Three-quarters of a million dollars to fund critical research
The Children’s Tumor Foundation (CTF) is pleased to announce an investment of $760,000 in NF2-related schwannomatosis and schwannomatosis-focused projects through the Young investigator Awards and Drug Discovery Initiatives, a group of grants that sit within the CTF Discovery Fund. This fund supports researchers and clinicians engaged in novel and fundamental NF investigations. These new projects will focus on tumor growth, DGCR8 syndrome, understanding inflammation and hearing loss, and several potential drug candidates.
Young Investigator Awards (YIA):
To understand the role of Apelin-mediated angiogenesis in NF2-associated tumors Srirupa Bhattacharya, Massachusetts General Hospital
NF2-associated tumors, however, have shown inconsistent response to treatment with the antiangiogenic drug Bevacizumab (BVZ)/Avastin, which targets vascular endothelial growth factor (VEGF). Also, BVZ/Avastin can cause severe side effects like bleeding and high blood pressure. Previous work from the Ramesh lab showed increased expression of the angiogenic peptide apelin (APLN) in NF2-negative tumor cells. Inhibiting apelin in other tumor types reduced tumor size and blood vessel formation. This study aims to understand the role of apelin in NF2 tumors and will explore if targeting apelin disrupts angiogenesis and NF2 tumor growth. Since apelin is only expressed in tumor tissues, targeting apelin will not affect normal blood vessels of the body, thereby bypassing the harmful side effects of Avastin.
Dissecting DGCR8 syndrome and the molecular mechanisms driving DGCR8-associated schwannomatosis Clara Nogue I Anson, IDIBELL Spain
The Rivera group recently identified a mutation in the DGCR8 gene, also located on chromosome 22, which was responsible for a familial form of multinodular goiter that manifests together with peripheral schwannomas. This proposal will investigate the characteristics of DGCR8-mutated schwannomas and identify the mechanisms that lead to their formation. Given the global role of DGCR8 in cellular processes, knowledge of key dysregulated events in DGCR8-schwannoma formation can also apply to other schwannomas with alterations on chromosome 22.
Tumor: Macrophage Interactions in Schwannoma Sara Veiga, Massachusetts General Hospital
Schwannomas are made of different cell types including Schwann cells, axons (part of a nerve cell), blood vessels, immune cells, and an extracellular matrix. This complex “tumor microenvironment” makes tumors very heterogeneous and is also suspected to contribute to the diverse clinical response of these tumors to drugs. Macrophages, a type of immune cells, are found in developing schwannomas and especially influence a tumor’s characteristics including presence or absence of pain. However, how these immune cells are recruited to the tumor is not yet very well understood.
The goal of this proposal is to study how macrophages are recruited to schwannomas over time and to understand how they interact with schwannoma tumor cells to help the tumor grow. Understanding these interactions can be valuable for developing new therapies to fight tumor growth and alleviate symptoms such as pain associated with the disease.
Co-Targeting HMGB1 and EGF signaling for the treatment of NF2 and associated hearing loss Zhenzhen Yin, Massachusetts General Hospital
Preliminary studies from the Xu lab showed that a protein called HMGB1, a potent inflammation initiator and amplifier, is released by the schwannomas and can cause inflammation in the ears, leading to hearing loss. The aim of this study is to test if blocking HMGB1 can prevent hearing loss in mice. Since HMGB1 blockade activates epidermal growth factor (EGF) signaling, which may compensate for tumor growth, this study will also explore combined HMGB1 and EGF receptor (EGFR) blockade can prevent hearing loss and delay tumor growth in mice with schwannomas. The study will help understand how HMGB1 causes inflammation in the ears and how we can stop the tumors from growing, which can be useful in designing future treatments for patients with vestibular schwannoma.
Drug Discovery Initiative (DDI):
Developing a thrombopoietin inhibitor to treat NF2 hearing loss and schwannoma growth Lawrence Sherman, Oregon Health and Science University
Patients with neurofibromatosis 2 (NF2) often suffer hearing loss, balance problems, and facial paralysis due to schwannomas on their acoustic nerves. The Sherman group previously found that a drug called losartan could prevent hearing loss in a mouse model of NF2. Although losartan is generally safe, it is unclear if it will be effective in NF2 patients and sometimes has severe side effects. Losartan works by inhibiting platelet activity and coagulation factors, which can contribute to inflammation around tumors and affect the cellular machinery needed for hearing. The proposed study will use a different drug, a thrombopoietin antisense oligonucleotide (TPO-ASO) that is being tested in clinical trials for other diseases and which also regulates platelets but does not have side effects linked to losartan. This study will help define how losartan functions to preserve hearing in the presence of acoustic nerve schwannomas and test if TPO-ASO could be a drug candidate to protect or improve hearing and reduce tumor growth in NF2 patients.
Development of cell penetrating peptides targeting the Yap/Tead complex in the context of Neurofibromatosis type 2 Dominique Lallemand, INSERM, France
Neurofibromatosis type 2 (NF2), characterized by the development of intracranial tumors, is caused by the inactivation of the NF2 gene. Absence of merlin, the NF2 gene product, inactivates the Hippo signaling pathway resulting in the accumulation YAP and TEAD proteins in the nucleus of affected cells. YAP and TEAD bind to each other and activate mechanisms that lead to tumor development. Thus, preventing the association of YAP with TEAD is a possible strategy to prevent tumor development.
Previous work by the Lallemand group identified a candidate peptide that can enter cells and disrupt the binding of YAP to TEAD. The current study aims to improve this peptide to make it more stable and more efficient at dissociating the YAP/TEAD complex. The study will also create new models of schwannomas that better replicate the proliferation of tumor cells and growth of schwannomas. The combination of rational peptide design and improved model systems will be a powerful approach to develop a peptide therapeutic for NF2.
Development of Nanobody-decorated Bacterial Outer Membrane Vesicles for Schwannoma Immunotherapy Sherif Ahmed, Massachusetts General Hospital
This research group recently showed that injecting attenuated Salmonella typhimurium alone or in combination with systemic checkpoint inhibitor directly into tumors in a schwannoma mouse model showed an anti-tumor effect. The present work, instead of using live bacteria, will utilize bacterial outer membrane vesicles (OMVs) for schwannoma therapy. OMVs are nanosized vesicles released by bacteria and possess the same immunostimulatory molecules and preferentially accumulate in tumor tissues. Preliminary data showed that a single systemic injection of attenuated S. typhimurium OMVs, loaded with novel bispecific nanobody against CD74 and PDL-1 receptors, resulted in rapid tumor cell death and synergistic tumor regression in schwannoma mouse models, without any noticeable adverse effects. This study will further evaluate the effect of this novel therapy on survival of schwannoma bearing mice and investigate its long-term effects.
The Young Investigator Award (YIA) provides seed funding to attract early-career researchers to the field and to produce data to secure larger grants, such as from the NIH and CDMRP NFRP. Several former YIAs are now leaders in the NF research and clinical communities. In fact, CTF’s ‘seeding’ of the NF field with new talent has been hailed as one of the key reasons for rapid advancements in NF research in recent years.
The Drug Discovery Initiative (DDI) stimulates NF drug discovery by funding researchers proposing to investigate novel or repurposed therapies for NF or to develop tools that support such research.
In addition this year, nearly $700,000 is also being invested in research projects focused on NF1. Click here to read about these investments.
Click here to learn more about funding opportunities from the Children’s Tumor Foundation.
