Novel Non-AR Targets in Castrate Resistant Prostate Cancer
Novel Non-AR Targets in Castrate Resistant Prostate Cancer
With increased understanding the importance of the tumour microenvironment on the progression of CRPC, therapeutic strategies are emerging to target the adjacent stroma. Further, it appears that treatments which target both the stroma and epithelium compartments may be expected to be more successful. Both androgen androgen deprivation and cabozantinib are examples of this approach: the AR and c-MET are both active in both the stroma and epithelial compartments during CRPC. IGF-IR inhibitors also target both stroma and tumour components. However, with the failure to date of several angiogenesis inhibitors in CRPC, agents targeting the microenvironment are likely best evaluated in rationale combination strategies with other treatments. For example, pre-clinical research suggests that IGF-IR blockade may enhance Src inhibition.
Hedgehog signalling is an important paracrine factor during organogenesis and appears to be de-regulated during prostate cancer progression. Sonic hedgehog secreted by the tumour appears to alter the tumour microenvironment to ultimately increase oncogenic Gli-1/2 transcription factors through paracrine signalling. Sonic hedgehog ligands signal via Patched-1 and result in the loss of the Smoothened repression on Gli-1 and Gli-2. Hedgehog signalling appears to be up-regulated following androgen deprivation conditions. Preclinical data on TAK-441 and GDC-0449 (vismodegib) in CRPC models and an ongoing neo-adjuvant study of GDC-0449 should lead to upcoming clinical trials in CRPC patients.
Another novel drug which targets the tumour microenvironment is the monoclonal antibody sibrotuzumab. It targets fibroblast-activated protein (FAP). This protein expressed in cancer-associated stroma, but not normal stroma-associated with epithelial cancers. It is considered to play a role in tumor growth and proliferation.
Targeting the Tumour Microenvironment
With increased understanding the importance of the tumour microenvironment on the progression of CRPC, therapeutic strategies are emerging to target the adjacent stroma. Further, it appears that treatments which target both the stroma and epithelium compartments may be expected to be more successful. Both androgen androgen deprivation and cabozantinib are examples of this approach: the AR and c-MET are both active in both the stroma and epithelial compartments during CRPC. IGF-IR inhibitors also target both stroma and tumour components. However, with the failure to date of several angiogenesis inhibitors in CRPC, agents targeting the microenvironment are likely best evaluated in rationale combination strategies with other treatments. For example, pre-clinical research suggests that IGF-IR blockade may enhance Src inhibition.
Hedgehog signalling is an important paracrine factor during organogenesis and appears to be de-regulated during prostate cancer progression. Sonic hedgehog secreted by the tumour appears to alter the tumour microenvironment to ultimately increase oncogenic Gli-1/2 transcription factors through paracrine signalling. Sonic hedgehog ligands signal via Patched-1 and result in the loss of the Smoothened repression on Gli-1 and Gli-2. Hedgehog signalling appears to be up-regulated following androgen deprivation conditions. Preclinical data on TAK-441 and GDC-0449 (vismodegib) in CRPC models and an ongoing neo-adjuvant study of GDC-0449 should lead to upcoming clinical trials in CRPC patients.
Another novel drug which targets the tumour microenvironment is the monoclonal antibody sibrotuzumab. It targets fibroblast-activated protein (FAP). This protein expressed in cancer-associated stroma, but not normal stroma-associated with epithelial cancers. It is considered to play a role in tumor growth and proliferation.
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