New way to fight therapy-resistant prostate cancer found

Scientists have identified a signalling circuit in cells that can be targeted to treat advanced prostate cancer in patients who are resistant to existing therapies.
Prostate cancer is the second-leading cause of death after lung cancer in American men, researchers said.
Currently, the most effective treatment for advanced prostate cancer is to deprive the cancer of what feeds it - androgen hormones, such as testosterone.
However, almost all patients eventually develop resistance to this therapy, leaving doctors with no options to counteract the inevitable.
The study at The Scripps Research Institute (TSRI) in the US shows that a "constitutively active" signalling circuit can trigger cells to grow into tumours and drive therapy resistance in advanced prostate cancer.

A cell signal pathway with constitutive activity requires no binding partner (ligand) to activate; instead, the signalling circuit continually activates itself.

This signalling circuit, which is composed of a protein complex IkBa/NF-kB (p65) and several other molecules, controls the expression of stem cell transcription factors (proteins that guide the conversion of genetic information from DNA to RNA) that fuel the aggressive growth of these resistant cancer cells.
"The fact that the constitutive activation of NF-kB in the circuit is independent of traditional activation opens the door for potential treatment options," said Jun-Li Luo, associate professor at TSRI.
NF-kB plays important roles in cancer development, and it is regarded as one of the most important targets for cancer therapy.

However, the use of NF-kB inhibitors in treating cancer is complicated by severe side effects related to immunosuppression caused by indiscriminate inhibition of NF-kB in normal immune cells.
Luo noted that targeting the other non-IkBa/NF-kB components in this signalling circuit would avoid the suppression of NF-?B in normal immune cells while keeping the potent anti-cancer efficacy.
In addition to IkBa/NF-kB, the signalling circuit includes the microRNA miR-196b-3p, Meis2 and PPP3CC. While miR-196b-3p promotes tumour development, Meis2, which is an essential developmental gene in mammals, can disrupt the circuit when overexpressed.
The protein PPP3CC can inhibit NF-kB activity in prostate cancer cells.

"Disrupting this circuit by targeting any of its individual components blocks the expression of these transcription factors and significantly impairs therapy-resistant prostate cancer," said Ji-Hak Jeong, research associate at TSRI.
The study was published in the journal Molecular Cell.