Stress resistance and cancer evolution
John Black Research Fellow in Prostate Oncology
My research focuses on understanding how treatment-resistant prostate cancers (PCa) adapt to conventional therapies and as such design new therapies or combination therapies to treat them.
There have been huge advances in prostate treatment and oncology. However, the fact remains, that PCa is an extremely common diagnosis and results in thousands of deaths every year as well as contributing to inordinate psychological burden as well as diminished quality of life of those unfortunate enough to be diagnosed with it.
Solid tumours arise and eventually thrive in a hostile environment that initially lacks nutrients, blood supply and suffers from low oxygen. PCa cells in particular manage to branch out to try to overcome these stresses through androgen receptor mediated metastasis. Upon diagnosis such tumours are affected by the added burden of treatment be that chemotherapy, radiotherapy, surgery or a combination of all three. Normal cells would not survive such heavy assault. However, some cancer cells have the ability to adapt to stress. In particular some PCa cells manage to become AR-independent and use a mechanism that all cells use to stay alive through stress. This mechanism is called the Unfolded Protein Response and in cancer cells is so robust, that it helps them survive a huge amount of stress. It seems that the UPR is a key pro-cancer mechanism that is interconnected with AR dependent biology. As such what we propose is to understand the molecular pillars upon which this synergy is based, in order to exploit it and make treatment-resistant cells sensitive to current therapies or uncover new potential targets and biomarkers to aid prognosis.
Over the past few years our cancer research has highlighted the importance of the androgen receptor and transducers of the UPR such as IRE1 and XBP1 in supporting stress adaptation. By discerning and subsequently targeting these major pillars that support cancer cell survival I hope to cripple the ability of cancer cells to adapt when subjected to treatment thus maximising curative effects.
The impact of cancer diagnosis has severe implications for the patients and their immediate environments as it affects families, their support networks and of course their working life that may need to be maintained to support such environment. With this in mind if we manage to sensitise tumours to currently available therapies or more effectively treat AR-independent PCa, not only will we manage to prolong life but also reduce the need for repeat dosage of toxic therapeutics that reduce quality of life.
Pharmacological Targeting of IRE1 in Cancer
Raymundo DP. et al, (2020), Trends in Cancer
Peptidomimetic‐based identification of FDA‐approved compounds inhibiting IRE1 activity
Doultsinos D. et al, (2020), The FEBS Journal
The role of the androgen receptor as a driver and mitigator of cellular stress.
Doultsinos D. and Mills I., (2020), J Mol Endocrinol
Doultsinos D, Avril T, Lhomond S, Dejeans N, Guédat P, Chevet E. Control of the Unfolded Protein Response in Health and Disease. SLAS Discov Adv Life Sci R&D. 2017 Apr 28;22(7):2472555217701685.
Lhomond S, Avril T, Dejeans N, Voutetakis K, Doultsinos D, McMahon M, et al. Dual IRE1 RNase functions dictate glioblastoma development. EMBO Mol Med. 2018 Jan 8;10(2):139–308.
Almanza A, Carlesso A, Chintha C, Creedican S, Doultsinos D, Leuzzi B, et al. Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications. FEBS J. 2018 Jul 20;0(0).
Doultsinos D, McMahon M, Voutetakis K, Obacz J, Pineau R, Le Reste P-J, et al. Constitutive UPRER activation sustains tumor cell differentiation. bioRxiv. 2019 Oct 22.