For the past 12 years, a major focus of Prof Robson?s laboratory is the development of novel approaches for sensitizing tumours to therapy using a personalised medicine approach. In particular, she has a major programme of research aimed at the functional characterisation of the FKBPL gene where she demonstrated an extracellular role for FKBPL as a naturally secreted, anti-angiogenic protein and demonstrated that peptides based on the active anti-angiogenic region are potent inhibitors of angiogenesis both in vitro and in vivo, resulting in tumour growth inhibition. Together with Almac Discovery, she has led the development of therapeutic peptide derivatives (AD-01 and ALM201) based on FKBPL?s active anti-angiogenic domain which have now entered phase I/II ovarian cancer clinical trials (EudraCT number: 2014-001175-31). Prof Robson is continuing to characterize the role of the endogenous protein using various in vitro and in vivo models where she has demonstrated a possible role for FKBPL in a number of other conditions associated with aberrant angiogenesis. Over the last 15 years she has attracted significant funding from UK research councils, MRC & BBSRC, and national charities, Cancer Research UK, Breast Cancer Now, Prostate Cancer Charity, HPSS R&D Office, and numerous other cancer charities.
McKeen HD, Byrne C, Jithesh PV, Donley C, Valentine A, Yakkundi A, O?Rourke M, Swanton C, McCarthy HO, Hirst DG, Robson T. (2010) FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy. Cancer Research 70(3):1090-1100
Valentine A, O?Rourke M, Yakkundi A, Worthington J, Hookham M, Bicknell R, McCarthy H, McClelland K, McCallum L, Dyer H, McKeen H, Waugh D, Roberts J, McGregor J, Cotton G, James I, Harrison T, Hirst D, Robson T (2011). FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism. Clinical Cancer Research 17(5):1044-56.
McClements L, Yakkundi A, Papaspyropoulos A, Harrison H, Ablett MP, Jithesh PV, McKeen HD, Bennett R, Donley C, Kissenpfennig A, McIntosh S, McCarthy HO, O?Neill E, Clarke RB, Robson T. (2013) Targeting treatment resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. Clin Cancer Res 19(14):3881-93.
Donley C, McClelland K, McKeen HD, Nelson L, Yakkundi A, Jithesh PV, Burrows J, McClements L, Valentine A, Prise KM, McCarthy HO, Robson T. (2014) Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen Oncogene. 33(26):3441-50.
Yakkundi A, Bennett R, Hern?ndez-Negrete I, Delalande J-M, Hanna M, Lyubomska O, Arthur K, McKeen HD, Nelson L, McClements L, McCrudden CM, McCarthy HO, Burns A, Bicknell R, Kissenpfennig A, Robson T. (2015) FKBPL is a critical anti-angiogenic regulator having an essential role in developmental and pathological angiogenesis. Artiosclerosis Thrombosis and Vascular Biology ATVBAHA.114.304539 doi: 10.1161/ATVBAHA.114.304539
Nelson L, McKeen HD, Marshall A, Mulrane L, Starczynski J, Storr SJ, Lanighan F, Byrne C, Arthur K, Hegarty S, Abdunnabi Ali A, Ellis IO, Green AR, Rakha E, Young L, Kunkler I, Thomas J, Jack W, Cameron D, Jirstr?m K, Yakkundi A, McClements L, Martin SG, Gallagher W, Dunn J, Bartlett J, O?Connor D, Robson T. (2015) Evaluating the prognostic potential of FKBPL; a novel breast cancer biomarker. Oncotarget 6(14): 12209-12223
Pathological blood vessel formation (angiogenesis) or the inability of endothelial cells (ECs) to perform their function (EC dysfunction) can lead to a wide variety of diseases; these include peripheral vascular disease, stroke, heart disease, diabetes, insulin resistance, chronic kidney failure, but also tumour growth, metastasis and venous thrombosis. The vascular endothelium is thus an important therapeutic target for the treatment and prevention of vascular disease. We have identified a novel protein, FKBPL, which occurs naturally in the body, and has potent anti-angiogenic activity. When we add FKBPL to growing tumours it prevents their growth by stopping angiogenesis within the tumour, starving it of oxygen and nutrients. We have developed therapeutic peptides based on the active region of this protein which are now in Phase I/II clinical trials for ovarian cancer. However, we now have preliminary evidence that this protein can directly affect EC function and need to understand the precise actions of this protein, allowing us to appreciate its potential role in a wide variety of other diseases associated with EC function. We will therefore study the normal role of FKBPL in a variety of models which will assess EC function. We will do this by examining blood vessels within mouse models that we have developed which are deficient in this protein. This will tell us how critical FKBPL is in controlling EC function. We will also study FKBPL's ability to regulate other critical proteins which have well established roles in EC function. In summary, we believe that this study will help our understanding of the role of FKBPL in a wide range of diseases that are associated with disrupted or imbalanced EC function. This could have a profound effect on how we develop new treatments for a wide range of common diseases and might suggest that the drug which we have already developed may have far reaching applicability in other diseases.