected to be significantly higher than the IC-50 identified in DIPG models.It is expected that panobinostat would be effective in CNS tumors where the IC-50 is in the low nanomolar range. Thus, our data demonstrate panobinostat crosses the BBB and achieves concentrations above the IC-50 for DIPG and other brain tumors and should be explored further for clinical efficacy.
View details for DOI 10.1007/s00280-021-04313-2
View details for Web of Science ID 000660340300002
View details for PubMedID 34115161
View details for PubMedCentralID PMC8896403
- COMPARISON OF TARGETED AGENTS RECOMMENDED BY THE CNS-TAP TOOL TO THOSE SELECTED BY A TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL OXFORD UNIV PRESS INC. 2021: 46
- Targeted agents recommended by the CNS TAP tool compared to those selected by a tumor board in a molecularly-driven clinical trial in children and young adults with DIPG. LIPPINCOTT WILLIAMS & WILKINS. 2021
Manufacturing Workers Have a Higher Incidence of Carpal Tunnel Syndrome
JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE
2021; 63 (3): E120-E126
It is unclear whether clerical or labor-type work is more associated with risk for developing work-related carpal tunnel syndrome (WrCTS).National employment, demographic, and injury data were examined from the Bureau of Labor Statistics databases for the years 2003 to 2018. Injuries for clerical and labor industries were compared using linear regression, two-group t test, and one-way analysis of variance (ANOVA) analysis.WrCTS injuries are decreasing over time (B = -1002.62, P < 0.001). The labor industry demonstrated a significantly higher incidence of WrCTS when compared with the clerical industries (P < 0.001). Within labor industries, the manufacturing industry had the highest incidence of WrCTS over time (P < 0.001).Our study showed WrCTS injuries have declined over time. Additionally, our findings may suggest that the labor industry has a stronger association with WrCTS than the clerical industry.
View details for DOI 10.1097/JOM.0000000000002122
View details for Web of Science ID 000663719200003
View details for PubMedID 33394876
- Comparative pharmacokinetic analysis of the blood-brain barrier penetration of dasatinib and ponatinib in mice LEUKEMIA & LYMPHOMA 2021; 62 (8): 1990-1994
Astrocytes in rare neurological conditions: Morphological and functional considerations
JOURNAL OF COMPARATIVE NEUROLOGY
2021; 529 (10): 2676-2705
Astrocytes are a population of central nervous system (CNS) cells with distinctive morphological and functional characteristics that differ within specific areas of the brain and are widely distributed throughout the CNS. There are mainly two types of astrocytes, protoplasmic and fibrous, which differ in morphologic appearance and location. Astrocytes are important cells of the CNS that not only provide structural support, but also modulate synaptic activity, regulate neuroinflammatory responses, maintain the blood-brain barrier, and supply energy to neurons. As a result, astrocytic disruption can lead to widespread detrimental effects and can contribute to the pathophysiology of several neurological conditions. The characteristics of astrocytes in more common neuropathologies such as Alzheimer's and Parkinson's disease have significantly been described and continue to be widely studied. However, there still exist numerous rare neurological conditions in which astrocytic involvement is unknown and needs to be explored. Accordingly, this review will summarize functional and morphological changes of astrocytes in various rare neurological conditions based on current knowledge thus far and highlight remaining neuropathologies where astrocytic involvement has yet to be investigated.
View details for DOI 10.1002/cne.25118
View details for Web of Science ID 000615777400001
View details for PubMedID 33496339
ELECTRONIC SEQUENCING PROVIDES OPTIMIZED QUANTIFICATION OF SERIAL, MULTI-GENE MOLECULAR RESPONSE IN THE CSF OF CHILDREN WITH HIGH-GRADE GLIOMA
OXFORD UNIV PRESS INC. 2020: 288
View details for Web of Science ID 000606080100060
Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
CLINICAL CANCER RESEARCH
2020; 26 (23): 6266-6276
Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods.We performed ultra-short fragment (100-200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed.Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response.Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.
View details for DOI 10.1158/1078-0432.CCR-20-2066
View details for Web of Science ID 000595599500021
View details for PubMedID 33087334
View details for PubMedCentralID PMC7710567
- Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma (vol 22, 19, 2020) CURRENT ONCOLOGY REPORTS 2020; 22 (5): 47
Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma
CURRENT ONCOLOGY REPORTS
2020; 22 (2): 19
H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy.Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response. While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.
View details for DOI 10.1007/s11912-020-0877-0
View details for Web of Science ID 000521197000002
View details for PubMedID 32030483
View details for PubMedCentralID PMC7501595