Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (nâ=â7) and prior BRAF inhibitor therapy (nâ=â7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

New approaches to risk stratification for Wilms tumor.

PURPOSE OF REVIEW: The treatment of Wilms tumor is one of the great achievements in the field of oncology. One of the key success factors has been improved risk stratification, enabling augmentation or reduction of therapy depending on a patient's risk of relapse. This article highlights the evolution of clinical and biological prognostic markers that have been applied in the treatment of Wilms tumor. RECENT FINDINGS: Historically, tumor stage and histology were the sole determinants of Wilms tumor treatment. Recent clinical trials conducted by the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP) Renal Tumor Study Group have expanded the menu of prognostic factors to include histologic and volumetric response to therapy and tumor-specific loss of heterozygosity (LOH) at chromosomes 1p and 16q. Augmentation of therapy has been able to overcome the adverse risk factors. An emerging prognostic marker is chromosome 1q gain, will be incorporated into future clinical trials. SUMMARY: The application of new clinical and biological prognostic factors has created unprecedented ability to tailor therapy for Wilms tumor, accompanied with improved outcomes. Current and future trials will continue to enhance precision medicine for Wilms tumor.

Targeting the HIF-1α-IGFBP2 axis therapeutically reduces IGF1-AKT signaling and blocks the growth and metastasis of relapsed anaplastic Wilms tumor.

For patients with anaplastic Wilms tumor (WiT), metastasis and recurrence are common, and prognosis is generally poor. Novel therapies are needed to improve outcomes for patients with this high-risk WiT. A potential contributor to WiT development is constitutive activation of AKT by insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) signaling pathway, but the complete underlying mechanism remains unclear. Here, we demonstrate that the hypoxia-inducible factor 1α (HIF-1α)-IGF binding protein 2 (IGFBP2) axis and the tumor-specific IGF1A are key players for constitutive activation of IGF1-AKT signaling leading to the tumor malignancy. HIF-1α and IGFBP2 are highly expressed in a majority of WiT patient samples. Deficiency of either HIF-1α or IGFBP2 or IGF1 in the tumor cells significantly impairs tumor growth and nearly abrogates metastasis in xenografted mice. Pharmacologic targeting of HIF-1α by echinomycin delivered via nanoliposomes can efficiently restrain growth and metastasis of patient-derived relapsed anaplastic WiT xenografts. Liposomal echinomycin is more potent and effective in inhibiting WiT growth than vincristine in an anaplastic WiT mouse model, and eliminates metastasis by suppressing HIF-1α targets and the HIF-1α-IGFBP2 axis, which governs IGF1-AKT signaling.