Researchers have discovered potential new treatment strategies for recurrent Sonic Hedgehog Medulloblastoma

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One of the most common brain cancers in children, Sonic Hedgehog (SHH) medulloblastoma, also is one of the more survivable for most kids.

Unfortunately, for a subset of patients, the cancer resists treatment and relapses with a vengeance to then turn deadly.

Researchers at Cincinnati Children’s Hospital Medical Center used a powerful new computer-assisted technology called single-cell transcriptomics that measures thousands of individual cells simultaneously to map cell types and molecular cascades that drive the growth of SHH-medulloblastoma.

In a study published Aug. 29 by the journal Cancer Cell, the scientists report they discovered new treatment strategies for the disease that may help patients fight a recurrent cancer.

Scientists used direct genetic manipulation to block genetic and molecular cascades they discovered in SHH-medulloblastoma tumors.

The genetic-molecular block stopped the cancer growth and prevented relapse in tumor-forming laboratory mice, according Q. Richard Lu, PhD, a senior study investigator and scientific director of the Brain Tumor Center at Cincinnati Children’s.

Medulloblastoma is driven by a diverse group of cell types and molecular pathways that haven’t been understood very well,” said Lu.

“But after identifying the molecular triggers and potential cells of origin for tumor initiation and recurrence, we determined from further testing that there are existing small molecule inhibitors that can target the oncogenic cascade pathways that cause SHH tumor initiation and recurrence.”

Cells of Origin Revealed

The researchers developed their new data by subjecting SHH-medulloblastoma tumors in lab animals at various stages of tumor growth to single-cell transcriptomic analysis.

The technique generated an extensive dataset that identifies the complete set of transcribed DNA sequences in every single cancer cell.

The scan revealed that immature oligodendrocyte progenitor cells in the brain–which can assume stem-cell-like qualities–grow out of control to form medulloblastoma tumors and the molecular cascade that fuels recurring brain cancer.

Although additional preclinical research is need before clinical testing can be proposed for patients, the current study points to several molecular targets that respond to combined treatment with existing drugs, according to study co-lead author Xuelian He, MD, PhD, a former member of the Lu laboratory and now at Boston Children’s Hospital. Combination therapies allow lower drug doses and improved drug tolerability for patients while achieving a certain level of therapeutic efficacy.

One treatment target proposed by the study is the HIPPO-YAP/TAZ molecular pathway, which can be targeted with an FDA-approved drug already in use for cancer treatment.

The pathway is normally responsible for helping control programs that turn cell growth on and off to ensure the body’s tissues and organs are accurately shaped and sized.

In SHH-medulloblastoma the pathway becomes overactive.

This prompts cells to expand rapidly and grow out of control near the lower central rear of the brain, which mainly controls balance and coordination.

This shows a medulloblastoma in a brain scan

Scientists looking for effective treatments against an aggressive form of medulloblastoma brain cancer, like the tumor shown in this MRI image of a child, report using a powerful new computer-assisted technology called single-cell transcriptomics to discover genetic drivers of the disease.

When they blocked those molecular pathways it stopped the cancer in laboratory models of the disease.

Researchers report in the journal Cancer Cell that there are existing drugs already in use for other forms of the disease that could be used to treat the aggressive cancer. The image is credited to Cincinnati Children’s.

The other potential target is the MYCN/AURORA kinase molecular pathway, which is important in regulating accurate cell structure.

In SHH-medulloblastoma, the pathway is overactive and disrupts the formation of cells that otherwise would be structured and function normally. Instead, the cells transform into cancer cells.

Prodrug Potential

Lu said his research collaborators are also working together on a prodrug that will target another molecular cascade related to OLIG2, a protein and transcription factor that is an important regulator in the development of oligodendrocyte cells and motor neurons in the central nervous system.

A prodrug is a compound designed as an inactive biological compound that doesn’t turn on and metabolize into a specific, active drug until it reaches the appropriate part of the body.

Molecular testing shows that OLIG2is often elevated in the early stage and treatment-resistant SHH-medulloblastomas. When OLIG2 is overexpressed its energies turn towards forming cancer cells.

Because the preclinical findings in the current study were obtained with human cell cultures and mouse laboratory models, the data will have to be rigorously tested and verified by additional research before clinical testing can be proposed, according to the authors.

Funding: Funding support for the research came from the National Institutes of Health (R01 NS078092 and R01 NS075243).


Medulloblastomas are heterogeneous, highly aggressive tumors of the central nervous system and are the most frequent malignant brain tumors in children [14,16,67].

Most medulloblastomas are sporadic and arise in the posterior fossa due to deregulation of cerebellar development [34].

In rare cases, medulloblastoma can be associated with inherited disorders such as Li-Fraumeni, Turcot or Gorlin syndrome [23,52].

Integrative genomic studies from several independent research groups have shown that medulloblastoma is not a single disease but is comprised of at least four subgroups with specific demographic, genetic, transcriptional, clinical, and prognostic characteristics [31,43,62,66,76,85,89].

The medulloblastoma subgroups are termed wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 and were agreed upon by experts from around the world during a consensus meeting in Boston in 2010 [85].

The 5-year overall survival of medulloblastoma patients is 60–70% under the current standard multimodal treatment consisting of maximal safe tumor resection, chemotherapy and, for non-infant (>3–5 years) patients, craniospinal irradiation [20,87].

Unfortunately, improved outcome has been associated with serious long-term treatment sequelae such as neurocognitive impairment, endocrine deficiencies, and secondary tumors [32,39,40].

During the last two decades, tumor staging of medulloblastoma patients has been solely based on clinical factors (patient’s age, presence or absence of metastases at diagnosis, postoperative residual tumor) and, in some studies, histopathological subtypes [85].

A recently proposed, refined risk stratification of non-infant medulloblastoma patients based on subgroup and outcome data allows a classification of patients into four groups with different prognoses : “low risk” (>90% survival), “standard risk” (75–90% survival), “high risk” (50–75% survival), and “very high risk” (<50% survival).

This new approach to patient stratification opens the door for future clinical trials including treatment de-escalation for patients with favorable outcomes and development of urgently needed new therapies for patients with high-risk disease [61].

Leptomeningeal dissemination occurs in up to 40% of patients at time of diagnosis and almost all patients present with metastases at time of recurrence [96].

Despite good progress in the clinical management of patients with medulloblastoma, recurrent and metastatic disease remain incurable and metastatic relapse is the primary cause of death in children with medulloblastoma.

Thus, characterization of the molecular mechanisms of metastatic spread and survival in the metastatic niche, coupled with the identification of targetable vulnerabilities in these processes is a key area of current and future investigation.

MOLECULAR SUBGROUPS

The four subgroups (WNT, SHH, group 3, and group 4) were identified based on integrated genomics studies and feature well-defined clinical, histopathological, genetic, transcriptional, and prognostic characteristics (Fig. 1) [45,46,57,62,63,70,73,76,85,95]. Recent research suggests that, based on genetic, transcriptional and epigenetic data, medulloblastoma can be divided even further into molecularly-determined subtypes which may potentially improve patient stratification in future clinical trials [6,42,50,74,75].

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Fig. 1.
Molecular subgroups of medulloblastoma [16,24,26,42,44,47,49,54,67,76,77,85,101]. WNT : wingless, SHH : sonic hedgehog, M : male, F : female.

WNT

This represents the rarest subgroup and accounts for approximately 10% of all medulloblastomas. Children and adolescents are the most commonly affected age groups [27]. WNT medulloblastomas are thought to arise from progenitor cells of the dorsal brain stem in the lower rhombic lip and typically present with somatic mutations in the CTNNB1 gene which encodes beta-catenin and leads to an overexpression of the subgroup-defining WNT signaling pathway [16,44]. Monosomy of chromosome 6 is characteristic of this subgroup [42,46]. TP53DDX3X, and SMARCA4 mutations have also been described in patients with WNT tumors [24,42,55,67,101]. WNT medulloblastomas are rarely metastatic and have a favorable outcome compared to the other subgroups [76].

SHH

A bimodal age distribution is typical for SHH tumors, with a peak incidence during infancy and adolescence [27]. About 30% of all medulloblastomas are classified as SHH tumors which are frequently located laterally in the cerebellar hemispheres [27,54]. There is evidence, that SHH medulloblastoma originates from cerebellar granule precursor cells of the external granule layer [8,16,44]. Hyperactivation of the SHH signaling pathway is characteristic of this subgroup and is often due to mutations in the tumor suppressor genes PTCH1, SMO and SUFU, or amplifications of GLI2 or MYCN [26,84,86]. TP53 mutations can be found in about 20% of all patients with SHH medulloblastoma and define a “very high risk” group of patients with poor outcome [61,101]. About 20% of patients with SHH tumors present with metastases at time of diagnosis.

Group 3

This subgroup represents about 25% of all medulloblastomas and affects almost exclusively infants and children. A male predominance is typical for this highly aggressive subgroup [27]. A commonly overexpressed pathway has not been identified, however, MYC amplification and isochromosome 17q are frequently observed alterations in these tumors [76,90,99]. In addition, amplification of OTX2, mutation of SMARCA4 and enhancer activation of GFI1 and GFI1B are recurrent genetic alterations [47,77]. Patients with group 3 tumors have the worst outcome and present with leptomeningeal dissemination at time of diagnosis in 40–45% of cases.

Group 4

These medulloblastomas affect patients of all age groups and account for approximately 35% of all medulloblastomas [27]. Although this subgroup is the most common, the underlying pathogenesis is poorly understood and the cells of origin have not been identified. Isochromosome 17q can be found in almost all group 4 tumors, however, there is no association with poor outcome in contrast to that described for group 3 medulloblastomas [76]. Mutation of KDM6A, amplification of MYCN and CDK6, loss of chromosome X in females and duplications of SNCAIP are also frequently detected cytogenetic alterations in this subgroup [44,49,77,79,85]. Despite the frequent presence of metastases at diagnosis, the overall outcome of patients with group 4 medulloblastoma is intermediate.


Source:
Cincinnati Children’s Hospital Medical Center
Media Contacts: 
Nick Miller – Cincinnati Children’s Hospital Medical Center
Image Source:
The image is credited to Cincinnati Children’s.

Original Research: Closed access
“Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse”. Q. Richard Lu et al.
Cancer Cell. doi:10.1016/j.ccell.2019.07.009

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