34 results match your criteria: "UNSW Centre for Childhood Cancer Research[Affiliation]"

Single-nucleotide variants (SNVs) are extremely prevalent in human cancers, although most of these remain clinically unactionable. The programmable RNA nuclease CRISPR-Cas13 has been deployed to specifically target oncogenic RNAs. However, silencing oncogenic SNVs with single-base precision remains extremely challenging due to the intrinsic mismatch tolerance of Cas13.

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Patient-Specific Circulating Tumor DNA for Monitoring Response to Menin Inhibitor Treatment in Preclinical Models of Infant Leukemia.

Cancers (Basel)

November 2024

Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW 2052, Australia.

Background: In infant ()-rearranged (MLL-r) acute lymphoblastic leukemia (ALL), early relapse and treatment response are currently monitored through invasive repeated bone marrow (BM) biopsies. Circulating tumor DNA (ctDNA) in peripheral blood (PB) provides a minimally invasive alternative, allowing for more frequent disease monitoring. However, a poor understanding of ctDNA dynamics has hampered its clinical translation.

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PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia.

Nat Commun

November 2024

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models.

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Lessons learned from 20 years of preclinical testing in pediatric cancers.

Pharmacol Ther

December 2024

RTI International, Research Triangle Park, NC, United States of America.

Programs for preclinical testing of targeted cancer agents in murine models of childhood cancers have been supported by the National Cancer Institute (NCI) since 2004. These programs were established to work collaboratively with industry partners to address the paucity of targeted agents for pediatric cancers compared with the large number of agents developed and approved for malignancies primarily affecting adults. The distinctive biology of pediatric cancers and the relatively small numbers of pediatric cancer patients are major challenges for pediatric oncology drug development.

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The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia.

Blood Cancer J

November 2024

Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs.

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Variants that alter gene splicing are estimated to comprise up to a third of all disease-causing variants, yet they are hard to predict from DNA sequencing data alone. To overcome this, many groups are incorporating RNA-based analyses, which are resource intensive, particularly for diagnostic laboratories. There are thousands of functionally validated variants that induce mis-splicing; however, this information is not consolidated, and they are under-represented in ClinVar, which presents a barrier to variant interpretation and can result in duplication of validation efforts.

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Article Synopsis
  • Hypomethylating agents (HMAs) are key treatments for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML), but patients often develop resistance and experience treatment failure.
  • Researchers conducted a genome-wide CRISPR-Cas9 screen in MDS-derived cells, discovering that targeting the gene TOPORS enhances the effectiveness of HMAs by making cancer cells more vulnerable to DNA damage.
  • The study suggests that combining HMAs with strategies to inhibit SUMOylation or TOPORS could be an effective treatment approach for patients with high-risk MDS or AML, without harming normal blood cell production.
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  • MYCN oncogene amplification is linked to aggressive childhood neuroblastoma, but a study found a germline mutation in Runx1t1 that can prevent tumor development associated with MYCN.
  • This mutation affects a conserved zinc finger domain and reduces the risk of neuroblastoma by inhibiting cell growth and reversing hyperplasia, which is a precursor to tumor formation.
  • RUNX1T1 is part of a transcriptional repression complex that impacts chromatin accessibility without directly regulating MYCN, and its silencing affects other cancers, indicating its broader significance in tumor biology.
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Article Synopsis
  • Recent research indicates that precision medicine is effective in developing new treatment options for childhood cancers, specifically for high-risk patients with a low expected cure rate.
  • In a study involving 384 patients, 67% received recommendations for precision-guided treatment (PGT), leading to a 36% objective response rate and better 2-year progression-free survival compared to standard treatments.
  • The most significant benefits from PGT were observed in cases targeting specific genetic markers and when treatment started before disease progression.
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Functional precision medicine for pediatric cancers.

Nat Med

April 2024

Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, New South Wales, Australia.

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translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression.

Haematologica

August 2024

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025.

Article Synopsis
  • ETV6::ACSL6 is a rare genetic alteration found in blood cancers, frequently linked to severe eosinophilia, which worsens the prognosis and demands extra anti-inflammatory treatments.
  • Research utilizing multi-omics approaches on leukemia cells from a patient revealed that a super-enhancer within the ETV6 gene locus is activated due to the translocation associated with ETV6::ACSL6, leading to the production of inflammatory factors like IL-3.
  • The study found that using a BET inhibitor alongside standard treatments successfully reduced IL-3 levels and suppressed leukemia growth, suggesting potential new strategies for treating this difficult subtype of acute lymphoblastic leukemia.
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Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound.

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Targeted delivery of polo-like kinase 1 siRNA nanoparticles using an EGFR-PEG bispecific antibody inhibits proliferation of high-risk neuroblastoma.

J Control Release

March 2024

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; UNSW Australian Centre for Nanomedicine, Faculty of Engineering, UNSW, Sydney, NSW 2052, Australia; School of Clinical Medicine, Faculty of Medicine & Health, UNSW, Sydney, NSW 2052, Australia; UNSW RNA Institute, Faculty of Science, UNSW, Sydney, NSW 2052, Australia. Electronic address:

High-risk neuroblastoma has poor survival due to treatment failure and off-target side effects of therapy. Small molecule inhibitors have shown therapeutic efficacy at targeting oncogenic cell cycle dysregulators, such as polo-like kinase 1 (PLK1). However, their clinical success is limited by a lack of efficacy and specificity, causing off-target toxicity.

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amplification occurs in approximately 20-30% of neuroblastoma patients and correlates with poor prognosis. The transgenic mouse model mimics the development of human high-risk neuroblastoma and provides strong evidence for the oncogenic function of MYCN. In this study, we identified mitotic dysregulation as a hallmark of tumor initiation in the pre-cancerous ganglia from mice that persists through tumor progression.

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An antibody fragment-decorated liposomal conjugate targets Philadelphia-like acute lymphoblastic leukemia.

Int J Biol Macromol

January 2024

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. Electronic address:

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is an aggressive B-ALL malignancy associated with high rates of relapse and inferior survival rate. While targeted treatments against the cell surface proteins CD22 or CD19 have been transformative in the treatment of refractory B-ALL, patients may relapse due to antigen loss, necessitating targeting alternative antigens. Cytokine receptor-like factor 2 (CRLF2) is overexpressed in half of Ph-like ALL cases conferring chemoresistance and enhancement of leukemia cell survival.

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Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting.

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Background: Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy with over 80% of cases already disseminated at diagnosis and facing a dismal five-year survival rate of 35%. EOC cells often spread to the greater omentum where they take-up cholesterol. Excessive amounts of cholesterol can be cytocidal, suggesting that cholesterol efflux through transporters may be important to maintain homeostasis, and this may explain the observation that high expression of the ATP-binding cassette A1 (ABCA1) cholesterol transporter has been associated with poor outcome in EOC patients.

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Patients whose leukemias harbor a rearrangement of the (/) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target -rearranged (KMT2A-r) leukemia cells.

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Article Synopsis
  • * The Th-MYCN mouse model is key for studying neuroblastoma, featuring the human MYCN gene and demonstrating similarities in tumor characteristics to human cases.
  • * Understanding the pathology of these mouse models is essential for research validity, allowing for better experiment design and more reliable comparisons across studies.
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Background: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA.

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Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting.

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Background: The prognosis for high-risk childhood acute leukaemias remains dismal and established treatment protocols often cause long-term side effects in survivors. This study aims to identify more effective and safer therapeutics for these patients.

Methods: A high-throughput phenotypic screen of a library of 3707 approved drugs and pharmacologically active compounds was performed to identify compounds with selective cytotoxicity against leukaemia cells followed by further preclinical evaluation in patient-derived xenograft models.

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B-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response of luciferase-positive LOUCY cells to ABT-199 monotherapy and observed specific residual disease in the splenic microenvironment.

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Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is characterized by aberrant activation of signaling pathways and high risk of relapse. Approximately 50% of Ph-like ALL cases overexpress cytokine receptor-like factor 2 (CRLF2) associated with gene rearrangement. Activated by its ligand thymic stromal lymphopoietin (TSLP), CRLF2 signaling is critical for the development, proliferation, and survival of normal lymphocytes.

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