Abstract
Non-small cell lung cancer (NSCLC), accounting for an estimated 85% of all lung cancers, retains its position as the most lethal type of cancer worldwide, with a 5-year survival rate for newly diagnosed cases below 20%. Despite the remarkable progress that has been made in the development of new treatment modalities, chemotherapy consisting of platinum-based doublets remains the standard first-line treatment for NSCLC patients. Anti-mitotic drugs are well-established components of the current combination treatment schedules in NSCLC patients. Nevertheless, serious adverse effects remain the dose-limiting factor.
New approaches target cardinal regulatory proteins of mitosis, with Polo-like kinase 1 (Plk1) as one of the most promising targets in this research field. Our previous research showed Plk1 overexpression in 65% of NSCLC patients while no or weak Plk1 expression was noted in normal lung tissue, making it a compelling target for the treatment of NSCLC. Volasertib, at present the lead agent in category of Plk1 inhibitors, has been shown to be highly effective in multiple carcinoma cell lines and xenograft models, with minimal toxicity in normal cells. However, only modest anti-tumour activity was reported for volasertib monotherapy in patients with solid tumours, including NSCLC. Remarkably, an encouraging percentage of these patients reaches stable disease, providing an intriguing window for improving patient outcome.
Based on promising results of our recent preclinical research at the Center for Oncological Research (CORE, UA), this proposed project will focus on (i) the identification of predictive biomarkers for Plk1 inhibition; and (ii) novel, rationally designed combination strategies with Plk1 inhibitors to improve therapeutic benefit.
We previously identified p53 and hypoxia as potential biomarkers for response to Plk1 inhibition. However, no conclusive evidence could be found yet. As such, in the first objective of the proposed study, we will gain conclusive insights in the predictive role of p53 and hypoxia for the response to Plk1 inhibition. Therefore, we will investigate the effect of Plk1 inhibitors in a panel of isogenic cell lines with a different p53 background, under both normoxic and hypoxic conditions.
Our second objective is to identify promising combination strategies with Plk1-inhibitors. In this regard, we will especially focus on drugs that eliminate senescent cells upon Plk1 inhibition. Recently, preclinical research by us has identified cellular senescence as an important outcome of Plk1 inhibition. Senescent cells are irreversibly growth-arrested, but remain metabolically active, thereby secreting multiple tumour-promoting factors to adjacent tumour cells. In-depth evaluation of the molecular pathways involved in induction of senescence after Plk1 inhibition will lead to the identification of potential targets to kill senescent NSCLC cells after Plk1 inhibition. At the time of writing this application, no investigation has been performed yet on the molecular pathways important for the survival of senescent cells after treatment, making this project challenging yet essential to enhance anti-tumour responses after Plk1 inhibition.
Lastly, our third objective is to evaluate a novel combination therapy of Plk1 inhibitors with agents eliminating senescent cancer cells, in both vitro and in vivo models of NSCLC.
We hypothesize that the anti-cancer effect of Plk1 inhibitors is synergistic with agents eliminating senescent cancer cells, so that this innovative combination strategy will ultimately result in improved survival and quality of life for patients with NSCLC. The proposed research project has the exciting potential to create a breakthrough in the optimization of Plk1 inhibition for patients with advanced NSCLC. Moreover, since Plk1 overexpression is found in multiple tumour types, our study results might also pave the way for improved treatment options for other malignancies.
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