Efficacy of convection enhanced delivery of MTX110 (soluble panobinostat) in preclinical Diffuse Intrinsic Pontine Glioma models using metabolic hyperpolarized 13C imaging

Justyna M. Przystal; Ilwoo Park; Jie Zhang; Piotr Hadaczek; Krystof Bankiewicz; Nalin Gupta; Javad Nazarian; Sabine Mueller

EJC Paediatric Oncology (Dec 2023)

Efficacy of convection enhanced delivery of MTX110 (soluble panobinostat) in preclinical Diffuse Intrinsic Pontine Glioma models using metabolic hyperpolarized 13C imaging

Justyna M. Przystal,
Ilwoo Park,
Jie Zhang,
Piotr Hadaczek,
Krystof Bankiewicz,
Nalin Gupta,
Javad Nazarian,
Sabine Mueller

Affiliations

Justyna M. Przystal: Department of Oncology, Children's Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
Ilwoo Park: Department of Radiology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea; Department of Artificial Intelligence Convergence, Chonnam National University, Gwangju, Republic of Korea
Jie Zhang: Department of Neurology, University of California, San Francisco, CA, USA
Piotr Hadaczek: Department of Neurological Surgery, University of California, San Francisco, CA, USA
Krystof Bankiewicz: Department of Neurological Surgery, University of California, San Francisco, CA, USA
Nalin Gupta: Department of Neurological Surgery, University of California, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA
Javad Nazarian: Department of Oncology, Children's Research Center, University Children’s Hospital Zurich, Zurich, Switzerland; Research Center for Genetic Medicine, Children's National Hospital, Washington, DC, USA; Corresponding author at: Department of Oncology, Children's Research Center, University Children’s Hospital Zurich, Zurich, Switzerland.
Sabine Mueller: Department of Oncology, Children's Research Center, University Children’s Hospital Zurich, Zurich, Switzerland; Department of Neurology, University of California, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA; Correspondence to: Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, 675 Nelson Lane Ring, Room 402, San Francisco, CA 94158, USA.

Journal volume & issue: Vol. 2
p. 100021

Abstract

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Background: Diffuse intrinsic pontine glioma (DIPG) usually occurs in children and has poor outcomes despite treatment. Large drug screens have identified the pan-histone deacetylate inhibitor panobinostat as a promising agent, however clinical response might be hampered by limited blood brain barrier penetration. Hyperpolarized 13C magnetic resonance (MR) metabolic imaging has successfully been applied to non-invasively assess metabolic activity of cancer therapies. Here, we use in vitro and in vivo DIPG models to validate the therapeutic efficacy of MTX110, an aqueous form of panobinostat delivered by convection enhanced delivery (CED) and apply metabolic imaging. Methods: MTX110 inhibitory effect was assessed in 11 DIPG cell lines. Caspase 3/7 levels were measured to assess mode of cell death. FACS analysis was utilized to determine impact on cell cycle. Hyperpolarized 13C imaging determined changes in pyruvate and lactate levels after treatment. In vivo activity of CED of MTX110 was assessed in a patient-derived xenograft rat model and tissue half-life of MTX110 was determined using mass spectrometry. Results: MTX110 showed similar IC50 to panobinostat ranging from 5.34 nM and 47.96 nM. Anti-proliferative effects of MTX110 are mediated by G1 cell cycle arrest and subsequent apoptosis. Drug treatment led to reduced pyruvate to lactate conversion. CED of MTX110 significantly prolonged survival of tumor-bearing rats (p = 0.0372) with no signs of systemic toxicity. Tissue half-life after single CED of MTX110 is 2 h. Conclusions: Our results demonstrate that CED of MTX110, has potent antitumor activity with limited systemic toxicity and that hyperpolarized 13C imaging is able to assess metabolic impact.

Published in EJC Paediatric Oncology

ISSN: 2772-610X (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.sciencedirect.com/journal/ejc-paediatric-oncology

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