Prostate cancer is a major cause of male cancer death in Western nations. Tumour development/progression is dependent on interactions between tumour cells and neighbouring stromal fibroblasts. The medical University of Innsbruck is investigating the therapeutic potential of targeting the enzyme NADPH oxidase 4 (Nox4), which plays a central role in stromal-tumour cell crosstalk in prostate cancer.
Eingereicht von: Priv. Doz. Dr. Natalie Sampson
Firma/Universität: Medical University of Innsbruck
Kooperationspartner: Genkyotex S.A.
Prostate cancer is a major cause of male cancer death in Western societies. In Europe alone, more than 90,000 men die from prostate cancer each year. Localised prostate cancer is frequently successfully treated via radiation therapy or surgical removal of the prostate. However, Treatment options for advanced prostate cancer whilst numerous, are merely palliative. Thus, a better understanding of the molecular mechanisms underlying progression to lethal prostate cancer is greatly needed in order to develop new therapeutic strategies.
At all stages of disease, there is a complex bidirectional crosstalk between prostate cancer cells and fibroblasts in the neighbouring supportive tissue, termed stroma. Via their production of secreted factors, tumour cells corrupt adjacent fibroblasts to an activated state. In particular, cancer cell-derived transforming growth factor beta 1 (TGFβ1) is the most characterised and correlates with decreased prostate cancer survival. Once activated, these so-called „cancer associated fibroblasts“ (CAFs) produce a variety of factors that in turn fuel cancer cell proliferation and migration (see Figure). Consequently, CAFs promote prostate cancer progression, therapy resistance and are an independent predictor of disease prognosis. Since current treatment strategies for prostate cancer fail to specifically address the stromal component of disease, targeting dysregulated stromal-tumour cell interactions represents a promising adjuvant to current therapeutic modalities.
The current collaborative project builds upon previous research by the project leader, which demonstrated that cancer cell-derived or recombinant TGFβ1 increases expression of the reactive oxygen species (ROS)-producing enzyme NADPH oxidase 4 (Nox4) in primary human prostate stromal fibroblasts. Whilst excessive ROS can damage biomolecules such as DNA and proteins, lower levels of ROS play important cellular signalling functions in diverse physiological processes, e.g. proliferation, differentiation and innate immune response. Indeed, Priv. Doz. Dr. Natalie Sampson reported that elevated Nox4-derived ROS signalling is essential for TGFβ1-driven activation of prostate fibroblasts to a CAF-like state (Sampson et al. 2011 Mol Endocrinol). Consistently, analyses of prostate cancer tissues from over 200 patients revealed elevated expression of Nox4 in the stroma adjacent to prostate cancer lesions that produce high levels of TGFβ1. Moreover, increased stromal Nox4 in prostate cancer patient tissues is associated with hallmarks of aggressive disease (Sampson et al. 2014 Eur Urol; Sampson et al. 2018 Int J Cancer). In collaboration with Genkyotex (Switzerland), the leading biopharmaceutical Company in NOX therapies, they recently showed that inhibiting Nox4-derived ROS signalling impairs tumour cell- and TGFβ1-driven activation of primary human benign prostate fibroblasts to the CAF phenotype. Furthermore, the Nox4 inhibitor GKT831 abrogated the paracrine onco-supportive effects of activated fibroblasts on prostate cancer cell proliferation and migration (Sampson et al., 2018 Int J Cancer).
These findings support the hypothesis that the TGFβ-Nox4 signalling axis is a key interface to dysregulated reciprocal stromal-tumour interactions in prostate cancer, and that inhibiting Nox4 may represent a novel stromal-targeted approach to complement current prostate cancer Treatment modalities (see Figure). This hypothesis will be tested in the second phase of this already high successful collaboration by addressing the following Aims:
- characterise the role of Nox4 in primary human prostate CAFs and patient-matched benign prostate fibroblasts,
- identify the molecular effectors through which Nox4-derived ROS mediate their tumour-promoting effects, and
- investigate the efficacy of GKT831/genetic Nox4 inhibition on tumour progression in mouse models of prostate cancer and in ex vivo cultured precision-cut human prostate cancer tissue slices.