The overall goal is development of a novel human protein, Galectin-3C, as a treatment for multiple myeloma (MM) that can be given with other agents to increase the percentage of patients who are responsive to therapy, and the survival rate. MM is rarely curable despite the introduction of new therapeutic regimens and more efficacious treatments are sorely needed. The 10-year survival rate has recently increased, but is still just 17.4%. Current therapeutic agents for MM including dexamethasone, thalidomide, and bortezomib are thought to act partially through induction of apoptosis. Galectin-3C contains the carbohydrate recognition domain of Galectin-3 but lacks its N-terminal domain that functions in multimerization. Galectin-3C acts as a dominant negative inhibitor of Galectin-3 by binding to the same carbohydrate ligands but not multimerizing. Previously, we showed that Galectin-3C reduced the growth and metastasis of tumors in a mouse model of human breast cancer. Our preliminary data indicate that Galectin-3C can induce or facilitate apoptosis mediated by anticancer agents such as dexamethasone in multiple myeloma and other types of cancer cells.
The Specific Aims of the Phase I research are as follows:
Aim #1. To determine the ability of Galectin-3C to inhibit growth of MM cells from patients and human cell lines and to provide evidence of the mechanism of action and potential biomarkers. The effect of GAL3C on proliferation and apoptosis of MM cell lines, and patient cells will be assessed. The CD138negative MM cells that are postulated to possess the tumor-initiating and maintaining characteristics of cancer stem cells will be isolated and tested with Galectin-3C. Efficacy will be tested on MM cells adherent to immortalized human stromal cells in conditions that give rise to """"""""extracellular matrix drug resistance"""""""" that protects MM cells from apoptosis. We will determine the expression of Galectin-3 and Bcl-2 family members, Mcl-1, Bax, Bad, and Bcl-2.
Aim #2. To assess the ability of Galectin-3C to facilitate response to dexamethasone, thalidomide, and bortezomib in MM cells from patients and human cell lines. Proliferation of cell lines with Galectin- 3C and each agent will be determined, and the best combination will be tested with patient cells.
Aim #3. To determine the effect of Galectin-3C alone and in combination therapy of NOD/SCID mouse models of disseminated and subcutaneous human MM. One agent will be selected based on results in Aim #2 and tested with Galectin-3C in disseminated and subcutaneous NOD/SCID mouse models of MM. Galectin-3C will be administered by intramuscular injection and continuous intravenous delivery by mini-pump in the disseminated model. The methodology producing the best response will be used for administration in the subcutaneous model. Phase II would focus on completing preclinical development towards initiation of a Phase 1 human clinical trial.
Multiple myeloma is rarely curable despite the introduction of new therapeutic regimens and more efficacious treatments are needed. More than 19,900 new cases and 10,700 deaths from multiple myeloma are expected in the U.S. in 2007. Although the 10-year survival rate has recently increased it is only 17.4%. The overall goal of this research is the development of a novel human protein, Galectin-3C, as a treatment for multiple myeloma that can be given with other agents to facilitate the induction of apoptosis, to increase the percentage of patients who are responsive to therapy, and the survival rate. ? ? ?
|Mirandola, Leonardo; Yu, Yuefei; Jenkins, Marjorie R et al. (2011) Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4. BMC Cancer 11:394|
|Mirandola, Leonardo; Yu, Yuefei; Chui, Kitty et al. (2011) Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma. PLoS One 6:e21811|