Description
The DF3/MUC1 transmembrane protein is aberrantly expressed at high levels on the surface of multiple myeloma (MM) cells. MUC1 forms complexes with EGFR and c-Src at the surface of carcinoma cells and is phosphorylated by these tyrosine kinases. Interaction of MUC1 with EGFR and c-Src also induces binding of the MUC1 cytoplasmic domain with beta-catenin. The available evidence indicates that MUC1 functions as an oncogene and that aberrant expression of MUC1 contributes to dysregulation of proliferative and anti-apoptotic signaling pathways.

In MM cells, stimulation with IL-7 induces interaction of MUC1 with the Lyn tyrosine kinase. Lyn phosphorylates the MUC1 cytoplasmic domain and increases binding of MUC1 to beta-catenin. The functional significance of this interaction is supported by the finding that MUC1 regulates nuclear targeting of beta-catenin and activation of gene transcription (c-myc, cyclin D1). Our hypothesis is that MUC1 expression contributes to the malignant phenotype of MM cells and that MUC1 represents a target in MM therapy.
The novel isocoumarin 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) proprionic acid (NM-3) induces endothelial cell death at low uM concentrations and direct killing of carcinoma cells at levels of 200-300 uM. Recent work has demonstrated that NM-3 also down-regulates MUC1 expression. In studies of MM cells, NM-3 induces apoptosis by a mechanism involving the release of mitochondrial cytochrome c. The results further demonstrate that NM-3 is synergistic with dexamethasone in inducing MM cell death.

1. To perform a Phase I/II pharmacokinetic trial of NM-3 alone in the treatment of MM.
2. To define the effects of NM-3 on MUC1 expression and apoptosis in MM cells in culture and from patients treated with this agent.
3. To define the mechanistic effects of NM-3 on sensitivity of MM cells to dexamethasone and other agents used to treat this disease.
4. To perform a Phase II pharmacokinetic/pharmacodynamic trial of NM-3 in combination with dexamethasone for the treatment of MM.
   

NM-3 has entered Phase I trials as an orally bioavailable agent. Plasma levels of 200-300 uM have been achieved without toxicity. We propose to define the clinical activity of NM-3 in the treatment of MM as a single agent and in combination with dexamethasone. Our hypothesis is that NM-3 will induce MM cell death, at least in part, by downregulating MUC1 expression and thereby sensitizes MM cells to dex and potentially other anti-MM therapies. This hypothesis will be addressed by studying the effects of NM-3 on MUC1 signaling in MM cells in vitro and in vivo.

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