Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas

Plexiform neurofibromas (pNF) are pathognomonic nerve and soft tissue tumors of neurofibromatosis type I (NF1), which are highly resistant to conventional chemotherapy and associated with significant morbidity/mortality. Disruption of aberrant SCF/c-Kit signaling emanating from the pNF microenvironment induced the first ever objective therapeutic responses in a recent phase 2 trial. Sunitinib malate is a potent, highly selective RTK inhibitor with activity against c-Kit, PDGFR, and VEGFR, which have also been implicated in the pathogenesis of these lesions. Here, we evaluate the efficacy of sunitinib malate in a preclinical Krox20;Nf1flox/− pNF murine model. Experimental Design Proliferation, β-hexosaminidase release (degranulation), and Erk1/2 phosphorylation were assessed in sunitinib treated Nf1+/− mast cells and fibroblasts, respectively. Krox20;Nf1flox/− mice with established pNF were treated sunitinib or PBS-vehicle control for a duration of 12 weeks. pNF metabolic activity was monitored by serial [18F]DG-PET/CT imaging. Results Sunitinib suppressed multiple in vitro gain-in-functions of Nf1+/− mast cells and fibroblasts and attenuated Erk1/2 phosphorylation. Sunitinib treated Krox20;Nf1flox/− mice exhibited significant reductions in pNF size, tumor number, and FDG uptake compared to control mice. Histopathology revealed reduced tumor cellularity and infiltrating mast cells, markedly diminished collagen deposition, and increased cellular apoptosis in sunitinib treated pNF. Conclusions Collectively, these results demonstrate the efficacy of sunitinib in reducing tumor burden in Krox20;Nf1flox/− mice. These preclinical findings demonstrate the utility of inhibiting multiple RTKs in pNF and provide insights into the design of future clinical trials

Toward Waveform Nonlinear Optics Using Multimillijoule Sub-Cycle Waveform Synthesizers

Waveform nonlinear optics aims to study and control the nonlinear interactions of matter with extremely short optical waveforms custom-tailored within a single cycle of light. Different technological routes to generate such multimillijoule sub-optical-cycle waveforms are currently pursued, opening up unprecedented opportunities in attoscience and strong-field physics. Here, we discuss the experimental schemes, introduce the technological challenges, and present our experimental results on high-energy sub-cycle optical waveform synthesis based on (1) parametric amplification and (2) induced-phase modulation in a two-color-driven gas-filled hollow-core fiber compressor. More specifically, for (1), we demonstrate a carrier-envelope-phase (CEP)-stable, multimillijoule three-channel parametric waveform synthesizer generating a >2-octave-wide spectrum (0.52-2.4 μm). After two amplification stages, the combined 125-μJ output supports 1.9-fs FWHM waveforms; energy scaling to >2 mJ is achieved after three amplification stages. FROG pulse characterization of all three second-stage outputs demonstrates the feasibility to recompress all three channels simultaneously close to the Fourier limit and shows the flexibility of our intricate dispersion management scheme for different experimental situations. For (2), we generate CEP-stable 1.7-mJ waveforms covering 365-930 nm (measured at 1% of the peak intensity) obtained from induced-phase modulation in a two-color-driven gas-filled hollow-core fiber. Using custom-designed double-chirped mirrors and a UV spatial light modulator will permit compression close to the 0.9-fs FWHM transform limit. These novel sources will become versatile tools for controlling strong-field interactions in matter and for attosecond pump-probe spectroscopy using VIS/IR and XUV/soft-X-ray pulses