Neurofibromatosis Type 1-Associated Optic Pathway Gliomas: Current Challenges and Future Prospects

Figures & data

Figure 1 NF1-OPGs in children. (A) A pre-chiasmatic OPG (red arrow) involving the left optic nerve. The optic nerve is enlarged and tortuous compared to the normal optic nerve on the right. (B) An OPG involving the optic chiasm. Red arrows point to the enlarged chiasm. (C) An OPG involving the bilateral optic radiations (red asterisks). The images are axial T2-weighted MRI scans.

Figure 2 Proposed flow diagram for NF1-OPG screening and monitoring. Children with NF1 should undergo ophthalmological exam annually until 8 years of age, then every 2 years until age 18 if asymptomatic. Once symptoms develop, especially visual symptoms, MRI should be performed, and screening frequency should be increased to every 3 months for the first year. The intervals of the ophthalmologic examinations and MRIs can be gradually increased if stability of vision is achieved.

Figure 3 Interaction of tumor cells, neurons, and immune cells in murine Nf1-OPGs. Nf1-deficient tumor (glioma) cells produce Ccl2 to attract T cells, which release Ccl4 following exposure to Nf1-mutant neuronal midkine to induce Ccl5 secretion from Nf1-mutant microglia. Ccl5 functions as a potent mitogen for glioma cell growth. In addition, Nf1-mutant RGCs also promote tumor initiation and expansion through the elaboration of neuroligin-3 (Nlgn3) in response to light (visual experience). The establishment of a supportive microenvironment for Nf1-OPG formation and growth allows for risk factor convergence at the level of neurons (light, specific Nf1 mutation), T cells (asthma), and microglia (other systemic exposures).

Table 1 Active Clinical Trials for NF1-OPG

Agent	Study Number	Status	Sponsor	Phase	Ages	Primary Outcome
Selumetinib	NCT03326388	Recruiting	Great Ormond Street Hospital	I/II	3 to 18 years	Maximum Tolerated Dose
Selumetinib	NCT01089101	Active, not recruiting	NCI	I/II	3 to 21 years	Maximum tolerated dose and response rate
Selumetinib	NCT03871257	Recruiting	NCI	III	2 to 21 years	Event-free survival and visual acuity improvement
Vinblastine ± bevacizumab	NCT02840409	Recruiting	The Hospital for Sick Children	II	6 months to 18 years	Response rate
Lenalidomide	NCT01553149	Active, not recruiting	NCI	II	Up to 21 years	Response rate
Poly-ICLC	NCT04544007	Recruiting	University of Alabama at Birmingham, NFCTC	II	Up to 22 years	Response rate

Abbreviations: Poly-ICLC, Polyinosinic-Polycytidylic; NCI, National Cancer Institute; NFCTC, Neurofibromatosis Clinical Trials Consortium.