A5022751358- Glioma Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Cancer, Hypoxia, and Metabolism
- Neuroblastoma Research and Treatments
- Polyamine Metabolism and Applications
- Amino Acid Enzymes and Metabolism
- Chromatin Remodeling and Cancer
- ATP Synthase and ATPases Research
- Ubiquitin and proteasome pathways
- Mitochondrial Function and Pathology
- Cellular transport and secretion
- Immunotherapy and Immune Responses
- Natural Compounds in Disease Treatment
- Circular RNAs in diseases
- Microtubule and mitosis dynamics
- Cancer-related molecular mechanisms research
- Cancer Research and Treatments
- Cancer Immunotherapy and Biomarkers
- Hedgehog Signaling Pathway Studies
- RNA modifications and cancer
- Metabolism and Genetic Disorders
- Cognitive Abilities and Testing
UNSW Sydney
2018-2025
Cancer Institute of New South Wales
2018-2025
Children's Cancer Institute Australia
2018-2024
Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that essential for DNA replication, translation cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show synthesis upregulated DIPG, leading to sensitivity DFMO. DIPG cells...
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a remodeling complex involved in transcription, replication, DNA repair. We show displays profound cytotoxic activity against panel of patient-derived DIPG cultures by restoring suppressor TP53 Rb activity. Moreover, orthotopic model DIPG, treatment with...
Abstract Background Diffuse midline glioma, characterised by H3K27 alteration (DMG), is the predominant high-grade glioma in children. It commonly originates brainstem, yet effective treatments for these patients remain elusive. Methods To identify novel therapies DMG, we conducted high-throughput drug screens (HTS) using biologically active, clinically approved compounds against DMG neurospheres. Multiple primary cultures were utilised conjunction with vitro cytotoxicity and clonogenic...
// Maria Tsoli 1 , Jie Liu Laura Franshaw Han Shen Cecilia Cheng MoonSun Jung 2 Swapna Joshi Anahid Ehteda Aaminah Khan Angel Montero-Carcabosso 3 Pierre J. Dilda 4 Philip Hogg 5 and David S. Ziegler 1, 6 Targeted Therapies Research Program, Children’s Cancer Institute, Lowy Centre, University of New South Wales, Sydney, Australia Experimental Therapeutics Preclinical Drug Delivery Department Oncology, Hospital Sant Joan de Déu, Barcelona, Spain Biophytis, UPMC, BC94, Paris,...
Abstract Background Diffuse intrinsic pontine gliomas (DIPGs) pose a significant challenge as highly aggressive and currently incurable form of pediatric brain cancer, necessitating the development novel therapeutic strategies. Omacetaxine, an FDA-approved protein synthesis inhibitor for treating certain hematological malignancies, was investigated its potential antitumor effects against preclinical DIPG models. Methods We employed primary cultures to study omacetaxine’s cytotoxicity impact...
Abstract Diffuse Midline Gliomas (DMG) are incurable pediatric brain tumors driven by histone mutation H3K27M, globally reducing H3K27 trimethylation altering the epigenome and deregulating gene expression. These mutations often partner with strongly integrated into kinase signaling metabolic alterations, driving aggressive tumor growth many mechanisms which can compensate for one another therefore evade traditional single agent therapies. Copper over-accumulation has been linked to...
Diffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments needed. DIPGs characterized by a mutation in the H3 histone (H3K27M), resulting loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is anticancer agent with preclinical activity demonstrated against range cancers. We examined antitumor DIPG neurosphere cultures observed tumor-specific IC50s ranging from 20 to 100 nmol/L, whereas no was normal human astrocyte cells....
Abstract Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable tumor that primarily arises in the brainstem young children. The H3K27M driver histone mutation and resulting permissive chromatin indicates targeting as key therapeutic strategy against this aggressive cancer. One such target Facilitates Chromatin Transcription (FACT) chaperone. FACT targeted by curaxin compound CBL0137 which currently phase I/II clinical trial for pediatric cancer patients...
Abstract Medulloblastoma is the most common pediatric malignant brain tumor. Polyamines, critical intracellular polycations governing key cell processes such as DNA replication, translation, and proliferation, are frequently upregulated in cancer. We previously showed that polyamine pathway to growth survival of diffuse midline gliomas MYC amplified neuroblastoma. Given activity inhibition DMG, given role medulloblastoma, we sought investigate potential a therapeutic approach for...
Abstract Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target Facilitates Chromatin Transcription (FACT) chaperone. We found FACT enriched at developmental gene promoters, coinciding with regions open chromatin...
Abstract BACKGROUND Polyamines, essential intracellular polycations, govern fundamental cell processes and drive oncogenesis. Our research unveiled the dependency of pediatric Diffuse Midline Gliomas (DMG) on polyamine pathway (Khan et al.,2021). Disruption this with synthesis inhibitor DFMO, transport AMXT1501, potently inhibited DMG tumors, yielding unprecedented survival in-vivo. We hypothesized that dual targeting could similarly suppress growth in other aggressive brain tumors....
Abstract BACKGROUND Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategy against this aggressive cancer. One such target Facilitates Chromatin Transcription (FACT) chaperone. FACT targeted by curaxin compound CBL0137 which currently in Phase I/II Children’s Oncology...
Abstract BACKGROUND Diffuse Midline Glioma (DMG) has a dire prognosis, with mortality rate nearing 100%. In the past, children diagnosed Acute Lymphoblastic Leukemia (ALL) faced similar prognosis until multi-agent chemotherapy revolutionized their survival rates. We hypothesized that implementing comprehensive treatment strategy for DMG could yield efficacy. This study aimed to test safety and efficacy of sequential, intensive, combinations targeting epigenetic/chromatin modification...
Abstract DIPGs are the most devastating of all brain tumors. There no effective treatments, hence almost children will die their tumor within 12 months. is an urgent need for novel therapies this aggressive tumor. We performed a high-throughput drug screen with over 3,500 biologically active, clinically approved compounds against panel neurosphere-forming DIPG cells. identified 7 compounds- auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine- that were confirmed...
Abstract Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumors. There no effective treatments, hence almost children will die their tumor within 12-months. is an urgent need for novel therapies this aggressive tumor. We performed a high-throughput drug screen with over 3,570 biologically active, clinically approved compounds against panel neurosphere-forming DIPG cells. identified 7 - auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and...
<p>SAHA significantly affects alpha acetyl tubulin and HDAC6 levels in DIPG.</p>
<p>SAHA significantly affects alpha acetyl tubulin and HDAC6 levels in DIPG.</p>
<p>Combination of TRX-E-009-1 and SAHA is synergistic against DIPG.</p>
<p>TRX-E-009-1 treatment indicates a change in the cell cycle process DIPG.</p>
<p>Microtubule disruption.</p>