Inhibition of S14 by Conjugated Linoleic Acid in Advanced Solid Tumor Patients

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DESCRIPTION (provided by applicant): Conventional anticancer therapies are generally acknowledged to be insufficiently effective and excessively toxic. This has prompted development of specific therapies targeting critical molecular pathways in cancer cells ('molecular targeted therapies'). Many cancers critically depend upon upregulated de novo lipid synthesis (such as fatty acid synthase (FAS)), and/or increased uptake of circulating lipids derived from diet (lipolysis). We have shown that Spot 14 (S14; THRSP), a central regulator of de novo lipid synthesis, is an attractive therapeutic target. In animal models, S14 expression is inhibited by tolerable oral doses of conjugated linoleic acid (CLA), a popular dietary supplement and bioactive food component. Despite widespread use in humans and animals, CLA has not been tested as anticancer agent in clinical trials. In addition, levels of CLA that can be safely achieved, its distribution, and its elimination kinetics are currently unknown. Thus, the first step towards development of CLA as a potential anticancer treatment is to define a safe and appropriate dose for clinical efficacy trials. Therefore, we will test the hypothesis that tolerable doses of CLA inhibit expression of S14 mRNA in normal human adipocytes and in tumor biopsies from patients with advanced solid tumors. There are two specific aims: (1) to define a tolerable dose of CLA that maximally suppresses S14 expression in adipocytes; and (2) to determine whether this dose suppresses S14 mRNA expression in tumor biopsy specimens of tumor types potentially sensitive to inhibition of lipogenesis. CLA is administered orally, once daily. Doses are escalated using an accelerated titration scheme (single patient cohorts), with expansion to conventional cohort sizes (3-6 patients) once inhibition of S14 expression or clinical toxicity is observed. Dose titration continues until a plateau in S14 response is observed, unless clinical toxicities or pharmacokinetics require stopping before that point. The study design seeks to identify a recommended dose for subsequent phase II trials (RP2D) which is tolerable and where maximal S14 response is seen (response defined as suppression of S14 m RNA expression by e 40%, a level associated with significant inhibition of lipogenesis in relevant animal models). Pharmacokinetic sampling and biopsies are performed on days 1 and 15, with quantification of plasma CLA levels by silver- ion HPLC. Molecular pharmacodynamic (PD) endpoints are assayed by RT-PCR and/or immuno- histochemistry. Secondary molecular endpoints include other lipogenic and lipolytic enzymes (such as FAS), SREBP1, phospho-AKT, biomarkers of cell-cycle/proliferation (Ki67, geminin), and apoptosis (cleaved caspase 3). This proof-of-principle trial - the first ever targeting lipogenesis in cancer patients, with any agent - is an example of ongoing efforts by Dartmouth investigators to develop novel therapies targeting lipid metabolism in cancer cells. Rapid translation of such therapies into the clinic has the potential to improve care of patients with advanced cancer, which is our ultimate goal. PUBLIC HEALTH RELEVANCE: It has become apparent that many cancers depend on specific fats (lipids) for their continued growth. Conjugated linoleic acid (CLA) is a safe, popular, and well-tolerated dietary supplement that promotes weight loss and loss of fat. CLA has recently been shown to inhibit uptake and production of lipids required for growth of some cancers, resulting in growth inhibition and killing of cancer cells. We propose a clinical trial to test whether oral administration of CLA block production and uptake of lipids in tumors of patients with advanced cancers. Information gained from these studies will then be used to design later trials testing the effectiveness of CLA against different types of cancer. Targeting lipids is a promising, new approach to cancer therapy - one with the potential to benefit patients with many common cancers (breast, prostate, lung, ovarian, and some leukemias). Successful completion of the proposed studies could therefore potentially translate into significant improvements in public health.