In the spirit of [Registered Reports](https://www.nature.com/articles/d41586-019-02674-6), I will state a weekend research deliverable goal for Team Shirin. The Hackathon demo notebooks show applications of PCA and clustering, which help to identify outliers and find similarities in a population of objects. There are a number of papers giving [published demonstrations of similar, novel drug discovery analytic techniques](https://www.synapse.org/#!Synapse:syn18666641/discussion/threadId=6038). There are few drugs (mainly [selumetinib](https://www.astrazeneca.com/media-centre/press-releases/2019/selumetinib-granted-us-breakthrough-therapy-designation-in-neurofibromatosis-type-1-01042019.html)) showing results for NF1 tumors. The story of the [signalling pathways and etiology of NF1 is evolving](https://www.synapse.org/#!Synapse:syn18666641/discussion/threadId=6039). NF1 is in the family of [RASopathies](https://rasopathiesnet.org/rasopathies/), so insight on other rasopathies could be transferable. The main story is that * There are 2500+ observed mutations * There are about [35 known complications of NF1](https://www.synapse.org/#!Synapse:syn18666641/discussion/threadId=5871) * Different mutations lead to differently broken neurofibromin 1 proteins with a diverse range of effects * We can say that [NF1 complications correspond to largely non-intersecting sets of mutations](https://www.synapse.org/#!Synapse:syn18666641/discussion/threadId=6005). Call this our **first Hackathon deliverable**. I think that's a unique claim. If anybody thinks it's interesting, let's follow up further. * NF1 mutations could interact with mutations in other genes to produce one of the known complications * NF1 is autosomal dominant and exhibits haploinsufficiency * NF1 functions to regulate cell growth, so defective neurofibromin 1 protein leads to uncontrolled cell growth * A CNF tumor is small and has a rapid growth phase and then stabilizes to very slow growth * Where there is one CNF tumor there will be many * Our dataset for the Hackathon focuses on CNF and one or two other tumor types The most recent etiology of CNF is [Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway](https://www.ncbi.nlm.nih.gov/pubmed/30348677). The paper gives a strong theory of CNF and PNF development and also one for bone dysplasia. They suggest that "dampening the Hippo pathway" will cure CNF and look to this paper for Hippo pathway targets: * [Drug development against the hippo pathway in mesothelioma](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504108/) There are more Hippo pathway papers that may also give ideas: * [The Hippo Signaling Pathway: A Candidate New Drug Target for Malignant Tumors](https://www.ncbi.nlm.nih.gov/books/NBK500335/) * [Repurposing of Drugs Targeting YAP-TEAD Functions](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162436/) * [Safety Considerations in the Development of Hippo Pathway Inhibitors in Cancers](https://www.frontiersin.org/articles/10.3389/fcell.2019.00156/full) * [Role of Hippo Pathway-YAP/TAZ Signaling in Angiogenesis](https://www.frontiersin.org/articles/10.3389/fcell.2019.00049/full) * [The Hippo Signaling Pathway: an Emerging Anti-cancer Drug Target](http://www.discoverymedicine.com/Yuquan-Tao/2017/08/the-hippo-signaling-pathway-an-emerging-anti-cancer-drug-target/) * [Analysis of the role of the Hippo pathway in cancer](https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1869-4) * [The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment](https://www.nature.com/articles/nrd4161) * [Hippo pathway mediates resistance to cytotoxic drugs](https://www.pnas.org/content/114/18/E3729) #### Goal for the weekend * Focus on CNF * Implement some combination of the above cited novel drug discovery analytic techniques * Operate on the datasets made available to the Hackathon * Find molecules which bind to sites in the Hippo pathway * The binding molecules should have a dampening effect * The binding molecules should be likely to have few side-effects, so only bind to the particular targets in the Hippo pathway, assuming they have a unique "binding signature"