ABSTRACT Prognosis for children and young adults with metastatic, relapsed, or refractory solid tumors remains unacceptably poor and has not improved significantly over the past three decades despite multimodality treatment including surgery, radiation, and chemotherapy. Current approaches have reached the limits of maximal dose intensification, and the acute and late effects of combination therapy are substantial. The goal of this proposal is to improve the cure rate and quality of life in pediatric cancer patients through approaches that maximize effects of current therapy while minimizing associated complications. Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) provides controlled delivery of heat through precise image guidance, real-time temperature mapping, and spatially well-defined deposition of energy using an external applicator that is completely non-invasive and non-ionizing. Lyso-thermosensitive liposomal doxorubicin (LTLD) is a heat-activated formulation of liposomal doxorubicin with the unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. The flexibility and control over low temperature local heating induced by MR-HIFU provides an ideal system to be used in conjunction with LTLD. Mathematical modeling and studies in rodents demonstrated that overall exposure of targeted tissue to drug can be significantly enhanced by pulse of higher temperature heating (++) following drug release from LTLD triggered by MR-HIFU mild hyperthermia (40 – 45 °C, HT++). The heating pulse is thought to not only prevent drug washout, but also to target those parts of the tumor that may not be exposed to a sufficient quantity of drug. The synergistic effects of this therapy are manifold and include enhanced permeability of the tumor vasculature, enhanced extravasation of the drug and subsequent high concentrations of doxorubicin in the targeted tumor, the expression of heat shock proteins, inhibition of DNA repair, and stimulation of immune responses. We propose to address the clinical challenges posed by advanced local disease through a robust bench to bedside proposal that combines the strengths of both the intramural and extramural teams. We will first evaluate the relative ability of this combination to improve the homogeneity and overall levels of drug delivery in preclinical rabbit Vx2 tumor model that is large enough to allow for precise spatial control of heating with MR-HIFU. We will evaluate the impact of LTLD combined with MR-HIFU mild hyperthermia and heating pulse on vasculature and nerve tissue function, its influence on host immune response and its impact on tumor growth delay and metastasis outside of treatment field in the same pre-clinical model. Following a comparative study of effects in the pre-clinical model, we will evaluate the safety and clinical benefit of LTLD-HT++ in Phase II clinical trial enrolling children...