Targeted therapy done right: Direct sonic hedgehog inhibition for sonic hedgehog medulloblastoma Free

Medulloblastoma is the most common malignant brain tumor of childhood and rarely occurs in adulthood. It is subdivided into 4 molecular alterations-based groups: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Standard of care includes maximally safe surgical resection, radiation therapy, and systemic chemotherapy. Very young children (<3 years old) who cannot safely receive craniospinal radiation are treated instead with myeloablative chemotherapy requiring autologous stem cell rescue. Intensive multimodal therapy is curative in approximately 70% of patients, but those who live free of disease incur at least 1 long-term side effect and an increased risk of secondary cancers.¹ As a result, there remains a great need to improve survival and mitigate therapy induced morbidity by developing new treatment approaches.

Targeted therapy utilizing the smoothened (SMO) inhibitor, vismodegib, in SHH medulloblastoma has been an active area of research spanning from the bench to bedside.² SHH medulloblastoma occurs in young children under 5 years of age and adolescents older than 16 years of age through adulthood. Despite clinical evidence that oral vismodegib benefits a subset of patients with SHH medulloblastoma harboring PTCH1 mutations, its development has been limited to older patients because of irreversible damage to the growth plate and bone development.³ Kresbach et al. evaluated an alternative method of delivering vismodegib via an intraventricular route in genetically engineered infant mice that spontaneously develop medulloblastoma.⁴ These studies are to be applauded for rigor and quality investigations that will definitely move the field forwards toward diminishing systemic toxicities for CNS tumors. Comparing intraventricular vismodegib to oral vismodegib, they found that intraventricular vismodegib regressed tumor growth (partial or complete) and prolonged rodent model survival. And only oral vismodegib led to bone abnormalities and growth delays. While these findings are very promising, they motivate further immunologic, pharmacokinetic, and toxicity studies for use in young children with SHH medulloblastoma.

The authors performed histologic analysis of immune cells in untreated and treated tumors utilizing antibodies against CD3, a pan-T-cell marker, IBA-1, a pan-microglia and macrophage marker, and iNOS, to identify inducible nitric oxide synthase within cells. They observed minimal to no T cells, increased IBA-1 positive microglia and/or macrophages, and no difference in iNOS expression with vismodegib treatment via oral or intraventiricular route compared with no treatment. These findings agree with published studies of increased tumor associated microglia and peripheral myeloid cells after oral vismodegib in a rodent SHH medulloblastoma model.⁵ These collective studies demonstrating a rise in immune cells post-vismodegib warrant follow-up with additional investigations identifying myeloid cell function within the tumor microenvironment. In vitro studies could consist of harvesting resident microglia and peripheral myeloid cells that infiltrate the tumor after treatment to determine effects on tumor growth and immune effector cells (eg, expansion, cytotoxicity, repair mechanisms), which may provide valuable information on how specifically vismodegib changes the tumor immune landscape.

Additionally, these studies were limited by the paucity of pharmacologic analyses associated with vismodegib treatment. Specifically, no investigations were performed to examine the CNS penetration of vismodegib post oral versus intraventricular administration. This such research would allow for a better understanding of drug delivery, and possibly distribution, differences within the brain and plasma. While it can be hypothesized that intraventricular administration delivers higher CNS concentrations than systemic administration, serial timed sacrifices to harvest brain and plasma would allow for determination of maximum concentration (Cmax) and time required to meet maximum concentration (Tmax) of vismodegib based on varied dosing methods. Comparisons to previously reported pharmacokinetic parameters in other solid tumors would be helpful in further understanding of vismodegib in these SHH models, as well as permit assessment of the role of ABC transporters (ABCB1 and ABCG2) and the blood–brain/blood–CSF barriers play in restricting drug permeability.^6,7 Combined, this pharmacologic data would complement future clinical data aimed at determining inter- and intra-patient variabilities while on vismodegib.

While acute growth studies on skeletal muscles were evaluated between oral and intraventricular delivery, all animals evaluated in this study were young in age. The inability to evaluate higher and potentially more effective doses causing tumor death using intraventricular vismodegib in their rodent medulloblastoma models poses a barrier. Thus, while SMO inhibitors have been proven to be bone toxic in developing youth, vismodegib administered systemically may still remain a viable option for adolescent patients with more skeletal maturity.³ Craniospinal radiation therapy is the backbone of medulloblastoma treatment, yet has been linked to growth hormone deficiency and impaired short stature. Resultantly, future studies with vismodegib should also evaluate growth hormone level differences alone and in combination with vismodegib therapy, with close attention of acute and chronic side effects.

With the success of intraventricular administration of vismodegib in these preclinical SHH medulloblastoma models, it is important to note the potential financial toxicity related to treatment with these agents. While both the Food and Drug Administration and European Medicines Agency have approved two SMO inhibitors (vismodegib and sonidegeb) for use in over 60 countries, the cost is approximately $500 per capsule, making affordability for such a drug in low- and middle-income countries financially challenging to provide alone or in combination with standard chemotherapy.^8,9 Yet, if found to be feasible in the clinical setting, lower dosing for intraventricular administration could help to combat costs but may still remain an obstacle for repeat use in clinical settings.

Collectively, these studies aimed at using vismodegib in a more directed treatment application continue to mark the need to provide less systemic toxicities for brain tumor patients. These reported findings are sound studies that excite embryonal brain tumor researchers to advance the field related to clinical tools, effective drug delivery, and minimization of long-term treatment sequelae. With recommended future SMO inhibitor studies focused on surveillance of (1) immune microenvironmental changes, (2) pharmacokinetic parameters (alone and in combination with other agents), (3) acute and chronic growth development, and (4) financial toxicity risks, it is anticipated these investigations will prove to be beneficial to the global neuro-oncology field.

Funding

This research is supported by the intramural program of the National Institutes of Health, NCI, NINDS.

Conflict of interest statement

None declared.

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