<div>AbstractPurpose:<p>The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced <i>BRAF</i> V600–mutated cancers.</p>Patients and Methods:<p>This phase I dose-finding part treated patients ages 1 to <18 years with <i>BRAF</i> V600 mutation–positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target.</p>Results:<p>Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1–17 years)] with <i>BRAF</i> V600–mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6–148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC<sub>0–12</sub> and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily.</p>Conclusions:<p>In this first clinical trial in pediatric patients with pretreated <i>BRAF</i> V600–mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.</p></div>
Abstract Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) chromosomal translocation, which fuses the transcriptional regulatory domain of EWSR1 with the zinc finger DNA-binding domain of WT1 , resulting in the oncogenic transcription factor EWS-WT1. DSRCT primarily affects young males and has a 5-year overall survival of about 15%. Typical treatment approaches for patients with DSRCT involve a multi-modal combination of surgery, chemotherapy and radiation. The paucity of DSRCT disease models has hampered functional and pre-clinical therapeutic studies in this aggressive cancer. Here, we developed robust preclinical disease models and mined DSRCT expression profiling data to identify genetic vulnerabilities that could be leveraged for the identification of rational therapies. Specifically, we developed four new DSRCT cell lines and one patient-derived xenograft (PDX) model. Transcriptomic and proteomic profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands and downstream signaling. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Conversely, targeting of EGFR using shRNA, small molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited growth and induced apoptosis in DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for the clinical evaluation of EGFR antagonists in patients with DSRCT.
Abstract Background: Neurofibromatosis type 1 (NF1) is a neurogenetic condition characterized by neurocognitive symptoms, cutaneous findings, and a predisposition for benign and malignant tumors including peripheral nerve sheath tumors (PNST). About half of patients with NF1 develop plexiform neurofibromas (pNF), non-malignant tumors that often grow rapidly during childhood and can cause significant deformity, disruption of function, and pain. Some lesions, denoted atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), exhibit atypia, loss of neurofibroma architecture, high cellularity and mitotic activity, as an immediate precursor to malignant transformation. For people with NF1 there is a 10-15% overall lifetime risk of developing the aggressive soft tissue sarcoma malignant peripheral nerve sheath tumors (MPNST). Despite many clinical trials of chemotherapy and targeted agents, there has been little advancement in treatment outcomes and overall patient survival remains poor; therefore, new therapeutic approaches are needed. PNST are made up of transformed Schwann cell precursors, which do not grow and survive in isolation but rather interact with infiltrating immune cells. A deeper understanding of the relationship between the pre-existing immunity and the tumor microenvironment (TME) will help unveil potential for new combinations and adjuvant therapies for patients with PNST. Methods: We have developed a unique Johns Hopkins biospecimen repository of human NF1-associated PNST specimens. We use quantitative and spatial resolution of the geography and nature of tumor infiltrating immune cells in human PNST and have determined the interactions of T cells, myeloid cells, and immunoregulatory molecules, using a combination of multiplex chromogenic, high-dimensional flow cytometry and gene expression profiling studies. We have also analyzed existing transcriptomic datasets from 21 pNF and 34 MPNST cases. Results: RNA sequence analysis revealed an accumulation of immunosuppressive Th2 cells and tumor infiltrating myeloid cells (TIM) in the TME of PNST, which we postulate generates an anti-inflammatory response against tumors. Immunophenotyping of 17 pNF, 8 ANNUBP, and 15 MPNST human specimens confirmed the higher presence of infiltrating myeloid compared to lymphoid cells, with a predominance of CD163+ myeloid cells (TIM) during progression to malignancy. We also detected a significant increase in regulatory T cells and cytotoxic CD8+ T cells in MPNST vs ANNUBP vs pNF and near absence of CD19+ B cells in all tumor types. Multiparameter flow cytometry of single cells suspensions are being studied to further investigate the association of myeloid inflammation leading to the immune evasion of PNST. Conclusions: An immunosuppressive microenvironment characterizes PNST during the process of malignant transformation, generating an immune-excluded phenotype. Leveraging the immune contexture and the mechanisms of immune modulation in PNST will inform interventions to stimulate anti-tumor immunity in this dire disease. Citation Format: Lindy Zhang, Kai Pollard, Ana Calizo, Alexandre Maalouf, Aditya Suru, Jiawan Wang, Jineeta Banerjee, Christine A. Pratilas, Nicolas J. Llosa. Mechanisms of immune escape in NF1-associated peripheral nerve sheath tumors [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A008.
