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Full NameDaniel Longley
Department:Centre for Cancer Research and Cell Biology
Organisation:Queen's University Belfast
- genetics, genomics and molecular biology
Postgrad Medical Specialties
- Public Health
- Clinical Trials
- Infectious diseases
My laboratory focuses on understanding the molecular basis of chemotherapy resistance in solid tumours, particularly colorectal cancer. Specifically, our focus is on overcoming chemo-resistance by activating cancer cell death. We are currently exploring a number of approaches to target genes and proteins that promote cell survival as well as using modern molecular pathology approaches to identify predictive biomarkers to enable the targeted use of novel anti-cancer therapeutics in molecularly-defined patient populations. Much of our recent work has focused on the anti-apoptotic protein FLIP, the high expression of which is found in a number of cancers and correlates with poor prognosis. These observations are relevant to drug resistance, as we consistently find that FLIP is a key determinant of response to standard-of-care therapies, with high expression conferring resistance to cell death induced by a range of chemotherapeutic agents. Conversely, we have found that FLIP downregulation synergistically enhances chemotherapy-induced apoptosis. These results suggest that targeting FLIP has therapeutic potential for overcoming drug resistance. Moreover, certain immune-suppressive, tumour-promoting immune cell populations, such as myeloid-derived suppressive cells (MDSCs) and Tregs, are FLIP-dependent; we are therefore currently developing small molecule inhibitors of this critical cell death regulatory protein.
Colorectal cancer (CRC) is the 3rd leading cause of cancer-related death in the Western world. Recently, we have found that significant subgroups of CRC patients benefit little if at all from current treatment strategies. Moreover, these subgroups are readily identifiable using modern molecular pathology techniques. In this project, we aim to identify better ways of treating these patient subgroups using a new drug called Entinostat that was recently approved by the FDA for use in a subtype of breast cancer. Our preliminary evidence suggests that this agent can act in a number of ways to improve the survival rates of CRC patients who do not benefit from current treatment:
1. Entinostat enhances the efficacy of standard chemotherapy agents by down-regulating the cell death regulatory protein FLIP, thereby promoting chemotherapy-induced CRC cell death.
2. Entinostat increases expression of genes that have been suppressed to enable the cancer to evade the immune system.
3. Entinostat kills rogue immune cells that protect the tumour, such as MDSCs.
So, overall Entinostat enables chemotherapy to work more effectively to kill cancer cells whilst at the same time reactivating the body's immune system to attack the tumour. In addition, we hypothesise that these effects make Entinostat an ideal combination partner for another emerging type of anti-cancer therapy, called immunotherapy, which has made a huge impact in a number of cancers (including cures in previously uniformly fatal diseases like advanced malignant melanoma), but which has yet to make the same level of impact in CRC. Subsequently, this project will also test whether immunotherapy combinations with Entinostat and standard-of-care chemotherapeutic drugs are effective in specific subgroups of CRC. The overall goal is to lay the foundations for new clinical trials involving Entinostat aimed at improving the survival of CRC patients.