bluuebunny/crossref_metadata_2025 huggingface dataset:
LGG-54. PEDIATRIC LOW-GRADE GLIOMAS TREATED WITH MEK INHIBITORS
Authors: Fraustro Milena , Maddox Breyonna , Valdes Lilibet Fernandez , Lopez Elizabeth , Niazi Toba , Maher Ossama , Khatib Ziad
Published: June 2024

BACKGROUND

Low-grade gliomas (LGG) represent the most common brain tumor in children. It is well known that these tumors present mutations involving the BRAF gene, causing activation of the MAPK/ERK pathway. MEK inhibitors have now become an important treatment option over the recent years, slowing the growth of cancer cells.

METHODS

Retrospective analysis of 23 patients with LGG that were treated with MEK inhibitors at Nicklaus Children’s Hospital between 2015-2022.

RESULTS

Of the 23 patients; 6 were males and 17 were females, with a median age at diagnosis of 9.5 years of age. BRAF V600E mutation was present in 52% of patients (9/17). Other mutations found were: BRAF, BRAF KIAA1549, p.Q61K, and FGFR. Six patients had known associations with NF1. 7 of 23 patients had not received any prior treatment before MEK therapy, 8 underwent partial or total resection only prior, 4 had previous chemotherapy treatment, 3 underwent resection with chemotherapy, and 1 patient had both chemotherapy and proton radiation prior to MEK therapy. Targeted therapies included Trametinib (17/23), Dabrafenib (9/23), Selumetinib (5/23), and Binimetinib (1/23). Of the 9 patients with BRAF V600E mutation, 7/9 were given dual targeted therapies whereas only two were treated with only one inhibitor. The average length of therapy was one year. Most reported side effects were dermatologic manifestations such as dry skin or acne (9/23). Five patients showed objective improvement, 16 patients had stable residual disease, one had local recurrence, and one patient expired. Currently 12 patients are off therapy and 10 remain on treatment. Of the patients with BRAF V600E mutation, 4 had clinical and/or radiologic response, 1 patient expired due to disease progression and 1 has stable disease.

CONCLUSION

MEK inhibitors as a treatment of pediatric low-grade gliomas demonstrated promise as a therapeutic approach, so far proving to slow progression of disease in some cases. However, long-term side effects and toxicity remain unknown. Further large-scale prospective analysis would be helpful in future studies.
LGG-59. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR; MOLECULAR IMPLICATIONS ON PROGNOSIS
Authors: Munir Faryal , He Jiasen , Stitzlein Lea M , Chen Melissa , McAleer Mary F , McGovern Susan , Paulino Arnold , Friedman Gregory K , Sandberg David , Zaky Wafik
Published: June 2024

BACKGROUND

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are extremely rare tumors that were first described in the WHO Classification in 2016. While usually considered low-grade tumors, DLGNTs currently lack a standard of care as well as literature on molecular profiling and treatment responses.

METHODS

Retrospective review of pediatric DLGNTs seen at MD Anderson Cancer Center with Institutional Board Review approval.

RESULTS

Twelve patients with a histopathological and neuroradiological diagnosis of DLGNT were identified with a median age at diagnosis of 7.5 years (range 4 months – 21 years). Histologically, 10/12 (83%) tumors were low-grade while 2 were reported as high-grade. BRAF gene alterations were reported in 50% (6/12; 4 fusions and 2 mutations). Other reported genetic alterations were mutations [PTPN11 (n=2), PIK3CA (n=1), FGFR1 (n=1), ALK (n=1)], amplifications [NOTCH1 (n=1) and STK11(n=1)], and fusion [NTRK (n=1)]. Upfront, 9 patients received chemotherapy including temozolomide (n=5), carboplatin (n=4), and vincristine (n=4) or vinblastine (n=1). Nine patients (88%) received proton radiation, including 5 upfront and 4 upon progression. Targeted therapy [NTRK (n=1), BRAF (n=1) or MEK inhibitors (n=6)] was initiated upon progression in 8 patients, and at diagnosis in one. The median progression-free survival (PFS) in the group receiving upfront chemoradiation (n=3) is 57 months versus chemotherapy alone (n=6) of 30.5 months, and 26.7 months for radiotherapy alone (n=3). The PFS at 2 years and 5 years were 58.3% and 17% respectively; OS was 100% at both time intervals. BRAF genetic alterations and younger age trended toward a worse outcome, hence upfront targeted therapy may be warranted when radiation needs to be avoided.

CONCLUSION

In our experience, DLGNTs are more commonly low-grade with frequent BRAF gene alterations; upfront chemoradiation provided the longest PFS compared to chemotherapy or radiation alone. In the absence of established standard of care, our case series emphasizes the potential role of targeted therapy upfront for younger patients and progressive disease post-chemoradiation. Larger prospective, collaborative studies are greatly needed for DLGNTs.
MDB-02. RECURRNET SPINAL DESMOID FIBROMATOSIS IN A CHILD WITH APC GERMLINE MUTATION-RELATED MEDULLOBLASTOMA
Authors: Mobarak Nahla Aly , Balbaid Ali Abdullah O , Alotabi Fahad , AlMalki Salman A , Alyamna Basma , Alharbi Musa
Published: June 2024

BACKGROUND

Familial adenomatous polyposis (FAP) is an autosomal-dominant dominant Familial Cancer Syndrome FCs Caused by Germline inactivation of adenomatous polyposis coli (APC) tumor suppressor gene, results in up-regulation of the WNT signaling pathway which increases the risk of colorectal cancer CRC, colon polyposis and extracolonic tumors like gastric and duodenal carcinomas WNT-activated Medulloblastoma MBL and Desmoid fibromatosis (DF) DF are locally aggressive soft tissue tumors with high local recurrence rates after Surgical excision role of adjuvant chemotherapy or Radiotherapy is still unclear.

METHODS

A 6-year-old boy product of non-consanguineous marriage with positive family HX brain tumor Diagnosed with Non-Metastatic Average Risk MBL WHO grade IV classic histology, he had craniotomy and Gross tumor resection followed by craniospinal irradiation at 23.4 Gy, plus a boost to posterior fossa/tumor bed up to 54 Gy, followed by 8 maintenance chemotherapy cycles as HIT-MED protocol Cisplatin/VCR/CCNU total. 3 years post end of therapy the pateint was in complete remission from MBL when routing MRI surveillance showed a new left paravertebral muscle lesion within the irradiation field from T1 to T4 levels which progressed gradually over a short follow-up time he had surgical resection of the tumor with Pathological diagnosis of Desmoid fibromatosis. after six months he had a second recurrence of the spinal tumor that needed a second surgical resection. Result: positive Genetic testing for Germline pathogenic mutation of APC gene exons 7 to 16 confirmed the diagnosis of autosomal familial adenomatous polyposis type 1(FAP1). Up to date, he is stable on endoscopic and MRI surveillance with radiological evidence of slow progression of the paraspinal tumor

CONCLUSION

Medulloblastomas associated with APC germline mutation have favorable outcomes that may need de-escalating therapeutic protocol with reduced intensity craniospinal irradiation aiming to reduce the incidence of secondary tumors after adjuvant treatment for MBL
MDB-03. MEDULLOBLASTOMA AT RELAPSE: FOR WHICH PATIENTS AND WHICH TUMORS REIRRADIATION IS THE BETTER CHOICE
Authors: Massimino Maura , Vennarini Sabina , Buttarelli Francesca Romana , Antonelli Manila , Minasi Simone , Pecori Emilia , Giussani Carlo , Trezza Andrea , Schiavello Elisabetta , Biassoni Veronica , Erbetta Alessandra , Chiapparini Luisa , Nigro Olga , Gianno Francesca , Miele Evelina , Modena Piergiorgio , Dossena Chiara , De Cecco Loris , Pollo Bianca , Barretta Francesco
Published: June 2024

BACKGROUND

First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not yet standardized. We report the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups.

METHODS

Patient’s staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported.

RESULTS

Between 2002 and 2019, relapsing patients were 25, median age at diagnosis 11.4 years, 8 had metastases, three LC/A histotype. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors (6 TP53 mutated,1 + MYC and 1 + NMYC amplification), 11 non-WNT/non-SHH (2 with MYC/MYCN amplification). Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in 9, distant-DR in 14, LR+DR in two) was 26 months. Fourteen patients were re-operated, in 5 excising single DR-sites, thereafter 3 received CT, two after re-RT; out of 11 not re-operated patients, 4 had re-RT as first treatment and 7 after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, CSI in 5, never resulting in radionecrosis. Median post-relapse-PFS/after re-RT were 16.7/8.2 months, while overall survival-OS were 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. MYC,MYCN,P53 status and molecular subgroups, RT extension/fractionation, gender and age were not statistically prognostic; in the multivariable model, OSs were positively influenced by longer intervals before re-RT, re-surgery and not-SHH subgroups (P=0.019 from recurrence and 0.004 from second RT).

CONCLUSIONS

Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belonged to SHH-subgroup.
MDB-08. MYC AND TGFΒ PROMOTE GROUP 3 MEDULLOBLASTOMA TUMOR RESISTANCE THROUGH DEREGULATION OF POLYCOMB TARGETS
Authors: Qadeer Zulekha A , Westelman Samantha , Johnson Mackenzie O , Hou Elise , Grele Shane , Smith Kyle , Hendrikse Liam , Siegel Dara , Wang Linyu , Beytagh Mary Clare , Schmidt Christin , Huang Miller , Taylor Michael D , Northcott Paul , Weiss William A
Published: June 2024

Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at <50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated new humanized models for G3MB by transforming neuroepithelial stem cells (NESC) derived from human induced pluripotent stem cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. Excitingly, both MYC and TGFβ effectors drove tumor formation in vivo with the combination of TGFβ effectors and MYC leading to more aggressive tumors. Moreover, NESC-derived tumors clustered with human G3/G4MB samples, indicating our models recapitulates human disease. We next found that NESCs expressing MYC with either TGFβR1 or TGFβ1 showed resistance to clinical TGFβR1 inhibitors, compared to cells driven by either TGFβR1 or TGFβ1 alone. To decipher mechanisms of resistance, we integrated CUT&RUN to probe for MYC genomic localization and relevant histone PTMs with RNA-seq analysis and discovered a subset of genes upregulated in MYC and TGFβ-driven lines that are targets of the histone demethylase KDM2B and Polycomb Repressive Complex 2 (PRC2) member SUZ12. Moreover, we found that MYC is bound to regions normally regulated by PRC interactors. We postulate that chromatin remodeling via MYC and recruitment of other MYC-interacting cofactors to PRC targets culminates in transcriptional changes that lead to aggressive disease. Work from others suggests that PRC-mediated chromatin regulation is critical in many adult and pediatric brain tumors, underscoring its significance in MB. Our studies provide important insight on identifying new therapeutic avenues with a focus on the epigenetic landscape for patients with MYC and TGFβ driven G3MB.
MDB-09. WNT AND GROUP 4 MEDULLOBLASTOMAS OF EARLY CHILDHOOD TREATED WITH HIGH DOSE CHEMOTHERAPY AND CRANIOSPINAL IRRADIATION SPARING APPROACH
Authors: Cansanay Rose Daynielle , Erker Craig , Ratterman Erin , Schlosser Mary Pat , Ronsley Rebecca , Cacciotti Chantel , Hukin Juliette , Cheng Sylvia , Pillay-Smiley Natasha , Magimairajan Vanan , Cluster Andrew , Abdelbaki Mohamed S , Margol Ashley , Michael George , Chi Susan , Salloum Ralph , Ramaswamy Vijay , Zapotocky Michal , Lopez Vicente Santa Maria , Toledano Helene , Dorris Kathleen , Mynarek Martin , Rutkowski Stefan , Lassaletta Alvaro , Bouffet Eric , Lafay-Cousin Lucie
Published: June 2024

BACKGROUND

WNT and group 4 medulloblastoma (MB) are rare in young children and their outcome when treated with radiation avoidance infant strategies is unknown.

METHOD

This retrospective international cohort included children less than 7 years of age, with molecularly characterized group 4 or WNT MB, treated with high-dose chemotherapy(HDC) and CSI sparing approach.

RESULTS

The current cohort includes 29 patients (19M/10F). For the 26 patients with group 4 MB (median age at diagnosis 45.9 months), 16 (61.5%) were M0 and 17 (65.3%) underwent initial gross total resection (GTR). The most common consolidation regimen used was three cycles of high dose carboplatin and thiotepa (65.5%) or a single cycle of high dose of carboplatin, etoposide and thiotepa (31%).Two received adjuvant focal radiotherapy. Sixteen patients (61.5%) relapsed at a median time of 21.4 months from diagnosis (median age of 5.2 years). Relapse was local for 50% of the patients. One patient underwent palliative management and 15 received radiation-based salvage therapy (2 focal, 13 CSI+/- boost).The median dose of CSI was 36Gy (18-36). Five of the 15 died of disease. Overall, at a median follow-up of 37.9 months from diagnosis, 17/26 (65.3%) patients were alive, six had died of disease and two of toxicity. All 3 WNT patients (median age at diagnosis 57.8 months) underwent GTR and two were M0. Two received sequential high dose carboplatin and thiotepa. One patient with initial partial response, progressed 2 months after treatment completion and received salvaged CSI (18Gy). All of them were alive at a median follow up of 88 months from diagnosis.

CONCLUSIONS

HDC and CSI sparing approaches led to a high rate of relapse for young patient with group 4 (61.5%). However, 2/3 were salvaged with radiation-based therapy given at a median age 5.2 yrs. Additional WNT patients are needed to better describe their management.
MDB-16. CLINICAL AND MOLECULAR CHARACTERISTICS OF JAPANESE MEDULLOBLASTOMA, WNT-ACTIVATED
Authors: Go Kohichi , Katsuma Asako , Makino Yasuhide , Yamamoto Etsuko , Yoshioka Ema , Shofuda Tomoko , Kanematsu Daisuke , Terada Yukinori , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Kodama Yoshinori , Mano Masayuki , Ichimura Koichi , Sasaki Atsushi , Hirato Junko , Inoue Takeshi , Nishikawa Ryo , Date Isao , Nonaka Masahiro , Nagane Motoo , Arakawa Yoshiki , Kanemura Yonehiro
Published: June 2024

BACKGROUND

Medulloblastomas are at least classified into four core subgroups, including WNT-activated, SHH-activated, group 3 and group 4. These molecular subgroups have been introduced in the latest WHO classification, which has become fundamental and indispensable. Medulloblastoma, WNT-activated (WNT-MB) accounts for about 10% of all medulloblastomas, and their prognosis is excellent, and it is desired to ensure that patients with WNT-MBs are diagnosed exactly. In this study, we have summarized results of molecular analysis of Japanese MBs collected by Japanese Pediatric Molecular Neuro-oncology Group (JPMNG) study, and analyzed clinical and molecular characteristics of WNT-MBs.

METHODS

We enrolled 267 cases of medulloblastoma from 44 centers participating in the JPMNG study since 2012.Central histopathological diagnosis was performed by three neuropathologists, and molecular genetic diagnosis was performed using molecular subgrouping, DNA sequencing (CTNNB1), and copy number analysis.

RESULTS

A total of 244 cases were finally analyzed, and the 4-subgroup classification was WNT: 39 (16%), SHH: 61 (25%), group3: 42 (17%), and group4: 102 (41.8%), respectively. The age at diagnosis was 3 years or older (6-40 years) in all cases, with no cases occurring in infants, the majority being children (6-18 years) (31/39: 79.5%), and 8 cases (8/39: 20.5%) in adults older than 18 years. Histological features were classic (CMB) in the majority of cases and large cell (LCA) type in only 2 cases. The positivity rate of nuclear β-catenin by Immunological staining was 9 out of 12 (75%) of the cases examined. While, CTNNB1mutation was positive in 39 of 39 cases (100%) and monosomy 6 was also positive in 35 of 35 cases (100%), respectively. The 5-year survival rate was 91.9%.

CONCLUSIONS

Clinical characteristics of Japanese WBT-MB were almost similar to those reported in other countries, which showed excellent prognosis, and their molecular genetic status were also identical with results from other ethnics.
MDB-17. A COMPARISON OF MAGNETIC RESONANCE IMAGING AND CEREBROSPINAL FLUID CYTOLOGY FOR DETECTING LEPTOMENINGEAL METASTASIS IN PATIENTS WITH MEDULLOBLASTOMA
Authors: Peeran Zain , Phelps Ryan , Aabedi Alexander , Fisher Edward , Khela Harmon , Rios Jennifer , Shukla Poojan , Reddy Alyssa , Kline Cassie , Aghi Manish K , Gupta Nalin
Published: June 2024

BACKGROUND

For medulloblastoma, CSF cytology and MRI together are considered to be superior to either modality alone in identifying leptomeningeal dissemination (LMD). However, MRI has vastly improved since the initial assessment of this approach.

METHODS

A retrospective medical record review of 130 patients (36.2% female) with medulloblastoma was performed. CSF samples and MR images (6.3% utilized FIESTA) obtained within 1 month of each other from 2000-2023 were analyzed. There were 302 CSF-MRI pairs (range: 1-12 pairs per patient) in total. A 3-tier system (negative, atypical/suspicious, positive) was utilized to account for equivocal findings.

RESULTS

The mean (SD) age at surgery was 13.2 (13.0) years. Mean (SD) postoperative follow-up time was 7.0 (5.2) years. 71.5% underwent gross or near-total resection, 80.8% received radiotherapy, and 93.1% received chemotherapy. The molecular subtypes were: SHH (24.6%), WNT (4.6%), non-WNT/non-SHH (38.5%), unknown (32.3%). MRI had an 89.8% sensitivity and CSF cytology had a 22.7% sensitivity for detecting LMD that was positive on CSF and/or MRI. MRI was positive in 23.1% of CSF negative cases. CSF was positive in 2.2% of MRI negative cases. For all CSF positive-MRI negative pairs, the CSF samples and MR images were obtained within 10 days of surgery. MRI was positive in 38.9% of CSF atypical cases. CSF was positive in 11.9% of MRI suspicious cases. MRI demonstrated greater or equal ability to CSF in 94.7% of pairs. MRI was more likely to exceed CSF at 3T versus 1.5T (51.3% vs. 27.4%; p<0.01). The overall concordance between CSF cytology and MRI was 61.3%, and this differed by subtype (75.4% SHH vs. 80.0% WNT vs. 52.3% NWNS; p<0.01).

CONCLUSIONS

Understanding the ability of CSF cytology and MRI to detect LMD is important. While MRI is superior overall, LMD detection varies by MRI Tesla, medulloblastoma subtype, and time since surgery.
MDB-29. SALL4 IS A CRL3REN/KCTD11 SUBSTRATE THAT DRIVES SONIC HEDGEHOG-DEPENDENT MEDULLOBLASTOMA
Authors: Severini Ludovica Lospinoso , Loricchio Elena , Navacci Shirin , Basili Irene , Alfonsi Romina , Bernardi Flavia , Moretti Marta , Conenna Marilisa , Cucinotta Antonino , Coni Sonia , Petroni Marialaura , De Smaele Enrico , Giannini Giuseppe , Maroder Marella , Canettieri Gianluca , Mastronuzzi Angela , Guardavaccaro Daniele , Ayrault Olivier , Infante Paola , Bufalieri Francesca , Marcotullio Lucia Di
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is the most common malignant pediatric brain tumor arising from alterations in cerebellum development. The Sonic Hedgehog variant (SHH MB) is the best genetically characterized, however the molecular mechanisms responsible for its pathogenesis are not fully understood and therapeutic benefits are still limited. Mutations in key components of the SHH pathway and cytogenetic alterations (such as chromosome 17p deletion) lay the pathogenetic foundation for SHH MB subgroup. RENKCTD11 (here REN) is a tumor suppressor and substrate-receptor subunit of the Cullin3 Ring E3 ubiquitin ligase (CRL3) complex mapping on chromosome 17p and frequently deleted in SHH MB. We wished to expand the knowledge of CRL3REN activity to unveil molecular circuitries whose deregulation can contribute to SHH MB onset and to uncover novel therapeutic targets.

METHODS

Affinity purification coupled to mass spectrometry was performed to identify new REN interactors. Co-immunoprecipitation and ubiquitylation assays validated proteomic data. The proliferation of primary murine SHH MB cells and Patient Derived Xenografts (PDXs) models was evaluated in vitro by using the IncuCyte imaging system. Heterotopic and orthotopic allograft in vivo models of SHH MB were established in immunodeficient mice.

RESULTS

Proteomic analysis revealed that the pro-oncogenic stemness Spalt-like transcriptional factor 4 (SALL4) interacts with REN. We found that SALL4 is re-expressed in mouse SHH MB models and its high levels correlate with worse overall survival in SHH MB patients. We demonstrate that CRL3REN induces polyubiquitylation and degradation of wild type SALL4, but not of a SALL4 mutant lacking zinc finger cluster 1 domain (ΔZFC1). Interestingly, SALL4 binds GLI1 and cooperates with HDAC1 to potentiate GLI1 deacetylation and transcriptional activity. Notably, inhibition of SALL4 suppress SHH MB growth both in murine and PDX models.

CONCLUSIONS

Our findings identify SALL4 as a CRL3REN substrate and a promising therapeutic target in SHH-dependent cancers.
MDB-65. RESULTS FROM THE SJ-ELIOT PHASE 1 CLINICAL TRIAL EVALUATING PREXASERTIB (LY2606368) IN COMBINATION WITH CYCLOPHOSPHAMIDE OR GEMCITABINE FOR CHILDREN AND ADOLESCENTS WITH REFRACTORY OR RECURRENT MEDULLOBLASTOMA
Authors: Gottardo Nicholas G , Endersby Raelene , Billups Catherine , Orr Brent , Hansford Jordan R , Hassall Tim , Zielgler David S , Stewart Clinton , Onar-Thomas Arzu , Clarke Molly , Roussel Martine F , Gajjar Amar , Robinson Giles W
Published: June 2024

BACKGROUND

SJ-ELIOT (NCT04023669) was a phase 1 trial that explored the combination of the checkpoint kinase inhibitor, prexasertib with the DNA-damaging agents, cyclophosphamide and gemcitabine, in recurrent or refractory medulloblastoma.

METHODS

Participants ≥ 1 year and < 25 years were stratified to one of two treatment strata: stratum A prexasertib and cyclophosphamide and stratum B prexasertib and gemcitabine. Patients with Group 3/4 medulloblastoma were assigned to either stratum A or B, whereas patients with SHH medulloblastoma were assigned to stratum A. A Rolling-6 design was used.

RESULTS

Fifteen patients were enrolled on stratum A and six patients on stratum B. The study was closed early due to drug supply issues. In stratum A, three patients were escalated to dose level (DL) 3 and none had dose limiting toxicity (DLT). For stratum B, of the first three patients enrolled on DL1, two had DLTs (grade 3 hypotension) related to drug reactions. Consequently, stratum B was amended to add hydrocortisone prophylaxis. A further three patients were enrolled. One patient had a grade 3 DLT (ALT increase). The remaining two patients electively stopped therapy within the first two courses. One patient on stratum A, with SHH TP53 mutant, MYCN amplified medulloblastoma, achieved a complete sustained response, received 12 cycles, and electively stopped treatment after 408 days. They progressed nine months later. The remaining 14 patients on stratum A progressed. There were no objective responses on stratum B. Median PFS were 1.9 and 2.1 months for stratum A and B respectively.

CONCLUSIONS

The MTD/RP2D was not established for either arm. In stratum A, DL3 was tolerated, whereas DL1 for Stratum B was not tolerated. Despite robust preclinical data, no efficacy signal was observed. Intriguingly, one patient with a highly aggressive tumor (SHH TP53 mutant, MYCN amplified) appeared to derive a sustained benefit from the combination of prexasertib and cyclophosphamide.
MDB-68. DISCOVERING DRUG SENSITIVITIES IN MEDULLOBLASTOMA USING PATIENT- AND PDX-DERIVED TUMOROIDS
Authors: Meulenbroeks Chris , Stathi Phylicia , van de Wetering Marc , Villarejo Chio Carranza , Mack Norman , Schwalm Benjamin , Geisemeyer Neal , Schueler Julia , Kolodziejczak Anna S , Milde Till , LA Plasschaert Sabine , Kranendonk Mariëtte E G , Hoving Eelco W , Northcott Paul A , Roussel Martine F , Pfister Stefan M , Bunt Jens , Kool Marcel
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor types and is subdivided into four major types: WNT, SHH, Group 3 and Group 4. Treatment, including resection, cranio-spinal radiotherapy, and chemotherapy, often leads to undesirable long-term side effects. MB prognosis depends on type, subtype, and genetic alterations, reflecting the high level of heterogeneity observed in these tumors and indicating that specific patient populations with particularly poor prognosis require alternative treatment approaches. Therefore, preclinical models are essential for recapitulating MB heterogeneity and developing subtype-specific treatments.

METHODS

Long-term in vitro MB tumoroid models were developed from patient and PDX tumors and molecularly characterized using DNA methylation and transcriptomic analyses. High-throughput single drug screening (225 compounds) and combination screening were performed to identify (subtype-specific) drug sensitivities.

RESULTS

Fifteen tumoroid lines were established from TP53-mutated SHH (n=6), Group 3 (G3) MYC-amplified (n=4) and non-amplified (n=5) patient (n=6) and PDX (n=9) tumors. DNA methylation analyses confirmed the maintenance of molecular identity in these tumoroids after long-term culture (>5 passages). Transcriptome analyses reveal a more proliferative, progenitor-like phenotype in these tumoroids compared to patient/PDX tumors. Hight-throughput drug screens identified both common and type-specific drug sensitivities within MB. Notably, drugs targeting CDK7, CDK12, CHECK1, BCL2L, and HDAC demonstrated efficacy in both G3 and TP53-mutated SHH-MB, while TOP1/2 and MDM2 inhibitors were specific for G3-MB. Currently, these drugs are being further investigated to select the most effective synergistic drug combinations for in vivo validation in PDX models.

CONCLUSIONS

Thus far, we have established already fifteen MB tumoroid models representing SHH-MB and G3-MB and identified several drug targets, including cell cycle kinases and HDACs. Tumoroids closely resemble patient tumors, based on methylome and transcriptome, enhancing their relevance for drug discovery applications in a high-throughput fashion and for prioritizing new treatment strategies for MB patients in clinical trials.
MDB-81. THE ROLE OF SURVEILLANCE IMAGING IN DETECTING RECURRENCE OF MEDULLOBLASTOMA
Authors: Dasgupta Archya , Dhele Rudrani , Sahu Arpita , Chatterjee Abhishek , Chinnaswamy Girish , Prasad Maya , Choudhary Amit , Bhattacharya Kajari , Epari Sridhar , Sahay Ayushi , Shah Aekta , Moiyadi Aliasgar , Shetty Prakash , Singh Vikas , Menon Nandini , Gupta Tejpal
Published: June 2024

BACKGROUND

In patients with medulloblastoma, imaging with magnetic resonance imaging (MRI) of the brain and spine plays an integral role in surveillance following treatment completion. The primary objective of imaging surveillance is to detect early recurrences, possibly leading to better salvage treatment. However, there is a lack of data to demonstrate the utility of imaging with possible demerits associated with increased resource utilization, scan-related anxiety, and lead or length time bias.

METHODS

Patients with histopathological confirmation of medulloblastoma treated in our institute between 2005 and 2022 were screened to identify patients with image-detected recurrences and corresponding documentation of symptoms and imaging intent (surveillance or directed by symptoms).

RESULTS

From a cohort of 545 patients treated during the period, 212 had disease recurrence, of which 153 had known symptomatology during the first recurrence. A total of 114 patients (75%) were having recurrence detected prompted by symptoms. Group 4 medulloblastomas were commonly seen to have recurrence detected on surveillance imaging (35%) compared to the SHH subgroup (25%) and group 3 (12%). During the final analysis, 141 of 153 patients had died. The median survival of patients detected to have asymptomatic relapse was 14 months compared to 5 months for symptomatic recurrences (p=0.03). The overall survival (calculated from index diagnosis) was not statistically significant between the two groups, with a 3-year survival of 53% (asymptomatic) vs 46% (symptomatic) (p=0.51).

CONCLUSION

In most patients, recurrences were detected by unplanned imaging ahead of scheduled surveillance imaging prompted by symptoms. Although the survival after recurrence is better in patients diagnosed on surveillance imaging, the overall survival was not different between the two groups, suggesting the possibility of lead time bias. Prospective studies are warranted to determine the role and appropriate frequency of surveillance imaging in patients with medulloblastoma.
MDB-84. IDENTIFICATION AND CHARACTERIZATION OF NOVEL TRANSCRIBED ULTRA-CONSERVED REGIONS AS LONG NON-CODING RNAS IN MEDULLOBLASTOMA
Authors: Hudson Kadie , Vernon Ashley , Zhang Myron K Gibert Jr Ying , Saha Shekhar , Dube Collin , Sun Yunan
Published: June 2024

BACKGROUND

Medulloblastoma is the most common malignant pediatric brain tumor. While medulloblastoma survival has improved with molecular subgrouping, children who undergo standard of care treatments frequently experience permanent neurological deficits and many still face poor prognoses. This work investigates the role of “Transcribed Ultra-Conserved Regions” (TUCRs) in medulloblastoma about which there is no published literature. TUCRs represent a distinct group of 481 putative lncRNAs that are 100% conserved across human, mouse, and rat genomes. These elements change 20 times slower than the average genomic region and are therefore under intense negative selection. Since their discovery, TUCRs have remained exceedingly underexamined within cancer research. We hypothesize that TUCRs play critical roles in the molecular basis of medulloblastoma which will lead to the development of targeted therapies for medulloblastoma of which there are none approved.

METHODS

We used RNA-sequencing and differential gene expression analysis of medulloblastoma tumors as compared to normal cerebellum samples to investigate TUCR dysregulation followed by Kaplan-Meier correlation to survival analysis. We generated a multifaceted scoring and prioritization system to rank TUCRs in medulloblastoma. Top ranked TUCRs were then investigated using in vitro functional experimentation in medulloblastoma cell lines.

RESULTS

Bioinformatics analysis of medulloblastoma tumors revealed significant TUCR dysregulation and identified numerous TUCRs whose expression correlated with overall survival. Application of the computational scoring system determined the top ten intergenic TUCRs in medulloblastoma. Analysis of medulloblastoma cell lines indicated significant dysregulation of these TUCRs and functional assays showed that uc.403 promoted cell proliferation.

CONCLUSIONS

We are continuing to investigate the functional effects and mechanisms of action of these select intergenic TUCRs in medulloblastoma. Altogether, our work investigates the oncogenic and tumor suppressive nature of TUCRs. It represents the first study of TUCRs in medulloblastoma that will significantly advance our basic understanding of this highly understudied class of molecules.
MDB-91. MEDULLOBLASTOMA – MOLECULAR CHARACTERISTICS AND RADIOLOGICAL ASPECTS OF A BRAZILIAN COHORT FROM A SINGLE CENTER
Authors: Martins Flávia Delgado , de Lima Benicio Oton , Arrais Bruna , da Silva Emanoelle Cristina , Marcelino Marcio Ferreira , Pinto Pedro Henrique , de Bispo Diogenes Diego Carvalho
Published: June 2024

BACKGROUND

Four molecular subgroups of medulloblastoma are distinguished by their genomic, epidemiological, and prognostic characteristics: Wingless (WNT), Sonic hedgehog (SHH), Group 3 and Group 4. Genotypic classification permits individualized therapeutic planning based on risk stratification, thereby improving patient outcome. This study aims to characterize the epidemiological and molecular data of a cohort treated at a single Brazilian center, as well as to correlate the heterogeneous aspects of magnetic resonance imaging (MRI) with the molecular characteristics of this tumor.

METHODS

The study analyzed 47 medulloblastoma cases, treated at the children’s oncology reference institution of a middle-income country between 2011 and 2021. The medical records, radiological findings and the histological and molecular classification are reviewed. The images were evaluated by an experienced neuroradiologist, blinded to clinical and molecular information.

RESULTS

Thirty-two out 47 patients met the eligibility criteria and were analyzed. The frequency of molecular groups found was 6.25% Non-SHH/ Non-WNT, 12.50% WNT, 34.38% SHH, 3% Group 3 and 44 % Group 4. The analysis revealed tumor location, presence of hemorrhage/calcification, limits and enhancement patterns are significant for molecular group prediction. SHH shows a significant prevalence in the cerebellar hemisphere, lower presence of hemorrhage/calcification and an ill-defined tumor margins when compared with other subgroups. Group 4 showed significantly less enhancement.

CONCLUSIONS

In accordance with the frequency observed in studies on childhood medulloblastoma, our series found a significant prevalence of Group 4 and a lack of representativeness of Group 3. Despite the limitations, it was possible to identify radiological tumor characteristics that may predict the molecular subgroup and contribute to a more effective therapeutic approach, thereby reducing the incidence of post-surgical complications.
MDB-94. RADIOMICS-BASED DECISION SUPPORT FOR PEDIATRIC MEDULLOBLASTOMA RISK STRATIFICATION ON MULTI-PARAMETRIC MRI
Authors: Reddy Kartik , Midya Abhishek , Hajibonabi Farid , Halicek Martin , Damaraju Eswar , Goldman-Yassen Adam , McThenia Sheila , Castellino Robert C , Mazewski Claire , Madabhushi Anant
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is the most common pediatric brain malignancy. Accurate risk stratification is crucial for prescribing appropriate therapy. However, current risk stratification into standard or high-risk groups is limited in scope and does not accurately address the unique biological behavior of each specific tumor, with approximately 30% of children diagnosed with MB suffering from treatment failure. We developed a radiomic tool to more accurately risk stratify children with MB.

METHODS

We collected 1.5T/3T MRI (Siemens, Philips, or GE scanners) and clinical data from 80 patients with MB treated at Children’s Healthcare of Atlanta. Radiomic features that quantify textural heterogeneity including first and second order statistics, Haralick’s features from Gray Level Co-occurrence Matrices, and CoLIAge were extracted from tumor volumes segmented by a board-certified radiologist from multi-parametric MRI data including Apparent Diffusion Coefficient (ADC), T2, and post-contrast T1 sequences. Continuous survival models were built using the Cox proportional hazard method with 70% of the data for progression free survival (PFS) and overall survival (OS) using the 5 most predictive features obtained by univariate analysis after removing correlated features within the training data.

RESULTS

We developed three models with T1, T2, and ADC separately to evaluate predictive power of radiomic signatures. Three models for predicting MB OS delivered Harrel’s concordance indices (C-index) of 0.72 and 0.61 (T1); 0.70 and 0.65 (T2); and 0.80 and 0.76 (ADC) for training and test, respectively. C-indices for PFS were 0.70 and 0.69 (T1); 0.73 and 0.67 (T2); and 0.63 and 0.61 (ADC).

CONCLUSIONS

Our preliminary results show the feasibility and efficacy of our approach for predicting MB OS and PFS. Future studies will build an integrated model combining T1,T2, ADC, and other clinical information for predicting MB OS and PFS using a large multi-center validation cohort.
MDB-99. SPATIAL AND TEMPORAL DEVELOPMENT OF GLI2-DRIVEN MEDULLOBLASTOMA
Authors: Murad Najiba , Xu Zhenhua , Zhang Jiao , Gamachchige Prathibhani Ramawickrama , Schoof Melanie , Schüller Ulrich , Dlugosz Andrzej , Taylor Michael D , Pei Yanxin
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is a highly malignant tumor of the cerebellum predominantly affecting children. It can be classified into four major molecular subgroups: WNT, SHH, Group 3, and Group 4. Among these subgroups, the SHH subgroup MB, characterized by GLI2 amplification, is associated with a poor prognosis. However, while GLI2 alterations have been linked to SHH-MB, evidence demonstrating its role as an oncogenic driver in an animal model is lacking. Understanding the mechanisms underlying GLI2-amplified MB initiation and progression is crucial for developing improved therapeutic strategies.

METHODS

By utilizing transgenic mouse models, our study aims to elucidate the role of GLI2 in SHH-MB tumorigenesis and uncover the underlying mechanisms driving tumor formation. This research effort seeks to identify novel therapeutic targets for the treatment of this disease.

RESULTS

We discovered that overexpression of GLI2 in embryonic Math1+ granule neuron precursors (GNPs) led to tumorigenesis within the cerebellum, resulting in 100% mortality in the mice. Importantly, the cellular and molecular characteristics of these tumors faithfully recapitulated those found in human SHH-MB. Further analysis revealed that only Math1+ GNPs specifically between E13.5 and E15.5 are susceptible to GLI2-induced tumorigenesis, while overexpression of GLI2 in embryonic GFAP+ stem cell/progenitors failed to induce tumorigenesis. Additionally, our single-cell RNA-seq analysis unveiled the heterogeneity of Math1+ cells during cerebellar development. Furthermore, we demonstrated that the MAPK signaling pathway was involved in the tumorigenesis of embryonic Math1+ GNPs by preventing cell apoptosis.

CONCLUSIONS

Our findings establish a pivotal oncogenic role of GLI2 in SHH-MB tumorigenesis, with GLI2-driven tumors developing within a specific spatial-temporal window from a distinct cell population during cerebellar development. Targeting the MAPK signaling pathway holds promise in preventing tumorigenesis and progression of GLI2-amplified MB.
MDB-104. TARGETING Y BOX BINDING PROTEIN (YBX1) IN PEDIATRIC MEDULLOBLASTOMA
Authors: Carney Stephen , Hemenway John , Rajendran Ashmita , Hathaway Matthew , Nealy Eric , Paese Christian Bonatto , Tailor Dhanir , Malhotra Sanjay , Evans II Myron
Published: June 2024

Medulloblastoma is the most common malignant pediatric brain tumor, with some patients having abysmal survival despite an intense therapeutic regimen. A significant barrier to effective outcomes is cell-intrinsic resistance to chemo- and radio- therapy. Using a batch-normalized bulk RNA-seq dataset (GSE124814) comprised of 1350 MB samples and 291 normal cerebella, we reveal upregulation of Y-box binding protein 1 (YBX1) in MB compared to normal cerebellum. Further analysis of this dataset and others demonstrates a significant correlation between MYC and YBX1 expression in G3 tumors. Proteomics analysis also reveals higher YBX1 in G3 tumors characterized by hyperstability of MYC. Using a well-established ex vivo model, we demonstrate increased YBX1 expression as normal cerebellar progenitor cells transition to tumorigenic G3 MB stem-like cells. Deletion of YBX1 in these progenitor cells limits tumorigenesis suggesting a requirement for YBX1 in tumor initiation. We utilized an orthogonal pharmacogenetic approach to inhibit YBX1 and determine its effects on G3 MB tumor biology. Genetic depletion of YBX1 significantly reduced cellular proliferation and antagonized MYC expression in vitro. Orthotopic implantation of these YBX1KO G3 MB cells leads to increased tumor latency and animal survival. Transcriptomic analysis reveals a de-repression of neuronal target genes as well as suppression of MYC-activated genes. Evaluation of SU056, a YBX1 targeting small molecule, revealed both single agent efficacy as well as synergism with chemo- and radio- therapy. Further analysis revealed efficacy in SHH MB, even in tumors with mutant p53, suggesting cross-subgroup use for SU056. In silico docking identified binding of SU056 in the mRNA recognition domain of YBX1. Disruption of YBX1-RNA binding impacts the stability of known oncogenic transcripts, important for tumorigenesis and progression. Our findings corroborate previous identification of YBX1 as a chemoresistance factor and validate pre-clinical targeting of YBX1 to improve patient outcomes.
NFS-01. EXTREMELY RARE CASE OF CHILDREN WITH NIJMEGEN BREAKAGE SYNDROME AND MEDULLOBLASTOMA – A THERAPEUTIC CHALLENGE
Authors: Krawczyk Malgorzata A , Bien Ewa , Perek-Polnik Marta , Abdelbaki Mohamed S
Published: June 2024

BACKGROUND

Nijmegen Breakage Syndrome (NBS) is an autosomal recessive inherited disorder characterized by DNA repair abnormalities. It manifests with heightened sensitivity to radiotherapy (RT) and predisposes individuals to neoplastic diseases. Antineoplastic treatment in NBS patients is particularly challenging due to concurrent immune disorders, intense toxicities, and contraindications for RT. Hematologic disorders, especially lymphomas, are among the most prevalent malignancies in NBS patients. Solid tumors in NBS are extremely rare, with only two pediatric cases documented in the literature, both succumbing due to severe complications of treatment.

METHODS

A review and analysis of the medical documentation of a child with NBS and MB treated at the Department of Pediatrics, Hematology, and Oncology, Gdansk, Poland, were conducted.

RESULTS

A genetically confirmed NBS girl displaying typical phenotypic features presents symptoms at the age of 2 years, such as headaches, reluctance to walk, and drowsiness. Imaging confirmed a tumor in the left cerebellar hemisphere, measuring 40x33x30mm, displaying radiological features consistent with Medulloblastoma (MB). The patient underwent gross total resection of the tumor. The pathology revealed a desmoplastic type of MB with SHH activation, TP53 wild type, and ongoing molecular analysis. Postoperative imaging confirmed clinical remission, and cerebrospinal fluid examination was negative. Considering the substantial toxicities of chemotherapy in NBS patients and the contraindications for RT, the patient received chemotherapy with reduced cytostatic doses. Treatment was complicated by profound and prolonged myelosuppression and infections. Currently, after completing six cycles of chemotherapy, the patient is still in remission. To maintain remission and address NBS, the patient will receive allogeneic bone marrow transplantation from a 9/10 HLA-matched unrelated donor.

CONCLUSIONS

Managing patients with NBS, complicated by neoplastic diseases, is exceptionally demanding and necessitates an individualized multidisciplinary approach. Modern diagnostic and therapeutic methods enhance the prospects of reducing the toxicity of oncologic treatment, improving quality of life, and extending overall survival.
NFS-22. INVESTIGATING MALIGNANT TRANSFORMATION IN NF1 PEDIATRIC GLIOMAS USING AN IPSCS-DERIVED CEREBRAL ORGANOID MODEL
Authors: Tomasso Federica , Chong Wai Chin , Bhuvanendran Shivaprasad , Yadavilli Sridevi , Packer Roger , Nazarian Javad
Published: June 2024

BACKGROUND

Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor predisposition syndrome affecting 1 in 3000 children around the world. Although NF1 inactivation is recognized as the cause of low-grade glioma (LGG) development, little is known about subsequent genetic alterations that lead to malignant transformation. One of the limitations in understanding the molecular events underlying the malignant transformation of NF1 gliomas is the lack of appropriate NF1 preclinical models for its comprehensive profiling.

OBJECTIVE

Brain organoids have emerged as powerful in vitro models for studying the interaction between tumor cells and the tumor microenvironment. In this study, we present a novel cerebral organoid model, developed to investigate the molecular events leading to malignant transformation in NF1 pediatric gliomas.

METHODS

Induced pluripotent stem cells (iPSCs)-derived cerebral organoids were generated using NF1wt and NF1mut iPSCs, the latter reprogrammed from patients with plexiform neurofibromas (Carlos III Health Institute, Spain). Immunofluorescence analysis was performed at four different developmental stages to confirm their correct cytoarchitectural development and differentiation into heterogeneous cell populations. Furthermore, four mCherry-labelled isogenic glioma cells lines, RES 186 wild type, NF1-/-, CDKN2a-/-,NF1-/-/CDKN2a-/- were co-cultured with the developed cerebral organoids and their migration potential and invasiveness were compared using two-photon microscopy.

RESULTS/DISCUSSION

NF1mut cerebral organoids display ventricular-like zone at early stages of development (d15-d30), characterized by luminal Sox2+ neural stem cells surrounded by Tuj1+ immature neuron. These organized structures disappear at later stages, while progenitor cells start to differentiate into fully mature neurons and glial cells (d45-d60). Additionally, after 10 days of co-culture, all four RES186 isogenic cell lines infiltrated the organoid structure with different invasion patterns. The established organoid model will provide a platform for evaluating the impact of sequential mutational events on LGG transformation, taking into consideration the role exerted by the tumor microenvironment in supporting tumor cell invasion and migration.