MARKERS OF RESPONSE IN CUTANEOUS T-CELL LYMPHOMA

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DESCRIPTION: (Applicant's Abstract) Cutaneous T cell lymphoma (CTCL) are increasing in incidence, but their cause is unknown. Mycosis fungoides, the most common form of CTCL, has similarities to benign skin diseases. Experimental retinoids are being developed for the therapy of CTCL, but their mechanisms of action are not fully understood. Retinoids influence gene transcription by binding to nuclear receptors that dimerize and interact with DNA sequences and transcription factors. Ligands for the RXR-alpha beta gamma receptors "rexinoids" have a wide range of potential dimer partners and thus may influence gene expression in many systems including thyroid (TR), liver cholesterol metabolism (LXR) and peroxisome-proliferator activators (PPARs). Targretin (LGD1069) is the first RXR selective retinoid to enter experimental trials for cancer and is being studied in MF patients topically and orally. Targretin is hypothesized to remit MF lesions by 1) reversing the decrease in retinoid receptors (and other RXR ligands), 2) modulating gamma IFN and key cytokines and 3) causing T cell apoptosis. To understand how Targretin improves early CTCL lesions the applicant proposes to study skin specimens from 30 CTCL patients in ongoing Phase 1 and 2/3 clinical trials. In Specific Aim 1, the hypothesis that Targretin increases its own receptors and its dimerization partners (RARs, TRs, LXRs) will be studied by digoxigenin based in situ hybridization. The lesions at baseline will be compared to normal skin and to the same following 8 weeks of therapy. Immunohistochemistry and QRT-PCR will be used for confirmation. Specific Aim 2 addresses whether Targretin's effect includes modulation of key cytokines: IFN-gamma, inducible protein 10, TNF and IL-8. In Specific Aim 3, the effect of Targretin on T cell infiltrates and keratinocyte apoptosis will be determined in a smaller subset of 10 patients' biopsies studies for DNA nicking by the tunel method. The pattern and intensity of expression of RARs, RXRs, LXRs, TR RNAs and protein (Specific Aim 1); cytokines (gamma-IFN, TNF-alpha and IL-8) and chemokine IP-10 (Specific Aim 2); and FasL and tunel positivity (Specific Aim 3) will be evaluated with semi-quantitative scales and groups will be analyzed by Kruskal-Wallis one way ANOVA and correlations. Effects seen with topical and oral administration should be similar if they are important for treatment of the disease. Studying the mechanism of action of this novel RXR retinoid in CTCL should increase our understanding of the disease pathogenesis and result in improved, safer biological therapies for this devastating lymphoma.