Through preclinical studies, CTI scientists found that LPAAT-beta is highly expressed in cancers of the lung, ovary, prostate, bladder, cervix and brain but is minimally expressed in most normal tissues. When LPAAT-b was over expressed in cell lines, they became more tumorigenic and this change was reversed when the over-expressed gene was removed. When LPAATb expression was decreased in tumor cells by a genetic technique known as RNAi, their proliferation decreased. CTI scientists also developed small molecule inhibitors specific to LPAAT-b and these compounds induce apoptosis (cell death) in a wide variety of tumor cell lines. When nude mice bearing HT-29 colon cancer were treated with the compound, it delayed tumor growth significantly without producing toxicities. Similar results were achieved with related compounds in mice with Lewis lung cancers or NCI-H460 human lung cancers.
"These data affirm what we had previously noted in our initial studies – that the enzyme LPAAT-b produces a cofactor for signalling pathways that may be essential to cancer cell growth and viability and the inhibition of this enzyme causes cancer cells to die," Dr Singer told a news briefing today (Thursday 21 November) at the EORTC-NCI-AACR[2] Symposium on Molecular Targets and Cancer Therapeutics.
He added: "The experiments in animal models show that the small molecule LPAAT-b inhibitors can effectively kill tumor cells without having pronounced effects on normal cells."
Notes:
[1] LPAAT-beta is an enzyme, initially cloned by CTI scientists, that regulates the production of a lipid known as phosphatidic acid (PA) that is thought to be critical in the activation of several key oncologic pathways, including the RAS/RAF/ERK pathway and the AKT/mTOR pathway.
[2] EORTC [European Organisation for Research and Treatment of Cancer; NCI [National Cancer Institute]; AACR [American Association for Cancer Research].
Cell Therapeutics, Inc. website: www.cticseattle.com .
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