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**The Children's Tumor Foundation Collection of Registered Research** ![CTF Logo][1] **About this Registry** This page curates the contents from the partnership between the Children's Tumor Foundation and PLOS ONE to jointly consider project proposals for funding and future publication. This partnership uses the [Registered Reports][2] model in which projects are considered for publication prior to results being realized. You can read more about the [partnership here][3]. Below are the accepted, registered versions of the research plans. Links to the registered projects are persistent. Projects protocols may be embargoed until final publication. @[toc](Funded Projects) ---------- ## Dietary Intervention for NF1 Muscle Weakness ## - **Authors** Aaron Schindeler, Emily Vasiljevski, Thusita Rupasinghe, Ute Roessner, Matthew Summers, Peter Houweling, David Little - **Organization** Children's Hospital at Westmead - **Location** Westmead, Australia - **Project Start Date** 2018-05-01 - **Project End Date** 2019-05-01 - **Grant Amount** $84,000.00 - **Registration** **Abstract** Neurofibromatosis type 1 (NF1) is associated with a high tumor burden in adulthood, but for many children their NF most profoundly impact on their school experiences through learning disabilities, muscle weakness, poor coordination, and fatigue. Recent clinical studies indicate muscle strength is reduced by 30-50% on average. Our breakthrough research has not only revealed that this weakness is linked to problems in fat metabolism in muscle, but in preclinical studies that dietary changes and supplements can overcome that weakness. We propose to complete a final series of preclinical studies with different diets and supplements to fine-tune our design for a dietary intervention trial in children, scheduled to start in 2018. ---------- ## Reprogramming the Tumor Microenvironment to Enhance Anti-Tumor Immunity in NF2 Vestibular Schwannomas Treatment ## - **Authors** Lei Xu, Jie Chen, Limeng Wu, Yao Sun - **Organization** Center for Human Genetic Research (CHGR) - **Location** Boston, MA USA - **Project Start Date** 2018-05-01 - **Project End Date** 2019-05-01 - **Grant Amount** $85,000.00 - **Registration** (Currently under embargo) **Abstract** Neurofibromatosis type II (NF2) is a disease that needs new solutions. The hallmark of NF2 is benign bilateral vestibular schwannomas (VS). Over time, these tumors grow and cause progressive hearing loss, which translates to social impairment and increased clinical depression.  The recent success of immune checkpoint inhibitors has demonstrated exciting and durable remissions across a spectrum of malignancies. However, as a benign tumor, little is known about whether NF2 patients are immune suppressed or how the benign schwannomas respond to immune therapy in patients.Fibrosis - high collagen content - contributes to solid stress, a type of mechanical force unique to tumors that causes blood vessels collapse and thus impaired perfusion. The resulting tissue hypoxia promotes aggressiveness, immunosuppression and resistance to therapy. Based on these, we propose to target the fibrogenic signaling pathway to reprogram the immunosuppressive microenvironment and enhance immunotherapy efficacy. Our research will generate important and translatable results for new combination therapy paradigms that are desperately needed for this dreadful disease.   ---------- ## Exploiting macropinocytosis for the development of exosome-mediated drug delivery in NF2 mutant tumors ## - **Authors** Andrea McClatchey, Christine Chiasson MacKenzie, Ching-Hui Liu, Shannon Stott - **Organization** Massachusetts General Hospital (the General Hospital Corp.) - **Location** Charlestown, MA USA - **Project Start Date** 2018-05-01 - **Project End Date** 2019-05-01 - **Grant Amount** $40,000.00 - **Registration** (Currently under embargo) **Abstract** Merlin, the protein encoded by the NF2 gene, is unique among tumor suppressors because it controls cell reproduction. Merlin controls how growth receptors respond to changes in the mechanical and physical properties of the cellular environment. We have recently discovered that Merlin regulates how cells take up fluids and nutrients from the environment, through a process called macropinocytosis. In the absence of Merlin, cells take in more fluids and nutrients. This project will seek to take advantage of this feature of NF2-mutant cells by utilizing this pathway for the delivery of drugs for the treatment of NF2 tumors. These studies will provide a foundation for the testing of this kind of treatment delivery for this and other therapies for NF2 patients. ---------- ## Evaluate Novel Hippo-Yap/Taz Inhibitors in Overcoming Therapy Resistance in NF2 ## - **Authors** Chunling Yi, Shannon M. White, Yang Yang, Shigekazu Murakami, Jeffery Field - **Organization** Georgetown University Medical Center - **Location** Washington, DC, USA - **Project Start Date** 5/10/2019 - **Project End Date** 5/10/2020 - **Grant Amount** $85,000 - **Registration** (Embargoed until 2023, or publication of results) **Abstract** NF2 is a chronic tumor syndrome that requires therapies that are both effective and durable. In order to circumvent treatment resistance, it is critical to develop combination strategies that target the redundant survival pathways in tumor cells. We have identified Hippo-Yap/Taz signaling as a major mechanism used NF2 tumor cells to overcome blockade of the RAS-RAF-MEK pathway and showed that NF2 tumor cells can be eradicated by combining a novel class of direct Hippo-Yap/Taz inhibitors with MEK inhibitors. Moreover, we have identified several other classes of drugs (including drugs that are FDA-approved and/or in clinical trials for NF2) that synergize with Yap/Taz blockade in selective killing of NF2 schwannoma cells. We propose to perform high throughput combination studies of four classes of drugs predicted by our preliminary studies to be synergistic with the above-mentioned clinical Hippo-Yap/Taz inhibitors developed by our industry partner Vivace Therapeutics (Aim 1), and select the most efficacious combinations for testing in mice (Aim 2). ---------- [1]: [2]: [3]:
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