Arginine depletion potentiates standard-of-care chemo-immunotherapy in preclinical models of high-risk neuroblastoma.

Background: Dysregulated amino acid metabolism creates cancer-specific vulnerabilities. Neuroblastoma tumors have dysregulated arginine metabolism that renders them sensitive to systemic arginine deprivation. Arginase therapy has been proposed as a therapeutic approach for neuroblastoma treatment and has a favorable safety profile in pediatric cancer patients, however optimal therapeutic combinations remain unexplored.

The cell-permeable iron chelator M606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response.

Despite Myc oncoproteins being major causal factors in human cancer, they remain "undruggable." The oncogene is one of the most powerful prognostic markers for the childhood cancer neuroblastoma and represents an important target for developing novel therapeutics. Here, we report the finding and characterization of M606, a selective small molecule inhibitor of MYCN, which was identified by screening a diverse chemical library.

Polyamine depletion limits progression of acute leukaemia.

Cancer cells are addicted to polyamines, polycations essential for cellular function. While dual targeting of cellular polyamine biosynthesis and polyamine uptake is under clinical investigation in solid cancers, preclinical and clinical studies into its potential in haematological malignancies are lacking. Here we investigated the preclinical efficacy of polyamine depletion in acute leukaemia.

The polyamine transporter ATP13A3 mediates difluoromethylornithine-induced polyamine uptake in neuroblastoma.

High-risk neuroblastomas, often associated with MYCN protooncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have previously shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), and this mechanism is thought to limit the efficacy of the drug in clinical trials. This finding resulted in the clinical development of polyamine transport inhibitors, including AMXT 1501, which is presently under clinical investigation in combination with DFMO.

Spatial profiling of endoplasmic reticulum stress markers in tumor associated cells predicts patient outcomes in pancreatic cancer.

Introduction: The impact of endoplasmic reticulum (ER) stress in tumor-associated cells, such as cancer associated fibroblasts (CAFs), immune cells and endothelial cells, on patient outcomes in clinical specimens have not been examined. For the first time, we characterized the expression and spatial locations of ER stress markers, BiP and CHOP, in tumor-associated cells and assessed their prognostic significance in a panel of pancreatic ductal adenocarcinoma (PDAC) patient samples.

Methods: Multiplex immunofluorescence was performed on tumor microarrays and images were analyzed using HALO AI software.

Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.

Background: The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy.

Methods: We performed a high-throughput, combination chromatin-modifier drug screen against NB cells.

FDA-approved disulfiram as a novel treatment for aggressive leukemia.

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.

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

Background: MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan.

Methods: Patients 2-30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m/day, with celecoxib (500 mg/m daily), cyclophosphamide (250 mg/m/day) and topotecan (0.

Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia.

High-risk childhood leukemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells.

Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma.

Gene expression noise is known to promote stochastic drug resistance through the elevated expression of individual genes in rare cancer cells. However, we now demonstrate that chemoresistant neuroblastoma cells emerge at a much higher frequency when the influence of noise is integrated across multiple components of an apoptotic signaling network. Using a JNK activity biosensor with longitudinal high-content and in vivo intravital imaging, we identify a population of stochastic, JNK-impaired, chemoresistant cells that exist because of noise within this signaling network.

Inflammatory response to retrotransposons drives tumor drug resistance that can be prevented by reverse transcriptase inhibitors.

Activation of endogenous retrotransposons frequently occurs in cancer cells and contributes to tumor genomic instability. To test whether inhibition of retrotranspositions has an anticancer effect, we used treatment with the nucleoside reverse transcriptase inhibitor (NRTI) stavudine (STV) in mouse cancer models, MMTV-HER2/Neu and Th-MYCN, that spontaneously develop breast cancer and neuroblastoma, respectively. In both cases, STV in drinking water did not affect tumor incidence nor demonstrate direct antitumor effects.

Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.

The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells.

The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression.

Rearrangements of the () gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models.

Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.

Background: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers.

Methods: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1.

Suppression of the ABCA1 Cholesterol Transporter Impairs the Growth and Migration of Epithelial Ovarian Cancer.

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.

Systematic Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia.

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.

GSH facilitates the binding and inhibitory activity of novel multidrug resistance protein 1 (MRP1) modulators.

MRP1 (ABCC1) is a membrane transporter that confers multidrug resistance in cancer cells by exporting chemotherapeutic agents, often in a reduced glutathione (GSH)-dependent manner. This transport activity can be altered by compounds (modulators) that block drug transport while simultaneously stimulating GSH efflux by MRP1. In MRP1-expressing cells, modulator-stimulated GSH efflux can be sufficient to deplete GSH and increase sensitivity to chemotherapy, enhancing cancer cell death.

In vitro and in vivo drug screens of tumor cells identify novel therapies for high-risk child cancer.

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found.

Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma.

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.

Immunometabolism: A 'Hot' Switch for 'Cold' Pediatric Solid Tumors.

Despite the success of immunotherapies in adult solid cancers and pediatric hematological malignancies, limited progress has been made towards implementing these strategies in pediatric solid tumors. These tumors exhibit a high potential to escape antitumor immunity, making them difficult to target by current immunotherapies. This review highlights the altered metabolic pathways in pediatric solid tumors that promote immune escape, and discusses current novel strategies targeting these pathways.

Cell-Based Methods for the Identification of Myc-Inhibitory Small Molecules.

Oncoproteins encoded by dominant oncogenes have long been considered as targets for chemotherapeutic intervention. However, oncogenic transcription factors have often been dismissed as "undruggable." Members of the Myc family of transcription factors have been identified as promising targets for cancer chemotherapy in multiple publications reporting the requirement of Myc proteins for maintenance of almost every type of tumor.