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Everyday we are reminded that there is a need for more targeted therapies to find specific, personalized and less toxic treatments for every patient. With the currently approved FDA cancer therapeutics drugs, we are only targeting the tip of the iceberg (85 targeted therapies for 105 gene products (1)) and with over 22,000 genes in our genome many genes are being neglected! At SEngine we are working to expand the pool of available drugs and, ultimately, be able to offer the patients a larger set of targeted therapies with our P.A.R.I.S test.

 

The Three Horsemen

*Based on The Cancer Genome Atlas of 11,130 patients

Unfortunately, not every gene product can be targeted with conventional small molecule inhibitors. Many of the major cancer-causing gene alterations, such as MYC, TP53, or KRAS, are not directly druggable (2–5). These three genes, which are sometimes referred as the “Three Horseman”, are altered in more than 60% of all tumors and finding a therapy targeting them would benefit a large group of patients. Interestingly, alterations in these un-druggable genes distinguish cancer cells from normal cells, conferring ‘synthetic lethal’ vulnerabilities that can be exploited by novel targeted therapies. A synthetic lethal target is a gene which is essential for optimal fitness of a cancer cell with a specific mutation. Potential therapies targeting this synthetic lethal target will have dramatically reduced toxicity since normal cells do not rely on these genes. These synthetic lethal gene-pairs are not evident by sequencing data alone or through expression correlations and are rarely mutated. The SEngine founders used a unique arrayed siRNA screening approach to specifically identify such gene pairs (6,7). The strategy of targeting non-recurrently mutated synthetic lethal genes with small molecule drugs has proven to be clinically effective, as illustrated by the favorable response of BRCA1 mutant cancers to PARP inhibitors (8).

cell death wide

We have hundreds of these gene pairs in hand and are now developing drugs targeting the synthetic lethal partner of major oncogenic drivers. We are developing the next generation of targeted therapies where we eliminate the synthetic lethal partner of the three most common cancer-causing genes: MYC, TP53 and KRAS. These 3 genes are the major driver for over 60% of all cancer based on “The Cancer Genome Atlas”.

 

Our Solution and Process. An Accelerated Drug Discovery and Validation Platform using Patient Derived Organoids

our process edited

The synthetic lethal pairs initially found in our screens are extensively validated using both, in vitro experiments and bioinformatics analysis. Next, we use three different approaches to find novel small molecules which are able to bind and inhibit specifically the synthetic lethal protein: 1) lead discovery using in vitro screens, 2) leveraging existing drugs (fallen angels and re-positioning), 3) artificial intelligence based in silico discovery of novel compounds. Historically, a potential therapeutic compound would be tested on cancer cell lines to validate the functional efficacy of the compound. However, this approach has proven to be problematic and has caused the failure of many potential therapeutics in downstream clinical trials. SEngine Precision Medicine, instead, is pursuing an innovative approach for the development of novel targets and drugs for cancer therapy by using primary patient organoids initially derived for our diagnostic assay. Guiding early stage drug development with patient cells and genomics will drastically increase the success of novel drug candidates and directly result in faster discovery processes and reduced costs. The end product of our pipeline provides high quality and specific compounds with a clear indication and biomarker, ready for submission as investigational new drug (IND).


We are currently pursuing multiple targets which are synthetic lethal with alterations in MYC, TP53 and KRAS and are actively looking for partners to further develop additional exciting new candidates for drug development. We have the unique ability to validate targets and candidate drugs in patient derived organoids from our constant flow of diagnostic samples, connecting potential drugs early in development with promising biomarkers.

Please contact us at targets@senginemedicine.com

 

1. Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2016).

2. Whitfield, J. R., Beaulieu, M.-E. & Soucek, L. Strategies to Inhibit Myc and Their Clinical Applicability. Front. Cell Dev. Biol. 5, 10 (2017).

3. Mantovani, F., Walerych, D. & Sal, G. Del. Targeting mutant p53 in cancer: a long road to precision therapy. FEBS J. 284, 837–850 (2017).

4. Roth, A. D. et al. Prognostic Role of KRAS and BRAF in Stage II and III Resected Colon Cancer: Results of the Translational Study on the PETACC-3, EORTC 40993, SAKK 60-00 Trial. J. Clin. Oncol. 28, 466–474 (2010).

5.        Papke, B. & Der, C. J. Drugging RAS: Know the enemy. Science (80-. ). 355, 1158–1163 (2017).

6.        Toyoshima, M. et al. Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc. Natl. Acad. Sci. U. S. A. 109, 9545–50 (2012).

7.        Moser, R. et al. Functional kinomics identifies candidate therapeutic targets in head and neck cancer. Clin. Cancer Res. 20, 4274–88 (2014).

8.        Lord, C. J. & Ashworth, A. PARP inhibitors: Synthetic lethality in the clinic. Science (80-. ). 355, 1152–1158 (2017).
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