LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration.

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

Pigment epithelium-derived factor short peptides facilitate full-thickness cutaneous wound healing by promoting epithelial basal cell and hair follicle stem cell proliferation.

A previous study by our group showed that a 44-amino-acid fragment of pigment epithelium-derived factor (PEDF) facilitated corneal epithelial wound healing. In the present study this fragment was shortened to obtain peptides of 18, 20 and 29 amino acids in length, and their promoting effects on the healing of full-thickness skin wounds were assessed. Peptides were delivered periodically by topical application to punch wounds of mice. The wound healing speed was evaluated by measuring the reduction of wound areas at 4 and 7 days after injury. Histological analysis with Masson's trichrome staining was used to confirm epithelialization and dermal collagen deposition. Proliferation of epithelial basal cells was documented by 5-bromo-2'-deoxyuridine incorporation. Hair follicle stem cells were identified by immunostaining for leucine-rich repeat-containing G protein-coupled receptor 6. The results indicated that the 20- and 29-amino-acid short peptides significantly reduced the time required for wound healing compared to the vehicle. Histological analysis confirmed faster epithelial cell coverage of open wounds. Treatment with the PEDF peptide fragments also contributed to granulation, tissue formation by increasing the fibroblast population and enhancing collagen deposition in the dermis. Wounds treated with PEDF peptide fragments contained more basal cells proliferated in the epithelium. Moreover, hair follicle stem cells were also stimulated to proliferate by peptide exposure. In conclusion, the present study reported the identification of two short peptides that can enhance the healing of full-thickness skin wounds following topical application. The underlying mechanisms may involve activation of basal cell proliferation and mobilization of hair follicle stem cells.

DDB2 is a novel AR interacting protein and mediates AR ubiquitination/degradation.

Damaged DNA-binding protein 2 (DDB2), a protein that binds damaged DNA, is a DDB1 and CUL4-associated factor. This study is the first to demonstrate that DDB2 is a novel androgen receptor (AR)-interacting protein; and mediating contact with AR and CUL4A-DDB1 complex for AR ubiquitination/degradation. DNA damage induces both p53 and DDB2 gene expression those two can inhibit AR expression. The former reduces AR via transcription regulation but the latter via proteosome degradation. Thereby DDB2 can inhibit cell growth rate in AR-expressing cells (LNCaP) but not in AR-null cells (PC3). Hence DDB2 may be a potential regimen for prostate cancer treatment, especially in androgen-refractory patients harboring high amount of AR who cannot be cured by androgen ablation.