HDAC Inhibitors and CTCL

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DESCRIPTION (provided by applicant): Cutaneous T cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas of "skin-homing" T- lymphocytes. The most common forms are skin associated mycosis fungoides (MF) and Sezary syndrome (SS), an aggressive leukemic variant. Early detection and treatment are directly correlated with favorable outcome for both MF and SS. Our previous studies identified markers for diagnosis and prognosis of SS by microarray analysis of RNA from PBMC of patients and healthy controls. We have now extended these studies on a small number of patient samples to the more common MF/CTCL to obtain a disease signature in the peripheral blood to assist clinicians in distinguishing MF from benign skin diseases with which it is frequently confused with good success. We expect the PBMC profiles will provide a non-invasive approach to monitoring disease progression and response to therapy. This preliminary PBMC signature must be confirmed using a greater number of patient samples. We will use the PBMC signatures for MF and SS to examine the mechanism of action of the HDAC inhibitor (HDCAIs), depsipeptide (DP), which has shown remarkably efficacy in CTCL treatment, in particular the treatment of highly refractory patients with limited options. We will use four parallel approaches based mainly on gene-expression microarrays. 1) We will develop biomarkers for MF patients, as we have done for SS, that will be used for diagnosis, prognosis, and responsiveness to therapy. We will profile heavily infiltrated plaque and tumor samples from formalin fixed paraffin embedded (FFPE) CTCL samples using the Illumina DASL system and in a complimentary study we will asses profiles in PBMC. 2) Gene expression profiles in PBMCs from patients in DP Phase II/III clinical trials will be assessed pre and post therapy and gene expression profiles used to determine whether markers for responsiveness are present pre-therapy and/or post-therapy and evaluate changes that occur during progressive treatments over a period of 4-6 months. 3) We will augment the in vivo studies with in vitro treatments of patient and control PBMC to study the effects of treatment on the malignant cells and the normal lymphoid populations, in particular the dendritic cells. Finally, 4) HDACI resistant CTCL cell lines will be used to develop models to study HDACI resistance. We present promisin preliminary results from DP clinical trials and in vitro studies. PUBLIC HEALTH RELEVANCE: CTCL is a cancer with many treatments but no cures. The proposed studies examine how a new and effective treatment for CTCL works in samples from patients in clinical trials and in studies in cell culture systems. Based on our preliminary studies we propose to develop tests that will identify those patients that will respond to therapy (approximately 35%) and those that will not before therapy is initiated. Understanding the characteristics that define why one patient responds and another patient does not, can lead to the identification of ways to convert the non-responsive patients to responsive ones.