IMMU-48. IMMUNOMODULATION WITH RESIQUIMOD REPOLARIZES THE IMMUNE MICROENVIRONMENT TO INHIBIT MEDULLOBLASTOMA PROGRESSION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi103-vi103
Author(s):  
Christopher Park ◽  
Coral Del Mar ◽  
Morrent Thang ◽  
Taylor Dismuke ◽  
Duhyeong Hwang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Median Survival ◽  
Sonic Hedgehog ◽  
Expression Patterns ◽  
Myeloid Cells ◽  
Pediatric Brain Tumor ◽  
Toll Like Receptor ◽  
Paracrine Signaling ◽  
Pediatric Brain

Abstract BACKGROUND New, non-cytotoxic treatments may improve outcomes for medulloblastoma, the most common malignant pediatric brain tumor. Sonic hedgehog (SHH) subgroup medulloblastoma, which includes subtypes with poor prognosis, can be modeled in immunocompetent, transgenic mice. These models are ideal for preclinical testing of immunotherapies. Here, we show that immune stimulation using resiquimod, a small molecule agonist of Toll-like receptor 7 and 8 (TLR 7/8), alters myeloid populations in medulloblastoma and significantly reduces tumor growth. METHOD We generated mice with medulloblastoma by interbreeding the hGFAP-Cre and SmoM2 mouse lines. The resultant hGFAP-Cre/SmoM2 (G-Smo) mice develop SHH medulloblastoma with 100% frequency. We analyzed myeloid populations and demonstrated TLR7/8 expression patterns in G-Smo tumors. We then compared survival of untreated G-Smo mice versus G-Smo mice treated with three doses of resiquimod at postnatal days 10, 12, and 14. We also assessed pharmacodynamic effects at progressive intervals after a single dose. RESULTS Approximately 10% of cells in G-Smo medulloblastomas were myeloid cells, and these cells were the only cells that expressed TLR7/8. Resiquimod slowed tumor growth and increased the survival of mice with medulloblastoma. Untreated median survival was 14.5 days (n=12), compared to resiquimod-treated median survival of 37 days (n=10; p=0.0003). All treated mice eventually demonstrated tumor progression. Immunohistochemistry for IBA1, a pan-macrophage marker, demonstrated significant increase in myeloid cells within the tumor by 24 hours after treatment (p=0.0178), however the IGF1+ fraction of myeloid cells decreased (p=0.0275). CONCLUSION Resiquimod prolongs survival in mice with SHH-driven medulloblastoma, demonstrating the potential for therapies that target myeloid cells to produce significant anti-tumor effects. Myeloid-derived IGF-1 has been shown to support tumor progression and resiquimod may act by disrupting this paracrine signaling.

scholarly journals IMMU-05. IMMUNOTHERAPY WITH RESIQUIMOD REPOLARIZES TUMOR-ASSOCIATED MYELOID CELLS AND IMPROVES EVENT-FREE SURVIVAL IN A TRANSGENIC MOUSE MODEL OF SONIC-HEDGEHOG (SHH) MEDULLOBLASTOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i27-i28
Author(s):  
Christopher Park ◽  
Morrent Thang ◽  
Duhyeong Hwang ◽  
Chaemin Lim ◽  
Taylor Dismuke ◽  
...  
Keyword(s):  
Mouse Model ◽  
Median Survival ◽  
Sonic Hedgehog ◽  
Dose Regimen ◽  
Prolonged Exposure ◽  
Inflammatory Marker ◽  
Myeloid Cells ◽  
Optimal Dose ◽  
Free Survival ◽  
The Common

Abstract Resiquimod is a synthetic small molecule agonist of Toll-like receptors 7 and 8 (TLR-7/8) that modulates innate immune cells. We found TLR-7/8 are expressed in medulloblastoma exclusively by tumor-associated myeloid cells (TAMs). We tested whether systemically administered resiquimod modulated TAMs in a genetic Sonic hedgehog (SHH) medulloblastoma model, and whether this modulation would be therapeutically beneficial. We generated mice with medulloblastoma by crossing hGFAP-Cre and SmoM2 mouse lines. The resulting hGFAP-Cre/SmoM2 (G-Smo) mice developed medulloblastoma with 100% frequency and showed a median survival of 14.5 days (n=12). Treatment with 3 doses of resiquimod at postnatal days 10, 12 and 14 reduced tumor size and increased median survival to 37 days (n=10) (p=0.003508). Cellular studies showed that resiquimod altered TAM phenotype, rapidly inducing expression of the inflammatory marker VCAM1, and more slowly increasing TAM populations. Responses to the 3-dose regimen were ultimately limited by recurrence and all mice eventually died of tumor progression. Continued resiquimod therapy with every other day dosing was less effective than the 3-dose regimen, suggesting that TAM responses to resiquimod are dynamic and change with prolonged exposure. Our data show that innate immunity, mediated by TAMs and stimulated by TLR-7/8 agonist therapy, can produce a significant anti-tumor effect in medulloblastoma. The common expression of TLR-7/8 on TAMs in patient-derived medulloblastoma samples and in the mouse model suggests that resiquimod may produce similar anti-medulloblastoma effects in humans. Further studies are needed to define the mechanism of the anti-tumor effect in detail, to determine the optimal dose regimen, and to determine if resiquimod can combine effectively with additional adjuvant therapies to produce curative effects.

scholarly journals Inhibition of Heparanase in Pediatric Brain Tumor Cells Attenuates their Proliferation, Invasive Capacity, and In Vivo Tumor Growth

2017 ◽  
Vol 16 (8) ◽  
pp. 1705-1716 ◽  
Author(s):  
Argyris Spyrou ◽  
Soumi Kundu ◽  
Lulu Haseeb ◽  
Di Yu ◽  
Tommie Olofsson ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Pediatric Brain Tumor ◽  
Brain Tumor Cells ◽  
Invasive Capacity ◽  
Pediatric Brain

scholarly journals DDRE-34. TARGETING RESISTANCE IN MEDULLOBLASTOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i14-i14
Author(s):  
Simone Chang ◽  
Evan Meiman ◽  
Sucheta Telang
Keyword(s):  
Sonic Hedgehog ◽  
Therapeutic Option ◽  
Pediatric Brain Tumor ◽  
Glycolytic Enzyme ◽  
Treatment Resistant ◽  
Shh Pathway ◽  
Survival Pathways ◽  
Poor Outcomes ◽  
Rate Limiting ◽  
Pediatric Brain

Abstract Medulloblastoma is the most commonly diagnosed pediatric brain tumor. Although therapeutic advances have improved survival from this cancer, they result in devastating sequelae and, additionally, have proven inadequate in metastatic disease and recurrence where survival remains <5%. Effective therapies are urgently needed to improve outcomes in medulloblastoma. Medulloblastoma development is driven by dysregulation of normal cerebellar proliferation. Mutations in the sonic hedgehog (Shh) pathway are found in ~30% of these tumors and responsible for their aggressive growth. The poor outcomes in Shh-driven medulloblastoma have prompted the evaluation of Shh-targeting agents in their treatment – with limited success likely attributable in part to the upregulation of alternate survival pathways (e.g. Ras/MAPK and HIF-1α). These alternate mechanisms stimulate glycolysis, in part by increasing the activity of the 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatases (PFKFB1-4) to produce fructose-2,6-bisphosphate (F26BP), a potent activator of the rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase. In recent studies, we have determined that the PFKFB4 enzyme is highly expressed in patient-derived Shh medulloblastomas. We have found that hypoxia, through HIF-1α, strongly induced PFKFB4 expression in Shh-driven medulloblastoma cells and that silencing PFKFB4 suppressed F26BP, glycolysis and proliferation in normoxia and, more markedly, in hypoxia, indicating that PFKFB4 may be required for growth under hypoxia. We found that simultaneously silencing PFKFB4 and Shh pathway effectors significantly reduced cell survival and that co-targeting PFKFB4 (with a novel inhibitor) and Shh effectors synergistically decreased cell viability. In order to simulate Shh antagonist resistance, we have now subjected Shh medulloblastoma cells to prolonged Shh inhibitor exposure and found that these cells exhibit increased proliferation, glycolysis and PFKFB4. Studies are underway to delineate their metabolic alterations. Taken together, our data indicate that targeting PFKFB4 may be a valid therapeutic option in aggressive, treatment-resistant medulloblastoma and strongly support the further examination of PFKFB4 inhibitors in these tumors.

scholarly journals Genomic and Transcriptomic Analyses Reveals ZNF124 as a Critical Regulator in Highly Aggressive Medulloblastomas

2021 ◽  
Vol 9 ◽  
Author(s):  
Zaili Luo ◽  
Xinran Dong ◽  
Jianzhong Yu ◽  
Yong Xia ◽  
Kalen P. Berry ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Disease Process ◽  
Pediatric Brain Tumor ◽  
Genetic Alterations ◽  
Tertiary Referral ◽  
Whole Exome ◽  
Rna Deep Sequencing ◽  
Group 3 ◽  
Asian Cohort ◽  
Pediatric Brain

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, however, the mechanisms underlying tumorigenesis in different MB subgroups remain incompletely understood. Although previous studies of MB predisposition have been conducted in tertiary referral centers primarily in Caucasian cohorts, it is not unclear clear whether there exist population-specific genetic alterations in MBs. In this study, we investigated the contribution of genomic and transcriptomic alterations to the risk of malignant MB in the Chinese population (designated as the Asian cohort). We analyze the genomic and transcriptomic alterations of the Asian MB cohort by using a combination of whole-exome sequencing (WES) and RNA-deep-sequencing. In addition, we integrate publicly available data with the Asian MB cohort and identify a subset of potential MB-driving genes specifically enriched in each of the MB subgroups. We further characterize a newly identified group-3-enriched transcriptional regulator, ZNF124, and demonstrate that ZNF124 is critical for the growth of the most aggressive group-3 MB cells. Together, our analyses indicate conserved yet distinct genetic alterations and gene expression patterns of MBs between different ethnic groups. Our studies further provide an important resource for identifying potential tumor-driving factors in MBs, enhancing our understanding of the disease process for developing ethnically targeted therapies in patients with MB.

scholarly journals Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sonia Coni ◽  
Anna Barbara Mancuso ◽  
Laura Di Magno ◽  
Giulia Sdruscia ◽  
Simona Manni ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Rapid Development ◽  
Pediatric Brain Tumor ◽  
Selective Inhibition ◽  
Preclinical Models ◽  
Anticancer Effects ◽  
Selective Targeting ◽  
Hh Signaling ◽  
Pediatric Brain

Abstract SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB.

scholarly journals Single-cell transcriptomic profile reveals macrophage heterogeneity in medulloblastoma and their treatment-dependent recruitment

2020 ◽  
Author(s):  
Mai T. Dang ◽  
Michael Gonzalez ◽  
Krutika S. Gaonkar ◽  
Komal S. Rathi ◽  
Patricia Young ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Single Cell ◽  
Rna Sequencing ◽  
Sonic Hedgehog ◽  
Radiation Treatment ◽  
Pediatric Brain Tumor ◽  
Single Cell Rna Sequencing ◽  
Human Medulloblastoma ◽  
Pediatric Brain

AbstractThe role of macrophages in medulloblastoma, the most common malignant pediatric brain tumor, is unclear. Using single-cell RNA sequencing in a mouse model of sonic hedgehog medulloblastoma and analysis of bulk RNA sequencing of human medulloblastoma, we investigated macrophage heterogeneity. Our findings reveal differential recruitment of macrophages with molecular-targeted versus radiation therapy and identify an immunosuppressive monocyte-derived macrophages following radiation treatment of mouse medulloblastoma, uncovering potential strategies for immunomodulation as adjunctive therapy.

scholarly journals PDTM-08. SINGLE-CELL GENOMICS REVEALS TUMOR-INITIATING PROGENITORS AND ONCOGENIC CASCADES DURING TUMORIGENESIS AND RELAPSE IN MEDULLOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi188-vi188
Author(s):  
Liguo Zhang ◽  
Xuelian He ◽  
Xuezhao Liu ◽  
Kalen Berry ◽  
Richard Lu
Keyword(s):  
Single Cell ◽  
Sonic Hedgehog ◽  
Single Cell Analysis ◽  
Pediatric Brain Tumor ◽  
Tumor Initiating Cells ◽  
Oncogenic Pathways ◽  
High Level ◽  
Glial Lineage ◽  
Pediatric Brain ◽  
Developmental Hierarchy

Abstract Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas, the most common malignant pediatric brain tumor, remain elusive. Here, by utilizing single-cell analysis at different stages of tumorigenesis, we demonstrated a developmental hierarchy of diverse progenitor pools in sonic hedgehog (SHH)-medulloblastomas. Unexpectedly, we identified Olig2-expressing progenitors as transit-amplifying cells at the onset of tumorigenesis. Although Olig2+ cells become quiescent stem-like progenitors in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. High-level OLIG2 expression is associated with poor outcome in human SHH-medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2-ablation impeded tumorigenesis. Transcriptome and chromatin-occupancy profiling revealed that Olig2 modulates the chromatin landscape and activates oncogenic networks including HIPPO-Yap/Taz and Aurora-A/MycN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results raise the unanticipated possibility that glial lineage-associated Olig2-expressing progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting Olig2-driven oncogenic networks as potential therapeutic targets.

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