Lead agents: IG4, IG7, IG14, IG17 and IG19.
US patent application No.15/455,665
US patent application title: Ceramide Analogs.
1. Genevieve L. Coe, Priscilla S. Redd, Amy V. Paschall, Chunwan Lu, Lilly Gu, Thomas Albers, Iryna O. Lebedyeva, and Kebin Liu. 2016. Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes. Rep. 6:30816. PMCID: PMC4973238.
2. Feiyan Liu, Xia Li, Chunwan Lu, Aiping Bai, Jacek Bielawski, Alicja Bielawska, Brendan Marshall, Patricia V. Schoenlein, Iryna O. Lebedyeva and Kebin Liu. Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells. Oncotarget. 7:83907-83925. PMCID: PMC27880732.
3. Amy V Paschall, Mary A Zimmerman, Christina M Torres, Dafeng Yang, May R Chen, Xia Li, Erhard Bieberich, Aiping Bai, Jacek Bielawski, Alicja Bielawska and Kebin Liu. 2014. Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression. BMC Cancer. 14:24. PMCID: PMC3898374.
4. Xiaolin Hu, Dafeng Yang, Mary Zimmerman, Feiyan Liu, Jine Yang, Swati Kannan, Andreas Burchert, Zdzislaw Szulc, Alicja Bielawska, Keiko Ozato, Kapil Bhalla, and Kebin Liu. 2011. IRF8 Regulates Acid Ceramidase Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia. Cancer Res. 71:2882-91. PMCID: PMC3078194.
The emerging clinical success of anti-PD-1/PD-L1-based immune checkpoint inhibitor immunotherapy in the last few years has significantly extended survival of many types of human cancer patients. However, colorectal cancer (CRC), except for the small subset (4%) microsatellite instable (MSI) CRC, stands out as one of the few human cancers where anti-PD-1/PD-L1 immunotherapy has been unsuccessful. The mechanism under CRC non-response to anti-PD-1 is unknown. It is generally believed that the expression level of PD-L1 is a response predictor to anti-PD-1/PD-L1 immunotherapy. In the literature, the expression levels of PD-L1 in human CRC cells are controversial and it has been proposed that the lack of PD-L1 expression is the underlying mechanism of CRC non-response to anti-PD-1/PD-L1 immunotherapy. However, our preliminary data challenge this notion. Using a recently developed highly specific and FDA-approved anti-PD-L1 mAb, we have demonstrated that PD-L1 is abundantly expressed in tumor cells and myeloid-derived suppressor cells in human colon carcinoma. Furthermore, our preliminary data demonstrated that anti-PD-1 and anti-PD-L1 immunotherapy can effectively activate cytotoxic T lymphocytes (CTLs). In addition, we have shown that FasL of CTLs is essential for tumor growth control in an orthotopic colon cancer mouse model. Because CTLs suppress tumor growth through inducing tumor cell death, our observations suggest that CRC resistance to cell death is an underlying mechanism of CRC resistance to anti-PD-1/PD-L1 immunotherapy.
Although it has been shown that Fas may promote tumor growth under certain cellular context, the best known Fas function is mediating FasL-induced apoptosis. The Fas-FasL pathway is one of the two effector mechanisms that CTLs use to kill target cells, including tumor cells. Fas is the death receptor that is often down-regulated in human colon carcinoma cells. The Fas receptor exists as a trimeric membrane-bound surface receptor and its clustering is essential for Fas function. Therefore, enhancing Fas receptor clustering is potentially a more effective approach to increase Fas receptor affinity to FasL of activated CTLs to booste CTL efficacy in cancer immunotherapy.
Ceramide is a key secondary messenger that mediates multiple cellular functions. Compelling experimental data have shown that ceramide deregulation is a key factor in tumor progression and cancer cell resistance to chemotherapeutic agents and radiation, which has led to extensive studies to target the ceramide metabolism pathways for development of potential anticancer therapies. However, an ignored and potentially significant function of ceramide is that ceramide can effectively enhance Fas receptor clustering and oligomerization.
We have recently discovered that ceramide plays an essential role in Fas-mediated apoptosis of tumor cells. Fas is a death receptor expressed on tumor cell surface. FasL is the physiological ligand of Fas and is expressed on the surface of activated T cells. The Fas-FasL pathway plays an essential role in host cancer immune surveillance. Tumor cells often use silencing Fas expression to escape from host cancer immune surveillance. We discovered that although Fas is silenced in tumor cells, low level of Fas is still expressed on tumor cell surface and ceramide can effectively increase Fas oligomerization to increase tumor cell sensitivity to FasL-induced cell death. Based on this discovery, we have designed a series of ceramide analogs as potential enhancer of Fas-mediated apoptosis of colon cancer cells. We have extensively tested these analogs and developed 5 ceramide analogs that significantly increase human colon carcinoma cell sensitivity to FasL-induced tumor cell death by tumor-specific T cells in vitro.
Current effort is to test these 5 compounds in vivo cancer immunotherapy mouse tumor models to develop these analogs as enhancer for anti-PD-L1/PD-1 mAb- and T cell adoptive transfer-based cancer immunotherapy.