High-grade Pediatric Tumors Research Articles

Abstract 3966: Targeting DNA repair and survival signaling in diffuse intrinsic pontine gliomas to prevent tumor recurrence

Abstract Therapeutic resistance remains a major obstacle in the successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor arising in the brain stem. Currently available therapies do not prevent tumor recurrence in nearly all patients diagnosed with this devastating disease. Innovative combinatorial therapies that penetrate the blood brain barrier and effectively lead to long-term control of tumor growth are desperately needed. Using RNA sequencing, we identified mechanisms of resistance of DIPG to radiotherapy (RT) standard of care. Not surprisingly, RT leads to upregulation of DNA repair and PI3K-mTOR signaling. Our team has rationally designed a brain-penetrant small molecule that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. This molecule, MTX-241F, developed at the University of Michigan, is an excellent candidate to target the compensatory escape mechanisms leading to radioresistance and drug evasion of DIPG. Due to achievement of micromolar levels of MTX-241F in mouse brain tissue, we anticipate that this development candidate will be highly efficacious and considerably more effective than predecessor combination therapies tested against DIPG. Preliminary studies carried out in patient derived DIPG neurospheres show that MTX-241F exhibits promising signs of single agent activity efficacy and radiosensitizing activity in the combination setting. The physiochemical properties of MTX-241F include remarkably high exposure in the brain, indicating efficient blood brain barrier penetrance. Since radiotherapy results in double strand breaks which are repaired by both homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have also tested the combination of MTX-241F with an inhibitor of ATM, to achieve blockade of HR and NHEJ, respectively in the absence or presence of radiotherapy. When the HR blockers were combined with MTX-241F and radiotherapy synthetic lethality was observed in clonogenic assays, providing impetus to explore combination of HR blockers with this novel first-in-class kinase inhibitor and radiotherapy in clinically relevant models of DIPG. In summary, our data provide proof of concept evidence to support the rapid clinical development of MTX-241F for the treatment of DIPG. Future studies have been designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease. Citation Format: Monika Sharma, Rachel Mumby, Varunkumar Krishnamoorthy, Brian Magnuson, Mats Ljungman, Chris Whitehead, Judith Sebolt-Leopold, Stefanie Galban. Targeting DNA repair and survival signaling in diffuse intrinsic pontine gliomas to prevent tumor recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3966.

Abstract 5268: The expression of lemur tyrosine kinase-3 in high grade pediatric tumors

Abstract High grade gliomas are the most common primary brain tumors in adults, but also occur in childhood, with a poor prognosis in all age groups . Lemur tyrosine kinase 3 (LMTK3) is a transmembrane tyrosine kinase that seems to play a pivotal role in oncogenesis in breast cancer. It regulates the estrogen receptor alpha and is evolutionarily selected for in humans compared to non-human primates. LMTK3 expression levels were strongly associated with survival and therapy response.This study assesses the role of LMTK3 in pediatric high grade brain tumors at both the protein and mRNA levels. We initially assessed by immunohistochemistry (IHC) the expression levels of LMTK3 in well described cohorts of patient specimens with brain cancer. First, we performed an IHC analysis using a brain tumor tissue microarray (TMA) purchased from US Biomax (#T175), in order to examine the LMTK3 levels in a variety of brain tumors. Preliminary analysis revealed variable LMTK3 expression levels in brain tissue, scored as negative, low, moderate and high. We demonstrate that LMTK3 appears to be expressed at low levels at normal brain tissue samples and epithelial meningioma tissues (benign tumors). On the contrary, LMTK3 was expressed at different levels in cases with grade 2 or grade 4 gliomas. Further immunohistochemical analysis was therefore undertaken on a selection of TMAs containing pediatric high grade gliomas. Genome wide gene expression analysis (using the Affymetrix U133plus2 chip) previously undertaken on a cohort of pediatric high grade gliomas demonstrated measurable LMTK3 mRNA expression in many samples. Our preliminary analysis was correlated with various tumor characteristics that are available in Nottingham datasets (including demographic and overall survival data). In conclusion, LMTK3 is expressed in pediatric high grade gliomas and may have differential expression depending on the histological grade of the tumor. This work will lead to larger scale studies to elucidate the exact role of LMTK3 in high grade brain neoplasms. Citation Format: Nektarios K. Mazarakis, Stuart Smith, Aikaterini Vraka, Donald Macarthur, Richard Grundy, Justin Stebbing, George Giamas. The expression of lemur tyrosine kinase-3 in high grade pediatric tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5268. doi:10.1158/1538-7445.AM2014-5268

Conventional magnetic resonance imaging in the differentiation between high and low-grade brain tumours in paediatric patients

ObjectiveIt has been described that hyperintensity in diffusion-weighted imaging (DWI) correlates with high-grade tumours, and high signal-intensity in T2-weighted (T2w) images identifies low-grade tumours. We aimed to investigate the potential of routine conventional MRI sequences, such as DWI and T2-w, to pre-operatively distinguish between low-grade and high-grade brain tumours in paediatric patients. Material and methodsTwo raters, blinded to the histological diagnosis, rated the aspect and signal intensity of MR images (T2w and DWI) from 37 children with newly diagnosed brain tumours. Histological diagnoses included 18 low-grade and 19 high-grade brain tumours. ResultsThe inter-rater agreement was 81–95%. High-grade tumours were never hypointense on DWI and low-grade tumours were usually hyperintense on T2w. Specificity was 100% for low-grade tumours and 90% for high-grade tumours. About 95% of the high-grade tumours and about 70% of the low-grade tumours were correctly diagnosed. ConclusionThe combination of general morphological aspect of the tumours and signals on T2-w and DWI yield a high accuracy of pre-operative differentiation between low-grade and high-grade paediatric tumours.

Differentiation between high and low grade tumours in paediatric patients by using apparent diffusion coefficients

ObjectiveThis study was performed to confirm the hypothesis that pre-operative apparent diffusion coefficient (ADC) can be used to distinguish between “low grade” and “high grade” tumours in paediatric patients. Material and methodsADC values were retrospectively evaluated in thirty-six paediatric brain tumours. Twenty-one children with low grade brain tumours (12 WHO I astrocytomas, 1 giant cell tumour, 1 pilomyxoid astrocytoma, 4 WHO II astrocytomas, 2 craniopharyngiomas and 1 ganglioglioma) and 15 children with high grade brain tumours (6 medulloblastomas, 3 WHO III ependymomas, 1 PNET, 1 malignant rhabdoid tumour, 1 malignant germ cell tumour, 1 WHO III astrocytoma, 1 WHO IV astrocytoma, 1 rhabdomyosarcoma metastasis) were included in this study. Minimum and mean ADC values were compared between low grade and high grade tumours and cut-off values were evaluated. ResultsThe cut-off values to differentiate low and high grade paediatric brain tumours were 0.7 × 10−3 mm2/s and 1.0 × 10−3 mm2/s for minimum ADC and average ADC values respectively. All but one high grade infratentorial ependymoma showed significantly lower ADC values than low grade brain tumours in children. ConclusionCombining the information obtained from conventional MR imaging with the ADC values may increase the accuracy of pre-operative differentiation between low grade and high grade paediatric tumours. Cut-off values can help to discern low from high grade tumours. However, it has to be considered that there is a substantial overlap between tumour types previously described in the literature.

Low-grade recurrence of a congenital high-grade supratentorial tumor with astrocytic features in the absence of adjuvant therapy

The biological behavior of pediatric gliomas and embryonal tumors can be highly variable. A few case reports have described differentiation of primitive neuroectodermal tumors (PNETs) and medulloblastomas, presumably induced by adjuvant chemotherapy and/or radiation. Herein we describe a case of a congenital supratentorial high-grade tumor with astrocytic features that, after near-total surgical resection, was not treated with adjuvant therapies. Thirteen years later the patient presented with recurrent tumor at the original surgical site. The recurrent tumor had completely different morphology compared to the original, with evidence of ganglion cell differentiation and changes more reminiscent of a low-grade pleomorphic xanthoastrocytoma. To the authors' knowledge, this is the first documented case of an untreated high-grade pediatric tumor that spontaneously differentiated into a low grade tumor. The clinical and biological implications of this are briefly discussed.