33 results on '"Andrea Franson"'
Search Results
2. Gene Therapy for High Grade Glioma: The Clinical Experience
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Maria Luisa Varela, Andrea Comba, Syed M Faisal, Anna Argento, Andrea Franson, Marcus N Barissi, Sean Sachdev, Maria G Castro, and Pedro R Lowenstein
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Pharmacology ,Clinical Biochemistry ,Drug Discovery - Abstract
High-grade gliomas (HGG) are the most common malignant primary brain tumors in adults, with a median survival of ~18 months. The standard of care (SOC) is maximal safe surgical resection, and radiation therapy with concurrent and adjuvant temozolomide. This protocol remains unchanged since 2005, even though HGG median survival has marginally improved.Gene therapy was developed as a promising approach to treat HGG. Here we review completed and ongoing clinical trials employing viral and non-viral vectors for adult and pediatric HGG, as well as the key supporting preclinical data.These therapies have proven safe, and pre- and post-treatment tissue analyses demonstrated tumor cell lysis, increased immune cell infiltration, and increased systemic immune function. Although viral therapy in clinical trials has not yet significantly extended survival of HGG, promising strategies are being tested. Oncolytic HSV vectors have shown promising results both for adult and pediatric HGG. A recently published study demonstrated that HG47Δ improved survival in recurrent HGG. Likewise, PVSRIPO has shown survival improvement compared to historical controls. It is likely that further analysis of these trials will stimulate the development of new administration protocols, and new therapeutic combinations which will improve HGG prognosis.
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- 2022
3. Supplementary Table S3A and S3B from Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
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Carl Koschmann, Tingtin Qin, Hugh J.L. Garton, Cormac O. Maher, Karin M. Muraszko, Patricia L. Robertson, Andrea Franson, Jonathan Schwartz, Rajen Mody, Ian Wolfe, Robert P. Dickson, Stefanie Stallard, Kyle Wierzbicki, Leo Tunkle, Evan Cantor, Clarissa May Babila, Jack Wadden, Ashwath Muruganand, Karthik Ravi, and Amy K. Bruzek
- Abstract
Nanopore Sensitivity/Specificity details
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- 2023
4. Supplementary Data from Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
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Carl Koschmann, Tingtin Qin, Hugh J.L. Garton, Cormac O. Maher, Karin M. Muraszko, Patricia L. Robertson, Andrea Franson, Jonathan Schwartz, Rajen Mody, Ian Wolfe, Robert P. Dickson, Stefanie Stallard, Kyle Wierzbicki, Leo Tunkle, Evan Cantor, Clarissa May Babila, Jack Wadden, Ashwath Muruganand, Karthik Ravi, and Amy K. Bruzek
- Abstract
All supplementary data except table S3A and S3B
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- 2023
5. Data from Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
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Carl Koschmann, Tingtin Qin, Hugh J.L. Garton, Cormac O. Maher, Karin M. Muraszko, Patricia L. Robertson, Andrea Franson, Jonathan Schwartz, Rajen Mody, Ian Wolfe, Robert P. Dickson, Stefanie Stallard, Kyle Wierzbicki, Leo Tunkle, Evan Cantor, Clarissa May Babila, Jack Wadden, Ashwath Muruganand, Karthik Ravi, and Amy K. Bruzek
- Abstract
Purpose: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.Experimental Design: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.Results: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.Conclusions: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.
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- 2023
6. GABAergic neuron-to-glioma synapses in diffuse midline gliomas
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Tara Barron, Belgin Yalçın, Aaron Mochizuki, Evan Cantor, Kiarash Shamardani, Dana Tlais, Andrea Franson, Samantha Lyons, Vilina Mehta, Samin Maleki Jahan, Kathryn R. Taylor, Michael B. Keough, Haojun Xu, Minhui Su, Michael A. Quezada, Pamelyn J Woo, Paul G. Fisher, Cynthia J. Campen, Sonia Partap, Carl Koschmann, and Michelle Monje
- Abstract
Pediatric high-grade gliomas are the leading cause of brain cancer-related death in children. High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling1,2and direct neuron-to-glioma synapses3–5. Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric3and adult high-grade gliomas4, but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology,in vivooptogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAAreceptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation3, we find that the activity of GABAergic interneurons promotes DMG proliferationin vivo. Increasing GABA signaling with the benzodiazepine lorazepam – a positive allosteric modulator of GABAAreceptors commonly administered to children with DMG for nausea or anxiety - increases GABAAreceptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAAreceptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and diffuse midline glioma cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context.
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- 2022
7. Hemophagocytic Lymphohistiocytosis as a Presenting Sign of Neuroblastoma
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Benison Lau, Thomas Michniacki, David Frame, Andrea Franson, and Kelly Walkovich
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Immunology ,Immunology and Allergy - Published
- 2023
8. CTNI-09. DIFFUSE MIDLINE GLIOMA-ADAPTIVE COMBINATORY TRIAL (DMG-ACT): A COMBINATION PLATFORM TRIAL IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH DIFFUSE MIDLINE GLIOMA
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Andrea Franson, Cassie Kline, Annette Molinaro, Yalan Zhang, Kelly Hitchner, Nalin Gupta, Carl Koschmann, Michael Prados, Javad Nazarian, and Sabine Mueller
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Despite advances in understanding the biology of diffuse midline gliomas (DMGs), clinical outcomes have not significantly improved. Therapy development is limited by: lack of preclinical data across multiple models and laboratories, limited knowledge about blood-brain barrier penetrance, and lack of multi-agent therapeutic approaches. We aimed to address these limitations by designing and implementing an innovative platform clinical trial (DMG-ACT). DMG-ACT is an open-label, multi-institutional, international trial of combination therapy for patients with DMG between 2 and 39 years of age. This study utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows for ongoing assessment of therapy efficacy with data borrowing across arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. The current treatment arms include ONC201 in combination with paxalisib. Patients enter one of three cohorts: newly-diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). Each cohort offers a target validation phase for patients who have not yet undergone biopsy to assess intratumoral pharmacokinetics/pharmacodynamics of pre-biopsy, single-agent dosing. Cohorts 1 and 3 offer radiation (Cohort 1) or re-irradiation (Cohort 3) with concomitant single-agent therapy followed by maintenance with combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohorts 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentrations; toxicity profile of combination therapy during radiation; toxicity profile and efficacy of combination therapy; CSF, ctDNA, stool, and flow cytometry biomarker analyses; and health related quality of life, cognitive, and patient/proxy-reported outcome measures. Additional therapy combinations that have shown additive or synergistic benefit in preclinical testing will be incorporated in future trial iterations and several are currently in development. The trial was launched in October 2021, with a total of 21 patients enrolled as of May 2022.
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- 2022
9. CTNI-61. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA
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Abed Rahman Kawakibi, Rohinton Tarapore, Sharon Gardner, Andrew Chi, Sylvia Kurz, Patrick Y Wen, Isabel Arrillaga-Romany, Tracy Batchelor, Nicholas Butowski, Ashley Sumrall, Nicole Shonka, Rebecca Harrison, John DeGroot, Minesh Mehta, Yazmin Odia, Matthew Hall, Doured Daghistani, Timothy Cloughesy, Benjamin Ellingson, Michelle Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Jonathan Schwartz, Sunjong Li, Rodrigo Cartaxo, Karthik Ravi, Evan Cantor, Jessica Cummings, Alyssa Paul, Dustin Walling, Matthew Dun, Jason Cain, Jiang Li, Mariella Filbin, Lili Zhao, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Ryo Kurokawa, Drew Pratt, Sriram Venneti, Jacques Grill, Cassie Kline, Sabine Mueller, Adam C Resnick, Javad Nazarian, Sebastian Waszak, Joshua E Allen, and Carl Koschmann
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson’s r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPK-pathway alterations, and patients with relatively high CBF.
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- 2022
10. Development of immunotherapy for high-grade gliomas: Overcoming the immunosuppressive tumor microenvironment
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Andrea Franson, Brandon L. McClellan, Maria Luisa Varela, Andrea Comba, Mohammad Faisal Syed, Kaushik Banerjee, Ziwen Zhu, Nazareno Gonzalez, Marianela Candolfi, Pedro Lowenstein, and Maria Graciela Castro
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General Medicine - Abstract
The preclinical and clinical development of novel immunotherapies for the treatment of central nervous system (CNS) tumors is advancing at a rapid pace. High-grade gliomas (HGG) are aggressive tumors with poor prognoses in both adult and pediatric patients, and innovative and effective therapies are greatly needed. The use of cytotoxic chemotherapies has marginally improved survival in some HGG patient populations. Although several challenges exist for the successful development of immunotherapies for CNS tumors, recent insights into the genetic alterations that define the pathogenesis of HGG and their direct effects on the tumor microenvironment (TME) may allow for a more refined and targeted therapeutic approach. This review will focus on the TME in HGG, the genetic drivers frequently found in these tumors and their effect on the TME, the development of immunotherapy for HGG, and the practical challenges in clinical trials employing immunotherapy for HGG. Herein, we will discuss broadly the TME and immunotherapy development in HGG, with a specific focus on glioblastoma multiforme (GBM) as well as additional discussion in the context of the pediatric HGG diagnoses of diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG).
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- 2022
11. Expanding Access to CNS-TAP: Design, Development, and Initial Use of a Complex Precision Health Specialty Web App for Neuro-Oncology
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Karthik Ravi, George Meng, Holly J. Roberts, Allison Schepers, Andrea Franson, Carl Koschmann, Bernard L. Marini, and Allen Flynn
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Precision Medicine ,Medical Oncology ,Mobile Applications ,Article - Abstract
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.
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- 2022
12. Comparative pharmacokinetic analysis of the blood-brain barrier penetration of dasatinib and ponatinib in mice
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Manjunath P. Pai, Karthik Ravi, Holly Roberts, Miao He, Lydia L. Benitez, Dale L. Bixby, Andrea Franson, Bernard L. Marini, Morgan J Homan, Zachary Miklja, Carl Koschmann, Bo Wen, and Anthony J. Perissinotti
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Cancer Research ,Dasatinib ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Text mining ,hemic and lymphatic diseases ,Blood brain barrier penetration ,Animals ,Medicine ,Protein Kinase Inhibitors ,neoplasms ,business.industry ,Ponatinib ,Imidazoles ,Hematology ,medicine.disease ,Fusion protein ,respiratory tract diseases ,Pharmacokinetic analysis ,Pyridazines ,Oncology ,chemistry ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Cancer research ,sense organs ,business ,Tyrosine kinase ,030215 immunology ,Chronic myelogenous leukemia ,medicine.drug - Abstract
The use of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein have dramatically changed the clinical management and outcomes for patients with chronic myelogenous leukemia (CML)...
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- 2021
13. A novel ATXN1-DUX4 fusion expands the spectrum of ‘CIC-rearranged sarcoma’ of the CNS to include non-CIC alterations
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Rohit Mehra, Martha Quezado, Rajen Mody, Kenneth Aldape, Marcin Cieślik, Drew Pratt, Andrea Franson, Arul M. Chinnaiyan, Evan Cantor, Hong Xiao, Zied Abdullaev, Chandan Kumar-Sinha, Lina Shao, and Sandra Camelo-Piragua
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Homeodomain Proteins ,Male ,CIC-Rearranged Sarcoma ,Oncogene Proteins, Fusion ,Brain Neoplasms ,business.industry ,Sarcoma ,Biology ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Text mining ,DUX4 ,Child, Preschool ,Cancer research ,Humans ,Neurology (clinical) ,business ,Ataxin-1 - Published
- 2021
14. Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
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Karthik Ravi, Ian Wolfe, Jonathan Schwartz, Jack Wadden, Leo Tunkle, Ashwath Muruganand, Carl Koschmann, Cormac O. Maher, Rajen Mody, Amy K. Bruzek, Hugh J. L. Garton, Kyle Wierzbicki, Patricia L. Robertson, Clarissa Babila, Andrea Franson, Tingtin Qin, Evan Cantor, Stefanie Stallard, Robert P. Dickson, and Karin M. Muraszko
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Male ,0301 basic medicine ,Cancer Research ,Adolescent ,Polymerase Chain Reaction ,Article ,Circulating Tumor DNA ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,law ,Glioma ,Biomarkers, Tumor ,medicine ,Humans ,Digital polymerase chain reaction ,Child ,Polymerase chain reaction ,Brain Neoplasms ,business.industry ,Amplicon ,Prognosis ,medicine.disease ,Molecular biology ,Nanopore ,030104 developmental biology ,Oncology ,Case-Control Studies ,Child, Preschool ,Molecular Response ,Mutation ,Female ,Nanopore sequencing ,Electronics ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.
- Published
- 2020
15. Enhancing GD2 CAR T-cell therapy with IGF-1R blockade: Are DIPG CAR T cells ready for combinatorial therapy?
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Carl Koschmann and Andrea Franson
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Cancer Research ,Receptors, Chimeric Antigen ,T-Lymphocytes ,Glioma ,Immunotherapy, Adoptive ,Receptor, Insulin ,Receptor, IGF Type 1 ,Oncology ,Glutamates ,Brain Stem Neoplasms ,Humans ,Neurology (clinical) ,Child ,Pediatric Neuro-Oncology - Abstract
Diffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.Our study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.
- Published
- 2022
16. Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma
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Evan Cantor, Kyle Wierzbicki, Rohinton S Tarapore, Karthik Ravi, Chase Thomas, Rodrigo Cartaxo, Viveka Nand Yadav, Ramya Ravindran, Amy K Bruzek, Jack Wadden, Vishal John, Clarissa May Babila, Jessica R Cummings, Abed Rahman Kawakibi, Sunjong Ji, Johanna Ramos, Alyssa Paul, Dustin Walling, Marcia Leonard, Patricia Robertson, Andrea Franson, Rajen Mody, Hugh J L Garton, Sriram Venneti, Yazmin Odia, Cassie Kline, Nicholas A Vitanza, Soumen Khatua, Sabine Mueller, Joshua E Allen, Sharon L Gardner, and Carl Koschmann
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Cancer Research ,Brain Neoplasms ,Pyridines ,Imidazoles ,Glioma ,Circulating Tumor DNA ,Histones ,Pyrimidines ,Oncology ,Mutation ,Humans ,Neurology (clinical) ,Child ,Pediatric Neuro-Oncology - Abstract
Background Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. Methods 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). Results 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. Conclusion 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.
- Published
- 2022
17. CTNI-68. FIREFLY-1 (PNOC026): PHASE 2 STUDY OF PAN-RAF INHIBITOR TOVORAFENIB IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RAF-ALTERED RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA OR ADVANCED SOLID TUMORS
- Author
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Lindsay Kilburn, Daniel Landi, Sarah Leary, David Ziegler, Patricia Baxter, Andrea Franson, Geoffrey McCowage, Angela Waanders, Jasper Van der Lugt, Michal Yalon Oren, Nicolas Gerber, Nicholas Gottardo, Dong-Anh Khuong-Quang, Karsten Nysom, Simon Bailey, Pablo Hernáiz Driever, Sebastien Perreault, Olaf Witt, Seungmin Hahn, Darren Hargrave, Timothy Hassall, Nada Jabado, Hyoung Jin Kang, Valerie Larouche, Helen Toledano, Cassie Kline, Mohamed Abdelbaki, Susan Chi, Sharon Gardner, Nicholas Whipple, Sabine Mueller, Samuel Blackman, Xin Zhao, Daniel Da Costa, Michael Cox, Roger Packer, and Jordan Hansford
- Subjects
Cancer Research ,Oncology ,Neurology (clinical) - Abstract
BACKGROUND RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. METHODS FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring an activating BRAF alteration. Patients aged 6 months–25 years who progressed following ≥ 1 prior line of systemic therapy were eligible. Tovorafenib 420 mg/m2 (≤ 600 mg) was administered weekly (tablet or liquid suspension formulation) until progression or for ≥ 26, 28-day cycles. The primary endpoint (arm 1) was overall response rate, as defined by RANO criteria, per independent review. RESULTS As of April 14, 2022, 25 patients were enrolled to arm 1 and had ≥ 6 months of follow-up. Median age at enrollment was 8 years (range 3–18). Most patients had astrocytomas (92%), 48% with optic pathway involvement. Patients were heavily pretreated (56% with ≥ 3 prior lines of therapy), and 72% previously received MAPK pathway-targeted agents. Tumors harbored BRAF fusions (84%) or BRAF V600E mutations (16%). Per independent assessment, partial responses (1 unconfirmed) were seen in 14 (64%) of 22 evaluable patients, with 6 additional patients having stable disease, and a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations. Most treatment-emergent adverse events (AEs) were grade 1 or 2 (96%). The most common grade ≥ 3 AEs were anemia (12%), vomiting, increased blood creatinine phosphokinase and maculopapular rash (8% each). Seven patients (28%) required dose modification for treatment-related AEs; no patients discontinued tovorafenib due to AEs. Updated results, including efficacy per RAPNO assessments will be presented. CONCLUSIONS Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children with pretreated BRAF-altered LGG.
- Published
- 2022
18. EOLP-02. THE EFFECT OF CLINICAL TRIAL ENROLLMENT ON SPECIALTY PALLIATIVE CARE RECEIPT IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH HIGH GRADE GLIOMAS
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Holly Roberts, Andrea Franson, and Yujie Wang
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
BACKGROUND Palliative care has been shown to provide numerous benefits to children with cancer. Pediatric patients with high grade glioma (HGG) are particularly well suited for early involvement of palliative care given their high symptom burden and relatively poor prognosis. However, a recent study revealed that pediatric patients with primary central nervous system malignancies missed multiple opportunities for appropriate palliative care involvement. We hypothesize that clinical trial enrollment may adversely impact palliative care involvement for children and young adults with HGG. METHODS We identified a cohort of 43 deceased patients with HGG treated at our institution. IRB exemption was obtained. For each patient, the electronic medical record was reviewed to collect demographic, diagnostic, clinical trial, treatment, and palliative care information. Statistical analysis was performed, employing Fisher exact and t tests. RESULTS Overall, 72% (31/43) of patients had at least one visit with a specialty palliative care provider. 56% (24/43) of patients enrolled in a clinical trial with HGG-directed therapy, with 71% (17/24) of patients who enrolled in a clinical trial receiving specialty palliative care compared to 74% (14/19) of patients who were not on a trial (p = 1.000). Among patients who received palliative care, there was no statistically significant difference in the timing of palliative care involvement, measured from the date of first palliative care contact to date of death, for patients who enrolled in a clinical trial (mean = 177 days) compared to those who did not (mean = 113 days, p = 0.180). CONCLUSIONS As our understanding of the genomic landscape of pediatric brain tumors increases, it can be expected that patients electing to enroll in targeted therapy clinical trials will also increase. As such, it is reassuring that our data suggest trial participation does not adversely impact the receipt of palliative care in children with HGG.
- Published
- 2022
19. EOLP-03. A RETROSPECTIVE STUDY ON CAUSE OF DEATH DUE TO HIGH-GRADE GLIOMAS IN PEDIATRIC VERSUS ADULT PATIENTS
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Andrea Franson, Larry Junck, and Samantha Lyons
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
BACKGROUND Limited literature exists on the presumed pathophysiologic mechanisms by which children, adolescents and adults die from high-grade gliomas (HGGs). This study aims to identify the likely specific cause of death in patients with HGG based on imaging review in proximity to death. A secondary aim is to assess the use and timing of palliative care/hospice in patients with HGG. We hypothesized that most patients with HGG, both adult and pediatric, die from primary neurologic failure as a result of local tumor progression, with additional causes including hydrocephalus with subsequent brainstem herniation or causes indirectly related to tumor progression such as systemic infection. METHODS We conducted a retrospective review of pediatric patients with WHO Grade 4 gliomas and adults with de novo Grade 3 or 4 gliomas or Grade 2 glial tumors that transformed to Grade 3/4, diagnosed from 2016 to 2021 at Michigan Medicine (IRB exemption obtained). We reviewed imaging and clinical records of patients who had brain MR and/or CT imaging within 3 - 6 weeks of death to determine a likely cause of death. RESULTS Twenty-six pediatric patients and 43 adult patients identified met inclusion criteria. Initial analysis reveals that the majority of patients with HGG died from local tumor progression and subsequent neurologic failure. We also noted a greater use of palliative care/hospice services in pediatric patients, with less frequent referral for adult patients at any time in their disease course. Pediatric patients are almost always supported by Child and Family Life, while psychological services are rarely received by adult patients. CONCLUSIONS Analysis is ongoing, though trends indicate that the primary cause of death in patients with HGG is through primary neurologic failure, and that there may be opportunities to lessen end-of-life suffering through patient education and the use of support services.
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- 2022
20. DIPG-49. International preclinical drug discovery and biomarker program informing an adoptive combinatorial trial for DMG
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Javad Nazarian, Matthew Dun, Lindsay Kilburn, Sebastian Waszak, Nicholas Vitanza, Andrea Franson, Mike Prados, Eric Raabe, Ron Firestein, Alexander Beck, Amanda Saratsis, Barak Rotblat, Dannis van Vuurder, Jessica Foster, Esther Hulleman, Cassie Kline, Nalin Gupta, Jason Cain, Carl Koschmann, and Sabine Muller
- Subjects
Cancer Research ,Oncology ,Neurology (clinical) - Abstract
INTRODUCTION: DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) will implement an innovative clinical trial design of combinatorial arms for patients with DMG at all disease stages, that is adaptive to pre-clinical and correlate data generated in eight collaborating institutions. The goal of the team is to rapidly identify and validate i) promising drugs and drug combinations for clinical use, and ii) predictive biomarkers of promising drugs. METHODS: In vitro (n=30) and in vivo (n=8) models of DMG across fourteen institutions were used to assess single and combination treatment of over 80 drugs and drug combinations. Predictive biomarkers of response for top candidate drugs were identified using extensive molecular assays including proteomics, CRISPR, RNAseq, ELISA, FACS, and IHC. RESULTS: Inhibitory concentration (IC50) of all drugs were established and validated across all participating sites. In vivo validation of single and combination drug assays confirmed drug efficacy as increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), ONC201+panobinostat (p=0.01). Marizomib was highly toxic in murine PDX and zebrafish larvae assays. Murine pharmacokinetic analysis showed peak brain levels of ONC201, and ONC206 above pre-clinical IC50 concentrations. Molecular testing and analyses of existing drug screen across 578 cancer cells validated mitochondrial stress and additional proteins, as the main targets induces by ONC201/6. CONCLUSION: Thorough preclinical testing in a multi-site laboratory setting identified promising therapeutics for DMGs, resulting in launch of two clinical trials (PNOC022, ONOC023). Validation of identified biomarkers are ongoing using clinical specimen as well as in vivo PDX models.
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- 2022
21. Panobinostat penetrates the blood–brain barrier and achieves effective brain concentrations in a murine model
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Morgan J Homan, Holly Roberts, Aleksas Matvekas, Manjunath P. Pai, Carl Koschmann, Bernard L. Marini, Andrea Franson, Karthik Ravi, Cai Liu, and Miao He
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0301 basic medicine ,Cancer Research ,Cmax ,Antineoplastic Agents ,Pharmacology ,Toxicology ,Blood–brain barrier ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,Panobinostat ,medicine ,Animals ,Pharmacology (medical) ,Tissue Distribution ,business.industry ,Brain ,Bioavailability ,Histone Deacetylase Inhibitors ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Murine model ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Brain concentrations ,Area Under Curve ,Female ,business - Abstract
PURPOSE: 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. METHODS: 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. C(max) and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines. RESULTS: 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 C(max) in humans is expected to be significantly higher than the IC-50 identified in DIPG models. CONCLUSION: 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.
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- 2021
22. BIOM-28. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (cf-tDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201
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Evan Cantor, Kyle Wierzbicki, Rohinton Tarapore, Karthik Ravi, Jack Wadden, Clarissa Babilla, Chase Thomas, Rodrigo Cartaxo, Vivek Anand Yadav, Ramya Ravindran, Amy K Bruzek, Jessica Cummings, Abed Rahman Kawakibi, Sunjong Ji, Alyssa Paul, Ian Wolfe, Marcia Leonard, Patricia Robertson, Andrea Franson, Rajen Mody, Hugh Garton, Yazmin Odia, Cassie Kline, Nicholas Vitanza, Soumen Khatua, Joshua Allen, Sabine Mueller, Sharon Gardner, and Carl Koschmann
- Subjects
Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Diffuse midline glioma (DMG) with H3K27M mutation is a lethal childhood brain cancer, with limited means of monitoring beyond serial MRI scans. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6-months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. We collected a total of 96 plasma-samples and 53 CSF-samples from 29 patients. We performed ddPCR analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal tumor area on MRI). For our H3F3A-mutated (K27M) patients, cf-tDNA was positive in 53/62 plasma samples (sensitivity 85.4%) and 28/29 CSF samples (sensitivity 96.5%) and overall specificity of 100%. There was no direct correlation between percent-change in tumor-area and plasma (p=0.47) or CSF VAF (p=0.89), implying that VAF provided information supplemental to radiographic assessments. “Spikes” in plasma cf-tDNA VAF (increase of ≥25%) co-occurred with progression in 2/9 (22%) cases and preceded progression in 5/9 cases (55%) by an average of 1.22 months. In CSF, spikes preceded progression in 4/6 cases (66%) by an average of 1.8 months. Two patients had increases in tumor-area with no increase in plasma VAF; both were later confirmed as pseudo-progressors, suggesting additional potential utility of cf-tDNA VAF monitoring. A 14yo male with spinal cord glioma received concurrent bevacizumab with ONC201, which resulted in a decrease in tumor area but continued increase in plasma VAF, predicting radiologic progression at the next time. In summary, we present data which suggests monitoring serial CSF/plasma H3K27M tDNA is a promising clinical tool. Changes in cf-tDNAVAF over time appear to correlate with response, predict progression, and differentiate pseudo-progression.
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- 2021
23. EPCT-03. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (CF-TDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201
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Ian Wolfe, Ramya Ravindran, Rajen Mody, Carl Koschmann, Joshua E. Allen, Hugh J. L. Garton, Sunjong Ji, Sabine Mueller, Andrea Franson, Evan Cantor, Abed Rhaman Kawakibi, Partricia Robertson, Clarissa May Babilla, Soumen Khatua, Rodrigo Cartaxo, Johanna Ramos, Nicholas A Vitanza, Alyssa Paul, Marcia Leonard, Sharon Gardner, Rohinton S. Tarapore, Yazmin Odia, Chase Thomas, Amy K. Bruzek, Kyle Wierzbicki, Jack Wadden, Viveka Nand Yadav, and Cassie Kline
- Subjects
Cancer Research ,Bevacizumab ,medicine.diagnostic_test ,business.industry ,Lumbar puncture ,Radiography ,Magnetic resonance imaging ,medicine.disease ,Spinal cord ,Translational/Early Phase Clinical Trials ,medicine.anatomical_structure ,Text mining ,Oncology ,Glioma ,Etiology ,Medicine ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,business ,Nuclear medicine ,medicine.drug - Abstract
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 ({"type":"clinical-trial","attrs":{"text":"NCT03416530","term_id":"NCT03416530"}}NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2, 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0–8 CSF samples and 0–10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Preliminary analysis of samples demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201, and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to
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- 2021
24. Clinical efficacy and predictive biomarkers of ONC201 in H3 K27M-mutant diffuse midline glioma
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Carl Koschmann, Abed Rahman Kawakibi, Rohinton Tarapore, Sharon Gardner, Chase Thomas, Rodrigo Cartaxo, Viveka Yadav, Andrew Chi, Sylvia Kurz, Patrick Wen, Isabel Arrillaga, Tracy Batchelor, Nicholas Butowski, Ashley Sumrall, Nicole Shonka, Rebecca Harrison, John De Groot, Minesh Mehta, Yazmin Odia, Matthew Hall, Doured Daghistani, Timothy Cloughesy, Benjamin Ellingson, Michelle Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Patricia Robertson, Jonathan Schwartz, Bernard Marini, Manjunath Pai, Timothy Phoenix, Sunjong Ji, Evan Cantor, Zachary Miklja, Brendan Mullan, Amy Bruzek, Ruby Siada, Jessica Cummings, Stefanie Stallard, Kyle Wierzbicki, Alyssa Paul, Ian Wolfe, Matthew Dun, Jason Cain, Li Jiang, Mariella Filbin, Pankaj Vats, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Drew Pratt, Sriram Venneti, Guangrong Lu, Sabine Mueller, Adam Resnick, Javad Nazarian, Sebastian Waszak, and Joshua Allen
- Abstract
Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation have no proven therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has induced early responses in patients with H3 K27M-mutant DMG. We performed an integrated pre-clinical and clinical assessment of ONC201 treatment, in order to define response rates in H3 K27M-mutant DMG patients and to clarify predictors of response. ONC201 was effective in murine H3 K27M-mutant gliomas with excellent CNS penetration and survival benefit. H3 K27M-mutant DMG patients treated with ONC201 on active clinical trials (n=50) showed significant survival benefit in recurrent and non-recurrent settings, with multiple sustained responses. Tumor sequencing from treated patients demonstrates an EGFR/FOXG1-driven telencephalic gene regulatory network that imparts a critical resistance phenotype to ONC201. Genetic and pharmacologic knockdown of EGFR in H3 K27M-mutant cell cultures results in improved sensitivity to ONC201 and reduced FOXG1 enhancer binding, suggesting possible future combinatorial opportunities.
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- 2020
25. Correction to: Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma
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Micah K Harris, Evan Cantor, Amy K. Bruzek, Bernard L. Marini, Carl Koschmann, Morgan J Homan, Andrea Franson, Abed Rahman Kawakibi, Ramya Ravindran, Viveka Nand Yadav, Kyle Wierzbicki, Karthik Ravi, and Rodrigo Teodoro
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Section (typography) ,Mistake ,medicine.disease ,Therapeutic monitoring ,Review article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Glioma ,medicine ,business - Abstract
The original version of this review article unfortunately contained a mistake in the author group section.
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- 2020
26. Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma
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Bernard L. Marini, Amy K. Bruzek, Kyle Wierzbicki, Carl Koschmann, Andrea Franson, Rodrigo Teodoro, Ramya Ravindran, Karthik Ravi, Evan Cantor, Morgan J Homan, Abed Rahman Kawakibi, Micah K Harris, and Viveka Nand Yadav
- Subjects
0301 basic medicine ,Oncology ,Jumonji Domain-Containing Histone Demethylases ,medicine.medical_specialty ,Treatment response ,Mutant ,Antineoplastic Agents ,Immunotherapy, Adoptive ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Glioma ,Panobinostat ,Internal medicine ,Humans ,Medicine ,Spinal Cord Neoplasms ,Liquid biopsy ,Cerebrospinal Fluid ,Clinical Trials as Topic ,Brain Neoplasms ,business.industry ,Liquid Biopsy ,Prognosis ,medicine.disease ,Therapeutic monitoring ,Histone Deacetylase Inhibitors ,Clinical trial ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,business ,Who classification - Abstract
PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.
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- 2020
27. INNV-16. 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)
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Bernard L. Marini, Carl Koschmann, Karthik Ravi, Holly Roberts, Sabine Mueller, Cassie Kline, Andrea Franson, and Allison J Schepers
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,medicine.disease ,Clinical trial ,Multidisciplinary approach ,Internal medicine ,medicine ,Tumor board ,Neurology (clinical) ,business - Abstract
Genetic sequencing of diffuse intrinsic pontine gliomas (DIPG) has revealed genomic heterogeneity, sparking an interest in individualized and targeted treatment options for this particularly devastating disease. A feasibility study, PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), was completed within the Pacific Pediatric Neuro-Oncology Consortium. In this study, a multidisciplinary tumor board reviewed detailed molecular and genomic profiling of each participant’s tumor and made molecularly-targeted treatment recommendations. Separately, our team developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to derive numeric scores for targeted anticancer agents, aimed to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in PNOC003. For each study participant, we used the genomic profiling report to identify actionable alterations and incorporated these data into CNS-TAP to identify the highest-scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the tumor board for each of the enrolled 28 participants. Overall, 93% of patients (26/28) had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% of all agents (36/95) recommended by the tumor board were also selected by CNS-TAP. We identified factors that likely contributed to the differences in therapy recommendations between these two methods: CNS-TAP requires additional clinician input to account for drug-drug interactions, includes only classically-defined anticancer agents, and cannot easily be updated in real-time as new data emerge. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. A prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in high-grade glioma is currently ongoing to further compare and objectively evaluate these methods.
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- 2021
28. CLRM-06. COMPARISON OF INDIVIDUALIZED ANTI-CANCER THERAPY REGIMENS RECOMMENDED BY A MULTIDISCIPLINARY MOLECULARLY-DRIVEN TUMOR BOARD IN A PEDIATRIC DIPG CLINICAL TRIAL (PNOC003) VERSUS THOSE SELECTED BY THE CNS-TAP TOOL
- Author
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Bernard L. Marini, Karthik Ravi, Holly Roberts, Sabine Mueller, Cassie Kline, Carl Koschmann, Allison J Schepers, and Andrea Franson
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Oncology ,medicine.medical_specialty ,Neurologic Oncology ,business.industry ,Cancer therapy ,Cancer ,medicine.disease ,Final category: Clinical Research Methods ,Supplement Abstracts ,Clinical trial ,Multidisciplinary approach ,Care plan ,Internal medicine ,Glioma ,medicine ,Tumor board ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,business - Abstract
Genetic sequencing of diffuse intrinsic pontine gliomas (DIPG) has revealed genomic heterogeneity, fueling an interest in individualized targeted therapies. A feasibility study, PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), was completed within the Pacific Pediatric Neuro-Oncology Consortium in which a multidisciplinary tumor board reviewed molecular and genomic profiling of each participant’s tumor to make targeted therapy recommendations. Separately, our team developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to derive numeric scores for anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that agents highly-scored by CNS-TAP would overlap with agents recommended by the PNOC003 tumor board. For each study participant, we retrospectively utilized the genomic profiling report to identify actionable alterations and incorporated these data into CNS-TAP to find the highest-scoring agents. We compared these CNS-TAP-recommended agents with recommendations from the tumor board for each of the 28 PNOC003 participants. Overall, 93% of patients (26/28) had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% of all agents (36/95) chosen by the tumor board were also selected by CNS-TAP. When only molecularly targeted anticancer agents were included in a sub-analysis, 60% of agents (34/57) were recommended by both methods. At present, we are prospectively evaluating the CNS-TAP tool within PNOC008: A Pilot Trial Testing the Clinical Benefit of Using Molecular Profiling to Determine an Individualized Treatment Plan in Children and Young Adults with High-Grade Glioma (NCT03739372). The CNS-TAP tool recommendations are shared during the PNOC008 molecular tumor board meetings once a consensus treatment recommendation has been reached. Subsequent analyses will focus on any adjustments in therapy decisions within the tumor board that result from the CNS-TAP tool output.
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- 2021
29. CTNI-17. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
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Pankaj Vats, Alyssa Paul, Yoshie Umemura, Timothy F. Cloughesy, Chase Thomas, Nicole Shonka, Daniel Martinez, Isabel Arrillaga-Romany, Ian Wolfe, Benjamin M. Ellingson, Arul M. Chinnaiyan, Evan Cantor, Zachary Miklja, John de Groot, Abed Rahman Kawakibi, Andrew S. Chi, Chandan Kumar-Sinha, Rebecca Harrison, Adam C. Resnick, Nicholas Butowski, Guangrong Lu, Minesh P. Mehta, Joshua E. Allen, Ashley Sumrall, Matthew Hall, Rajen Mody, Carl Koschmann, Mariella G. Filbin, Ruby Siada, Sylvia Kurz, Rohinton Tarapore, Sebastian M Waszak, Doured Daghistani, Hugh J. L. Garton, Viveka Nand Yadav, Javad Nazarian, Amy K. Bruzek, Patrick Y. Wen, Sabine Mueller, Tracy T. Batchelor, Sharon Gardner, Jessica R. Cummings, Sriram Venneti, Jonathan Schwartz, Brendan Mullan, Patricia L. Robertson, Li Jiang, Andrea Franson, Yazmin Odia, and Rodrigo Cartaxo
- Subjects
Drd2 gene ,Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Mutant ,Clinical Trials: Non-Immunologic ,medicine.disease ,Oncology ,Circulating tumor DNA ,Glioma ,Troponin I ,medicine ,Neurology (clinical) ,Clinical efficacy ,business ,Predictive biomarker - Abstract
Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in early phase studies in H3 K27M-mutant DMG. In order to define response rates in H3 K27M DMG patients and to clarify the genomic, anatomic and molecular predictors of response, we performed an integrated pre-clinical and clinical analysis of ONC201 treatment. ONC201 was effective in intra-uterine electroporation (IUE)-generated H3 K27M-mutant murine glioma models with excellent CNS penetration and survival benefit. Patients with H3 K27M-mutant DMG treated with ONC201 on active clinical trials (n=50, 27 thalamic, 23 brainstem) showed an overall survival (OS) of 28.1 (range: 5.9–105) months from diagnosis (enrollment by 4/29/19, data cut-off 12/28/19), compared to historical median OS of 12 months. Median OS for non-recurrent patients has not been reached (n=16, median follow-up: 16.8 from diagnosis). For non-recurrent thalamic patients (n=8), median PFS is 20.1 (range: 9.3–27.6) months from diagnosis (median time on drug: 14.5 months). Best response for thalamic patients by RANO: 1 CR, 5 PR, 7 SD, 8 PD, 6 not reported. Decreased H3 K27M cell-free tumor DNA in plasma and CSF at 6 months correlated with long-term response. Baseline tumor gene expression profiling in patients treated with ONC201 (n=14) identified EGFR and the cortical developmental transcription factor FOXG1 as the strongest biomarkers of radiographic response to ONC201. Analysis of 541 ONC201-treated human cancer cell lines from DepMap, provided evidence for an EGFR-dependent ONC201 resistance mechanism. Analysis of 38 glioma cell lines further supports FOXG1 as a glioma-specific predictive biomarker of ONC201 response. The unprecedented survival results and radiographic responses to ONC201 in H3K27M DMG make a compelling case for later phase and combinatorial studies.
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- 2020
30. EPCT-02. COMPARISON OF TARGETED AGENTS RECOMMENDED BY THE CNS-TAP TOOL TO THOSE SELECTED BY A TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL
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Carl Koschmann, Andrea Franson, Sabine Mueller, Bernard L. Marini, Holly Roberts, Karthik Ravi, and Cassie Kline
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Translational/Early Phase Clinical Trials ,Clinical trial ,Text mining ,Internal medicine ,Biopsy ,medicine ,AcademicSubjects/MED00300 ,Tumor board ,AcademicSubjects/MED00310 ,Neurology (clinical) ,business - Abstract
Recently, sequencing of diffuse intrinsic pontine glioma (DIPG) biopsy specimens has revealed genomic heterogeneity of these tumors, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed enrollment onto a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended molecularly-targeted agents based on genomic and molecular profiling of each patient’s tumor. Separately, our group developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to allow for numeric scoring of targeted anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in this study. For each PNOC003 participant, we utilized the genomic report to identify actionable alterations and input patient-specific data into CNS-TAP to identify the highest scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the PNOC003 tumor board for each of the enrolled 28 subjects. Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% (37/95) of all agents recommended by the tumor board were also selected by CNS-TAP. Furthermore, we identified factors that likely contributed to the discordance between these two methods. Without clinician input, CNS-TAP is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in DIPG patients is warranted.
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- 2021
31. 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
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Cassie Kline, Carl Koschmann, Sabine Mueller, Bernard L. Marini, Karthik Ravi, Holly Roberts, and Andrea Franson
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Clinical trial ,Internal medicine ,Glioma ,Biopsy ,medicine ,Tumor board ,Young adult ,business - Abstract
2048 Background: Genetic sequencing of diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) biopsy specimens has revealed genomic heterogeneity, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended targeted agents based on the molecular and genetic profiling of each patient’s tumor. Separately, our group developed a numeric scoring tool of targeted anticancer agents, the Central Nervous System Targeted Agent Prediction (CNS TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to generate a numeric score for each agent to objectively evaluate these targeted therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within the CNS-TAP tool would overlap, at least in part, with the agents recommended by the molecular tumor board in PNOC003. Methods: For each study participant (n=28), a retrospective analysis was completed, utilizing the genomic report to identify actionable genetic alterations and to input patient-specific data into CNS TAP to identify the highest scoring agents. We compared high-scoring agents within the CNS TAP tool with recommendations from the PNOC003 tumor board for each of the enrolled 28 patients. Results: Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS TAP. Additionally, 39% (37/95) of all agents recommended by the tumor board were also selected by CNS TAP, with additional analysis ongoing. Conclusions: There was significant overlap between the highest-scoring and selected agents via CNS TAP compared with those chose by the molecular tumor board. Through this work, we also identified factors that likely contributed to the discordance in choice of targeted therapies. Without clinician input, the CNS TAP tool is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time, requiring extensive manual literature review for each included agent. However, CNS TAP provides an objective evaluation of targeted therapies, in contrast to inherently subjective recommendations of a tumor board. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS TAP and a molecular tumor board for targeted therapy selection in patients with high grade glioma is warranted.
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- 2021
32. Serial plasma and CSF cell-free tumor DNA (cf-tDNA) tracking in diffuse midline glioma patients undergoing treatment with ONC201
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Sabine Mueller, Amy K. Bruzek, Viveka Nand Yadav, Hugh J. L. Garton, Yazmin Odia, Joshua E. Allen, Nicholas A Vitanza, Carl Koschmann, Rohinton Tarapore, Cassie Kline, Sharon Gardner, Andrea Franson, Rodrigo Cartaxo, Ramya Ravindran, Soumen Khatua, Chase Thomas, Kyle Wierzbicki, Rajen Mody, and Evan Cantor
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Transfer DNA ,Cancer Research ,Mutation ,business.industry ,Cell free ,medicine.disease ,medicine.disease_cause ,Brain cancer ,chemistry.chemical_compound ,Oncology ,chemistry ,Glioma ,medicine ,Cancer research ,business ,DNA - Abstract
2012 Background: Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. There are few available means of monitoring the disease beyond serial MRI scans, making clinical decision making slow, difficult, and often reactive. Methods: 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 (baseline, 2 and 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected a total of 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0-8 CSF samples and 0-10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results: Preliminary analysis of samples (n=58) demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. Analysis of remaining CSF and plasma samples is ongoing, including analysis of novel biomarkers of response. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201 and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed an increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to
- Published
- 2021
33. DIPG-08. ELECTRONIC SEQUENCING PROVIDES OPTIMIZED QUANTIFICATION OF SERIAL, MULTI-GENE MOLECULAR RESPONSE IN THE CSF OF CHILDREN WITH HIGH-GRADE GLIOMA
- Author
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Karin M. Muraszko, Ian Wolfe, Evan Cantor, Hugh J. L. Garton, Karthik Ravi, Ashwath Muruganand, Cormac O. Maher, Patrica Robertson, Leo Tunkle, Carl Koschmann, Tingting Qin, Rajen Mody, Stefanie Stallard, Andrea Franson, Clarissa Babila, Kyle Wierzbicki, Amy K. Bruzek, and Jack Wadden
- Subjects
Cancer Research ,Oncology ,Molecular Response ,Diffuse Midline Glioma/DIPG ,Cancer research ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,Biology ,Multi gene ,High-Grade Glioma - Abstract
BACKGROUND For pediatric high-grade glioma (pHGG), non-invasive methods for diagnosis and surveillance are needed. Tumors release DNA (tDNA) into cerebrospinal fluid (CSF), allowing for detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of tDNA with a novel, hand-held platform (Oxford Nanopore MinION) could quantify patient-specific CSF tDNA variant allele fraction (VAF) with improved speed and limit of detection compared to established methods. METHODS We integrated required multi-timepoint (0, 2, and 6 months) correlate lumbar punctures (LP) in two ongoing pHGG clinical trials. Using Nanopore technology, we performed amplicon-based PCR on CSF tDNA for recurrent mutations from patient samples (n=19) and normal controls. VAF were determined via MinKNOW, Guppy, MiniMap2, and Integrated Genome Browser. RESULTS Nanopore CSF tDNA demonstrated improved sensitivity (91%) when compare to NGS sequencing (50%). Nanopore analysis of serially diluted CSF sample demonstrated significantly lower limit of detection (attomolar) than typical NGS sample requirement (nanomolar). H3K27M mutation was reliably detected with 1,000x depth sequencing, which was achieved in less than 15 minutes of sequencing after amplification. Multiplexed Nanopore analysis of H3F3A and HIST1H3B was employed when H3 status was unknown. Serial CSF tDNA analysis confirmed multi-gene (H3F3A K27M, PIK3CA, and TP53) molecular remission in a 17-year-old with thalamic diffuse midline glioma that correlated with sustained clinical response to ONC201 (14 months and ongoing). CONCLUSIONS Use of a hand-held, electronic DNA analysis platform allows quantification of multi-gene molecular response with improved speed and limit of detection in the CSF of children with high-grade glioma.
- Published
- 2020
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