Immunotherapy approaches for the treatment of diffuse midline gliomas.

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis.

Correction: HDAC6 inhibitor WT161 downregulates growth factor receptors in breast cancer.

[This corrects the article DOI: 10.18632/oncotarget.19019.

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.

H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts.

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).

We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1.

Gliomas in Children.

Gliomas are the most common primary central nervous system (CNS) neoplasms in children and adolescents and are thought to arise from their glial progenitors or stem cells. Although the exact cells of origin for most pediatric gliomas remain to be identified, our current understanding is that specific cell populations during CNS development are susceptible to particular oncogenic events during certain time windows and thus give rise to pediatric gliomas with distinct histological, molecular, and clinical features. These may be roughly segregated into low-grade gliomas (WHO grades I or II; including most mixed glial-neuronal tumors) and high-grade gliomas (WHO grades III or IV) according to their clinical course when untreated, even though this is not yet entirely clear for some of the recently emerging groups.

HDAC6 inhibitor WT161 downregulates growth factor receptors in breast cancer.

We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines.

Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood.

Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand.

Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq.

Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation.

Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma.

Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures.

Solid Cancers in the Premature and the Newborn: Report of Three National Referral Centers.

Background: Advances in multidisciplinary care for pediatric cancer have resulted in significant improvement in cure rates over the last decades; however, these advances have not been uniform across all age groups. Cancer is an important cause of perinatal mortality, yet the full spectrum of malignant neoplasms in newborns is not well defined.

Methods: The authors have reviewed the clinical features and outcomes of 37 newborns with congenital malignant tumors treated at three referral centers in North, Central, and South Poland between 1980 and 2014.

Management and follow-up of Ewing sarcoma patients with isolated lung metastases.

Background: Ewing sarcoma (ES) is the second most common pediatric malignant bone tumor with a wide spectrum of clinical presentations. Although metastatic disease to the lungs is often the cause of death, isolated lung metastases at diagnosis are not frequent. The specific role of chemotherapy, surgery, and lung radiation has not been clearly defined.

Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation.

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of "second-generation" ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance.

Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients.

Regulation of mitochondrial ceramide distribution by members of the BCL-2 family.

Apoptosis is an intricately regulated cellular process that proceeds through different cell type- and signal-dependent pathways. In the mitochondrial apoptotic program, mitochondrial outer membrane permeabilization by BCL-2 proteins leads to the release of apoptogenic factors, caspase activation, and cell death. In addition to protein components of the mitochondrial apoptotic machinery, an interesting role for lipids and lipid metabolism in BCL-2 family-regulated apoptosis is also emerging.

Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.

Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment.

Intrinsic susceptibility MRI identifies tumors with ALKF1174L mutation in genetically-engineered murine models of high-risk neuroblastoma.

The early identification of children presenting ALK(F1174L)-mutated neuroblastoma, which are associated with resistance to the promising ALK inhibitor crizotinib and a marked poorer prognosis, has become a clinical priority. In comparing the radiology of the novel Th-ALK(F1174L)/Th-MYCN and the well-established Th-MYCN genetically-engineered murine models of neuroblastoma using MRI, we have identified a marked ALK(F1174L)-driven vascular phenotype. We demonstrate that quantitation of the transverse relaxation rate R2* (s(-1)) using intrinsic susceptibility-MRI under baseline conditions and during hyperoxia, can robustly discriminate this differential vascular phenotype, and identify MYCN-driven tumors harboring the ALK(F1174L) mutation with high specificity and selectivity.

Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance.

Purpose: To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion.

Experimental Design: We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed.

Results: Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival.

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy.

Histone deacetylase (HDAC) inhibitors (HDACis) are well-characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome-associated myeloid leukemia (DS-AMKL) blasts.

Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities.

In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma.

SYK regulates mTOR signaling in AML.

Spleen tyrosine kinase (SYK) was recently identified as a new target in acute myeloid leukemia (AML); however, its mechanistic role in this disease is poorly understood. Based on the known interaction between SYK and mammalian target of rapamycin (mTOR) signaling in lymphoma, we hypothesized that SYK may regulate mTOR signaling in AML. Both small-molecule inhibition of SYK and SYK-directed shRNA suppressed mTOR and its downstream signaling effectors, as well as its upstream activator, AKT.

Male reproductive health after childhood, adolescent, and young adult cancers: a report from the Children's Oncology Group.

The majority of children, adolescents, and young adults diagnosed with cancer will become long-term survivors. Although cancer therapy is associated with many adverse effects, one of the primary concerns of young male cancer survivors is reproductive health. Future fertility is often the focus of concern; however, it must be recognized that all aspects of male health, including pubertal development, testosterone production, and sexual function, can be impaired by cancer therapy.

Tumor histology during induction therapy in patients with high-risk neuroblastoma.

Background: In high-risk neuroblastoma patients, response to induction chemotherapy is emerging as an important determinant of overall survival. We sought to determine whether histological changes in the primary tumor following induction therapy could be used as a marker of response.

Procedure: Second-look primary tumor specimens from 43 patients were reviewed according to specific morphological features.

Targeting NOTCH1 in hematopoietic malignancy.

NOTCH1 is a well-validated target in hematopoietic malignancy, with NOTCH1 activating mutations identified in more than 50% of T-cell acute lymphoblastic leukemias. Moreover, a recent report has identified NOTCH1 activating mutations in 12% of chronic lymphocytic leukemias. While the frequency of NOTCH1 mutations and the well-documented role of this protein in the pathogenesis and maintenance of T-ALL support targeting NOTCH1 as a therapeutic strategy, the critical role of this protein in normal cell-fate specification and differentiation lead to complexities in its successful targeting.

Zebrafish as a model for the study of human cancer.

Zebrafish provide an exciting animal model system for the study of human cancers. During the last few years many zebrafish models of cancer have been generated that recapitulate human hematologic malignancies and solid tumors. Concurrent technological advances have significantly improved the genetic tractability and unique advantage of in vivo imaging in zebrafish, providing a means to dissect the molecular pathways underlying tumor initiation, progression and metastasis.

Emerging importance of ALK in neuroblastoma.

Since the original descriptions of gain-of function mutations in anaplastic lymphoma kinase (ALK), interest in the role of this receptor tyrosine kinase in neuroblastoma development and as a potential therapeutic target has escalated. As a group, the activating point mutations in full-length ALK, found in approximately 8% of all neuroblastoma tumors, are distributed evenly across different clinical stages. However, the most frequent somatic mutation, F1174L, is associated with amplification of the MYCN oncogene.