Study Shows that Drug Combination Therapies Effective in Treating Schwannomas and Meningiomas
The Synodos for NF2 consortium of the Children’s Tumor Foundation (CTF) today published its first set of results and released its second set of data in the leading scientific journal PLOS ONE. Synodos is the Foundation’s innovative team science collaborative that brings researchers, clinicians and patients together in a shared data environment, in order to develop treatments for NF patients at an accelerated pace. Established in 2014, the $3 million project is a combined effort among 12 leading research labs at 8 institutions.
The Synodos for NF2 team released its first set of results and data in the scientific journal PLOS ONE, entitled Traditional and Systems Biology Based Drug Discovery for the Rare Tumor Syndrome Neurofibromatosis Type 2. In line with the Foundation’s principles of open-access and data sharing, the journal is making the full article available to all, with immediate access to the data.
The primary aim of the Synodos for NF2 team was to find treatments that could be used for both meningioma and schwannoma by using a drug discovery approach of selecting mechanistically relevant compounds. The team integrated innovative research approaches such as Next Generation Sequencing (NGS) and Kinome profiling. These two techniques allow analysis of the alteration in expression of genes and proteins in cells or animal models.
A core finding was that while schwannomas and meningiomas are both initiated by merlin loss, the distinctly different responses to that loss of function are likely to prescribe that a single drug (target) is unlikely to be optimally effective in both cell types. Instead, it is likely that different drugs or combos (a cocktail of two or more drugs) aimed at distinct targets will be required to treat these two tumor types. In fact, the first three single drugs tested (Panobinostat, CUDC-907 and GSK2126458) were only mildly active in preventing tumors from growing. The next set of experiments started looking at drug combinations and the team reported that the drug Dasatininb, a multi-kinase inhibitor in combination with AZD-2014 or INK128, both dual mTORC1/2 inhibitors, suppressed tumor growth up to ~85% in a meningioma animal model (this last result was reported earlier in March 2018 by the Synodos team in the scientific journal Neuro-Oncology. That publication can be found here: https://doi.org/10.1093/neuonc/noy046).
Additionally, the work of the Synodos for NF2 consortium has filled a critical gap in the understanding of how the NF2 mutation and the absence of merlin influence tumor cell behavior in both meningiomas and schwannomas. The collective effort of twelve research groups succeeded in:
(1) creating a new pipeline of well-validated tools for NF2-associated drug discovery with fully characterized isogenic pairs of meningioma and schwannoma cell systems;
(2) gaining conceptual insights into disease mechanisms via transcriptome and kinome interrogation that indicate that different drugs are likely to be needed to treat meningioma and schwannoma;
(3) validating pathways and targets that are altered based on tumor type and in response to targeted pathway inhibition in the setting of NF2; and
(4) building an openly accessible (http://www.synapse.org/SynodosNF2) database for community sharing and mining of drug treatment, transcriptome and kinome data from isogenic schwannoma and meningioma cell systems. This data presents several targets to consider for single agent and combination therapy in the short term, and provides a deep and rich open access data resource for the broader research community seeking treatments for NF2-associated meningioma and schwannoma for the long term.
The Synodos team is actively working on finalizing the latest findings, which will also be published as a follow up to this research release.
Ultimately, these newly released results and data are providing, for the first time, a critical resource that will be invaluable to the NF2 research community. This work illustrates that the CTF model of bringing together scientists of diverse expertise areas improves the ability to discover new therapeutic strategies to treat these highly devastating tumors.
The full article in PLOS ONE can be found here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197350
ABOUT THE CHILDREN’S TUMOR FOUNDATION:
The Children’s Tumor Foundation is a 501(c)(3) not-for-profit organization dedicated to funding and driving innovative research that will result in effective treatments for the millions of people worldwide living with neurofibromatosis (NF), a term for three distinct disorders: NF1, NF2, and schwannomatosis. NF causes tumors to grow on nerves throughout the body and may lead to blindness, deafness, bone abnormalities, disfigurement, learning disabilities, disabling pain, and cancer. NF affects 1 in every 3,000 births across all populations equally. There is no cure yet – but the Children’s Tumor Foundation mission of driving research, expanding knowledge, and advancing care for the NF community fosters our vision of one day ending NF. For more information, please visit www.ctf.org.
