The study of colorectal cancer has shown that MERTK (TYRO3 / AXL / MER, TAM receptor kinase family) is an important target for cancer cell immune response evasion mechanism. Thus, Deargen is researching by focusing on small molecule inhibitors.
Colorectal cancer is a disease that anatomically refers to malignant tumors that occur in the caecum, colon, rectum of the large intestine. It occurs primarily with adenocarcinoma, but can also appear in the form of lymphoma, carcinoid, etc.
Cancer immunotherapy is one of the treatment for cancer, based on third-generation immune check point inhibitors overcoming the down sides of the existing first-generation chemotherapy and second-generation target therapy. Cancer immunotherapy targets the body’s immune system. In other words, it is a therapy that induces the patients to heal cancer on their own.
The main targets of this immunotherapy are immune cells that catch and remove abnormal cells like cancer such as CD8 T cell, NK cell, Macrophage, Dendritic cell, etc. Immune cells use a biological system called an immune checkpoint for identification of friend and foe(IFF).
In the example at the top, the proteins called PD-1 (Programmed death cell protein 1) and PD-L1 (Programmed death-ligand 1) can be IFF protein for cells that come in contact with immune cells. Abnormal cells do not produce PD-L1 by nature and must be killed by immune cells, but cancer cells produce excessive amounts of PD-L1 to evade immune responses and survive. As a result, the immune cells of the human body recognize cancer cells as an ally and keep them alive, and the disease progresses.
There are a variety of cell-surface proteins such as CTLA-4, A2AR, LAG3, KIR, and VISTA, etc. including PD-1, PD-L1 that were mentioned earlier in the immunosuppressive checkpoints that confuse the immune systems. The mechanism of cancer immunotherapy is to activate the body’s immune system and kill cancer cells through blocking these immunosuppressive checkpoints. And MERTK that we pay attention also plays an important role in immune evasion and survival of cancer cells with the expression of PD-L1. (Lee-Sherick et al., 2018)
Among biopharmaceuticals using antibodies, representative cancer immunotherapy for colorectal cancer is Opdivo (Nivolumab). Immune checkpoint is not the target, but there is Avastin (Bevacizumab) with a mechanism that inhibits cancer cell metastasis by inhibiting VEGF. The colorectal cancer drug market was estimated at $ 7 billion in 2014 and shows constantly its growth trend. In the United States that is the leading pharmaceutical market, 39,910 new cases of rectal cancer were reported in 2017 and 95,520 cases of colorectal cancer were reported.
In 2016, 28,127 patients with colorectal cancer were reported in South Korea. Overall, the colorectal cancer diagnostic and treatment market is expected to show the Compound Annual Growth Rate (CAGR) of around 4.6% between 2019 and 2024. In this market where chemotherapy and cancer immunotherapy are the mains, we elicit mechanisms similar to cancer immunotherapy by returning to small molecular and are looking for a win-win market through sequential and/or co-treatment therapy rather than compete with the latest antibody drugs.
In academia and pharmaceuticals, a result that MERTK (TYRO3 / AXL / MER, TAM receptor kinase family) is important in the immune response evasion mechanisms of lung and breast cancer cells has been derived (Yi et al., 2017). Therefore, we are discovering small molecule inhibitors for this. As it has been announced that if MERTK is targeted, it can be effectively applied to cancer cells resistant to EGFR, It is expected to have great potential. So we consider that it is possible to develop anticancer drugs that are different from those targeted for the existing immune checkpoints such as PD-1 / PD-L1 and CTLA-4.
In addition to lung and breast cancers, MERTK is reported to be also effective in gastric cancer, head and neck cancer, glioblastoma, and leukemia. To be differentiated from existing development trends, we expect to develop therapeutics for colorectal cancer. Also, we are screening drug candidates with multi-targeting by selecting targets that synergize with MERTK. Of course, we’re also considering the possibility that our treatment will be applied to other cancers.
We are conducting non-clinical verification through partnership with Sookmyung Women’s University to see if the small molecules that we discovered for colorectal cancer, cervical cancer and liver cancer shows apoptosis effect by inhibiting MERTK and AXL.
 Ribas, A., & Wolchok, J. D. (2018). Cancer immunotherapy using checkpoint blockade. Science, 359(6382), 1350-1355.
 Lee-Sherick, A. B., Jacobsen, K. M., Henry, C. J., Huey, M. G., Parker, R. E., Page, L. S., … & Jordan, C. T. (2018). MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity. JCI insight, 3(21).
 Byun, D. J., Wolchok, J. D., Rosenberg, L. M., & Girotra, M. (2017). Cancer immunotherapy—immune checkpoint blockade and associated endocrinopathies. Nature Reviews Endocrinology, 13(4), 195.
 Nishino, M., Ramaiya, N. H., Hatabu, H., & Hodi, F. S. (2017). Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nature reviews Clinical oncology, 14(11), 655.
 Yi, J. H., Jang, J., Cho, J., Do, I. G., Hong, M., Kim, S. T., … & Park, Y. S. (2017). MerTK is a novel therapeutic target in gastric cancer. Oncotarget, 8(57), 96656.
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