Background and Therapeutic
The non-canonical (alternative) NF-κB pathway is controlled by the activity of the I kappa B kinase alpha (IKKα) and is stimulated in response to a range of TNF superfamily cytokines including Lymphotoxin β (LTβ), CD40 ligand (CD40L) and BAFF. There is strong evidence in the literature that in addition to the classical (IKKβ) pathway, in a number of cancers the IKKα driven alternative NF-κB signalling pathway is constitutively active and plays an important role. In a number of leukaemias and lymphomas oncogenic rearrangement of the nfkb2 gene (p100) has been reported and its constitutive activation requires IKKα (Ref3). Similarly, constitutive activation of the alternative IKKα pathway has been reported in
pancreatic cancer (Ref4). Castrate Resistant Prostate Cancer: Recent data has indicated that Lymphotoxin B, which activates the alternative pathway via IKKα, is an important driver of castrate resistant prostate cancer and may stimulate tumour progression/proliferation following androgen deprivation therapy (Ref 5). Androgen independent prostate
cancer lines such as PC3 and DU-145 have also been shown to haveconstitutive activation of IKKα (Ref 6) and the presence of activated nuclear IKKα has been reported to correlate with more advanced cases of prostate cancer and have a role in driving metastasis (Ref7).
siRNA studies have also confi rmed a role for IKKα in the survival and proliferation of androgen independent prostate cancer cell lines further highlighting the attractiveness of this target in prostate cancer.
CRT is seeking a co-development partner to drive candidate selection and entry into formal pre-clinical studies