Research

 Cell Signalling - Translational Cancer Research Group

 (For more information see: Giamas research group www site)

 

As personalised medicine represents the future for cancer therapy, there is a need of further understanding the molecular basis of cancer and develop better diagnostic tools. The Giamas laboratory focuses on the identification and elucidation of the role of proteins implicated in the progression of cancer and the development of novel therapeutic targets.

Our translational research laboratory combines a variety of molecular, cellular and biochemical techniques along with established in vitro/in vivo models and patients' specimens to study relevant pathways in cancer.

In aggregate, our research links ‘bench work to bedside’ and can have an enormous impact to patients while at the same time supporting the entire scientific community.

 

Cancer

Cancer is a heterogeneous disease and the leading cause of death in the world. In 2012, there were approximately 14.1 million new cancer cases and 8.2 million cancer deaths, making up 14.6% of all human deaths worldwide. In addition, about 32.6 million people were living with cancer in 2012 (within 5 years of diagnosis). It is also predicted that the number of annual cancer cases will increase from 14 to 22 million in the next two decades. On the positive view, despite the increase in cancer incidence, cancer mortality has been decreasing. Between 1990-1992 and 2009-2011, the European AS mortality rates decreased by 26% in males and 20% in females. A further 17% decrease of cancer deaths is expected between 2011 and 2030 in the UK. There are more than 200 different types of cancer diagnosed in the UK, among which, breast, lung, prostate and bowel cancers account for over half (53%) of all new cases. 

 

• Protein Kinases

There are approximately more than 500 protein kinase genes throughout the human genome, making up 2% of all human genes. Importantly, up to 30% of all human proteins can be phosphorylated by kinases.  Phosphorylation plays an essential role in regulating intracellular signal transduction pathways involving every aspect of cell activity including survival, proliferation, differentiation, apoptosis, metabolism, angiogenesis, immune surveillance and motility.

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Targeted therapies against kinases have improved the clinical outcome of patients in the past decade. However, resistance to these treatments often develops, largely due to the aberrant activation of other kinases possessing a complementary or compensatory function.

For example, clinical resistance to Tyrosine Kinase inhibitors may arise by other kinases phosphorylating the same site(s) as the targeted kinase, and it is not necessarily the case that homologous or closely related kinases are able to do this.

Therefore, an understanding of the phosphorylation signature of all kinases is needed to allow prediction of inhibitor combinations that could target the primary kinase and those that could redundantly achieve equivalent phosphorylation.

Only a small number of kinases described thus far have been thoroughly studied and even in these cases a global functional analysis and understanding of their proteomic and phospho-proteomic portrait is lacking; a complete proteomic portrait is likely to yield new translational insights.

 

 

The interplay of kinases and phosphatases in cancer

Professor Giamas’s group is focused on identifying novel kinases and phosphatases and elucidate their role and contribution in the development of cancer. Protein kinases are relevant in intracellular signal transduction, with more than 150 already implicated in disease development.

Over two-thirds of breast tumors express the Estrogen Receptor-alpha (ERα) and patients with ERα+ disease respond to anti-estrogens (tamoxifen-(Tam)), estrogen withdrawal (aromatase inhibitors) or ERα downregulation (fulvestrant). However, resistance frequently occurs with tumours recurring as metastatic. Mutations in ERα are rarely found; instead other mechanisms have been associated with tamoxifen resistance, among them phosphorylation of ERα. Apart from regulating transcriptional activity of ERα, phosphorylation at multiple sites also alters its stability.

Moreover, Tam-resistant ERα+ cells exhibit a transition towards a more aggressive phenotype displaying augmented motility and invasiveness. Accumulating evidence suggests that ERα extra-nuclear signaling (cross-talk with kinases and phosphatases) can promote cell migration and metastasis.

Professor Giamas's team has identified Lemur Tyrosine Kinase 3 (LMTK3):

  • as a regulator of ERα with prognostic and predictive significance for breast cancer (BC) patient survival (Giamas et al., 2011-Nature Medicine / Stebbing et al., 2012-BCRT),
  • that possesses a role in innate (intrinsic) and acquired (adaptive) endocrine resistance in BC (Stebbing et al., 2012-Oncogene) as well as in chemotherapy resistance ((Stebbing et al., 2018-Oncogene),
  • which is also implicated in invasion and migration (Xu et al., 2014-Science Signalling),
  • as well as in transcriptional regulation (Xu et al., 2015 - Cell Reports).

 Taken together, we believe that deciphering the mechanisms of LMTK3 action will reveal fundamental insights into the role of ERα signaling in endocrine resistance and metastasis, and derive new druggable targets.

 

Schematic of research work.

Clarifying the molecular, functional and regulatory properties of LMTK3 (aim 1) will provide us with additional information that will help us elucidate the involvement of LMTK3 in the regulation of ERα (aim 2) as well as its contribution in the development ERα-dependent and ERα-independent mediated metastatic processes (aim 3). In parallel with these goals, we are working in solving its crystal structure and identifying novel kinase inhibitor(s) for LMTK3 (aim 4) that can be used i ultimately in the future for in vivo and pre-clinical studies.