The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

Figures & data

Figure 1. Cells of origin of SHH-MB. (A) The figure depicts the cerebellum development at embryonic early stage. Under SHH stimuli secreted from Purkinje cells (orange), granule neuron precursors (GNPs, blue) migrate from the rhombic lip to the external granule layer (EGL), then undergo the subsequent differentiation and migration into the inner granule layer (IGL). (B) Schematic representation of SHH-induced GNPs development, and its deregulation in the tumorigenesis of MB

Figure 2. Demographic, molecular and clinical features of SHH-MB and its four subtypes. SHH-MB accounts for 30% of MBs, has a 5-years survival rate of 75%, and occurs predominantly in male. Most SHH-MB patients are adult or infant. Values for histology variants (blue bars) and main gene alterations (orange bars) in SHH-MB are reported

Figure 3. SMO antagonists in SHH-MB. The figure highlights the compounds in preclinical and clinical studies impairing SMO receptor activity, and their action sites. Red stars indicate the SMO mutations involved in drug-resistance. Compounds entered in clinical trials for SHH-MB treatment are indicated in red. SHH: Sonic Hedgehog; PTCH: Patched receptor; SMO: Smoothened receptor; CRD: cysteine-rich domain; LD: linker domain; TMD: transmembrane domain; GLIs: glioma-associated oncogene transcriptional factors

Table 1. Clinical trials targeting SHH/GLI pathway for the treatment of newly diagnosed and relapsing/refractory MB patients

Target	Intervention	ID*	Title	Phase	Status	Combination drug	Patient population	Sponsor	Results posted	Ref.
SMO	Vismodegib	NCT01878617	A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma	II	Recruiting	· Radiotherapy · Chemotherapy (Cyclophosphamide, Cisplatin, Vincristine)	· 625 estimated enrolments (3 to 39 years) · Stratification on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH).	St. Jude Children’s Research Hospital	-	-
		NCT00939484	A Phase II Clinical Trial Evaluating the Efficacy and Safety of GDC-0449 in Adults With Recurrent or Refractory Medulloblastoma	II	Complete	-	· 32 enrolled patients (22.4 to 51.9 years) · Classification in: Stratum A, PTCH/SHH Pathway Inactivated (8); Stratum B, PTCH/SHH Pathway Activated (21); Stratum C, Unknown PTCH/SHH Pathway Activation (3). One patient in Stratum B was declared ineligible.	National Cancer Institute (NCI)	Yes	[95]
		NCT01601184	An International, Randomized, Open-label Phase I/II Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Adult Patients With Recurrent or Refractory Medulloblastomas Presenting an Activation of the Sonic Hedgehog (SHH) Pathway	I	Terminated^1	Temozolomide	· 24 enrolled patients (18 years and older) · Only 9 adult patients with relapsing or refractory MB received drugs combination.	Centre Leon Berard	-	-
		NCT01239316	A Phase II Clinical Trial Evaluating the Efficacy and Safety of GDC-0449 in Children With Recurrent or Refractory Medulloblastoma	II	Completed	-	· 12 enrolled pediatric patients (3 to 21 years)	National Cancer Institute (NCI)	Yes	[95]
		NCT00822458	A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449	I	Completed	-	· 34 enrolled patients (3 to 21 years) · Classification in: SHH-MB (7); WNT-MB (1); non-SHH/WNT-MB (21). One patient did not meet the eligibility criteria; 4 patients had inadequate tissue available to determine their MB subtype.	National Cancer Institute (NCI)	-	[30]
	Sonidegib	NCT01708174	A Phase II, Multi-center, Open-label, Single-arm Study of the Efficacy and Safety of Oral LDE225 in Patients With Hh-pathway Activated Relapsed Medulloblastoma	II	Completed	Temozolomide	· 22 enrolled patients (4 months and older) · Eligibility of only indicating HH-activated MB patients, who have experienced relapse or progression after standard-of-care therapy including radiotherapy.	Novartis Pharmaceuticals	Yes	-
		NCT01208831	An East Asian Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LDE225 in Patients With Advanced Solid Tumors	I	Completed	-	· 45 enrolled patients (18 years and older) · Only 2 patients with recurrent MB whose disease progressed despite standard therapy or for whom no standard therapy was available.	Novartis Pharmaceuticals Protocol number: CLDE225X1101^†	-	[32]
		NCT00880308	A Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LDE225 in Patients With Advanced Solid Tumors	I	Completed	-	· 103 enrolled patients (18 years and older) · Confirmed diagnosis of advanced solid tumor (including recurrent MB) that had progressed despite standard therapy or for which no therapy exists.	Novartis Pharmaceuticals Protocol number: CLDE225X2101^†	-	-
		NCT01125800	A Phase I/II Study of LDE225 in Pediatric Patients With Recurrent or Refractory Medulloblastoma or Other Tumors Potentially Dependent on the Hedgehog-signaling Pathway and Adult Patients With Recurrent or Refractory Medulloblastoma	I/II	Completed	-	· 76 enrolled patients (12 months to 18 years) · Classified in: Phase I (aged ≥12 months and <18 years) histologically confirmed diagnosis of MB, or other potentially HH-dependent tumors; Phase II (aged ≥12 months) histologically confirmed diagnosis of recurrent or relapsed MB with at least one measurable lesion.	Novartis Pharmaceuticals	Yes	[31]
		NCT03434262	Molecularly-Driven Doublet Therapy for All Children With Refractory or Recurrent CNS Malignant Neoplasms and Young Adults With Refractory or Recurrent SHH Medulloblastoma	I	Recruiting	Ribociclib	· 108 estimated enrolments (1 to 39 years) · Patients with refractory or recurrent SHH-MB >6 months off SMO inhibitor, presence of 9q loss or PTCH1 mutant, skeletally mature.	St. Jude Children’s Research Hospital	-	-
HDAC	MTX110	NCT04315064	Infusion of Panobinostat (MTX110) Into the Fourth Ventricle or Tumor Resection Cavity in Children and Adults With Recurrent Medulloblastoma: A Pilot Study	Early I	Recruiting	-	· 5 estimated enrolments (1 to 80 years) · Histologically verified MB with recurrence or progression involving anywhere in the brain and/or spine.	The University of Texas Health Science Center, Houston	-	-
CK2	CX-4945	NCT03904862	A Pediatric Brain Tumor Consortium Phase I/II and Surgical Study of CX-4945 in Patients With Recurrent SHH Medulloblastoma	I/II	Recruiting	-	· 60 estimated enrolments (3 years and older) · Classification in: Phase I, skeletally-immature children with refractory or recurrent SHH-MB; Phase II, skeletally-mature subjects with refractory or recurrent SHH-MB.	Pediatric Brain Tumor Consortium	-	-

*ClinicalTrials.gov Identifier, https://clinicaltrials.gov/ct2/home; updated August 2020.

¹The number of successes is not reached at the end of first stage of the phase II. The study is stopped.

2Trial stopped early for poor accrual.

^†Novartis Clinical Trial Database, https://www.novctrd.com/CtrdWeb/trialresults.nov

Figure 4. GLIs inhibitors in SHH-MB. The figure shows indirect (black) and direct (red) GLIs inhibitors. Negative regulators of GLIs activity are illustrated in blue boxes; positive regulators are illustrated in orange boxes. SHH: Sonic Hedgehog; PTCH: Patched receptor; SMO: Smoothened receptor; GLIs: glioma-associated oncogene transcriptional factors

Table 2. Ongoing clinical trials for the treatment of MB patients with immunotherapy

Immuno-based strategy	Intervention	ID*	Title	Phase	Status	Combination drug	Patient population	Sponsor
NK	Natural Killer Cell Therapy	NCT02271711	Phase I Study of Intraventricular Infusions of Autologous Ex Vivo-Expanded NK Cells in Children With Recurrent/Refractory Malignant Posterior Fossa Tumors of the Central Nervous System. NOAH’s (New Opportunity, Advancing Hope) Protocol	I	Active, not recruiting	-	· 12 enrolled patients (up to 21 years) · Inclusion of patients with recurrent/refractory MB.	M.D. Anderson Cancer Center
CAR T Cell	HER2-specific	NCT03500991	Phase 1 Study of HER2-Specific CAR T Cell Locoregional Immunotherapy for HER2 Positive Recurrent/Refractory Pediatric Central Nervous System Tumors	I	Recruiting	-	· 36 estimated enrolments (1 to 26 years) · Histologically diagnosed HER2-positive CNS tumor; evidence of refractory or recurrent CNS disease that has failed first-line therapy.	Seattle Children’s Hospital
	NKG2D-based	NCT04270461	A Phase I Clinical Trial of NKG2D-based CAR T-cells Injection for Subjects With Relapsed/Refractory NKG2DL+ Solid Tumors	I	Not yet recruiting	-	· 10 estimated enrolments (17 to 70 years)	Jiujiang University Affiliated Hospital
	EGFR806-specific	NCT03638167	Phase 1 Study of EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric Central Nervous System Tumors	I	Recruiting	-	· 36 estimated enrolments (1 to 26 years) · Histologically diagnosed EGFR positive CNS tumor; evidence of refractory or recurrent CNS disease that has failed first-line therapy.	Seattle Children’s Hospital
	SCRI-CARB7H3(s); B7H3-specific	NCT04185038	Phase 1 Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors	I	Recruiting	-	· 70 estimated enrolments (1 to 26 years) · Diagnosis of refractory or recurrent CNS disease for which there is no standard therapy.	Seattle Children’s Hospital
ICIs	Pembrolizumab	NCT02359565	A Safety and Preliminary Efficacy Trial of MK-3475 (Pembrolizumab; Anti-PD-1) in Children With Recurrent, Progressive or Refractory Diffuse Intrinsic Pontine Glioma (DIPG), Non-Brainstem High-Grade Gliomas (NB-HGG), Ependymoma, Medulloblastoma or Hypermutated Brain Tumors	I	Recruiting		· 100 estimated enrolments (1 to 29 years) · Inclusion criteria for patients with a histologically confirmed diagnosis of MB that is recurrent, progressive or refractory following therapy which included radiotherapy.	National Cancer Institute (NCI)
	Nivolumab	NCT03173950	Phase II Trial of the Immune Checkpoint Inhibitor Nivolumab in Patients With Select Rare CNS Cancers	II	Recruiting	-	· 180 estimated enrolments (18 years and older) · Histopathologically proven diagnosis of Rare CNS cancers, including MB. Patients must have progressive tumor growth after having received established standard of care treatment for their disease. Patients will be enrolled into 2 different cohorts (cohort 1 or heavily pretreated; cohort 2 or not heavily pretreated)	National Cancer Institute (NCI)
		NCT03130959	An Investigational Immuno-therapy Study of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Patients With High Grade Primary CNS Malignancies	II	Active, not recruiting	Ipilimumab	· 170 estimated enrolments (6 months to 21 years) · Inclusion of patients with recurrent/progressive MB.	Bristol-Myers Squibb
OVs	G207	NCT03911388	Phase 1 Trial of Engineered HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors	I	Recruiting	-	· 15 estimated enrolments (3 to 18 years) · Pathologically proven malignant cerebellar brain tumor (including MB) which is progressive or recurrent despite standard care including surgery, radiotherapy, and/or chemotherapy.	University of Alabama at Birmingham
	PVSRIPO	NCT03043391	Phase 1b Study PVSRIPO for Recurrent Malignant Glioma in Children	I	Recruiting	-	· 12 estimated enrolments (12 to 21 years)	Istari Oncology, Inc.
Vaccine Immunotherapy	TTRNA-xALT TTRNA-DCs	NCT01326104	Vaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor	I II	Active, not recruiting	-	· 17 enrolled patients (up to 30 years) · Inclusion of patients with suspected first recurrence/progression of MB/PNET since completion of definitive focal ± craniospinal irradiation. Disease progression prior to receiving definitive focal ± craniospinal irradiation will not disqualify patients from enrolment if they have subsequently failed definitive radiotherapy and are at first recurrence/progression at time of enrolment.	University of Florida

*ClinicalTrials.gov Identifier, https://clinicaltrials.gov/ct2/home; updated August 2020.

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