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.

  

The interplay of kinases and phosphatases in cancer

 Dr 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.

Dr 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),
  • 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.