Thiamine Starvation with Thiaminase I for Breast Cancer Therapy

  • Moscow, Jeffrey (PI)

Grants and Contracts Details


Selective nutrient starvation is an important strategy in the treatment of certain cancers. For example, in the treatment of acute lymphoblastic leukemia, the down-regulation of the enzyme that makes the amino acid asparagine in leukemia cells is exploited clinically by using the bacterial enzyme I-asparaginase, which digests asparagine. This proposal investigates the potential of creating acute thiamine starvation for the treatment of breast cancer. The vitamin thiamine is a critical factor in cellular pathways that turn sugar (glucose) into energy. Cancer cells consistently use glucose in an abnormal way (called the Warburg effect). This is the underlying principle behind PET scans that are currently being used to improve breast cancer imaging. We have previously shown that a protein that transports thiamine into cells, THRT2, is decreased 7-fold in breast cancer compared to normal tissue, a finding related to the Warburg effect. This down-regulation of thiamine uptake may make these tumor cells more sensitive to thiamine starvation. In preliminary studies, we have created models of thiamine starvation in a breast cancer cell line and in normal breast cells, and we have shown that the breast cancer cells react differently than normal breast cells to thiamine starvation. Also, we have cloned the bacterial gene for the enzyme thiaminase I, an enzyme that digests thiamine and which could create acute thiamine starvation in the clinic, and have purified this recombinant enzyme. In our model, we would create acute thiamine starvation for breast cancer treatment by administration of the bacterial enzyme thiaminase I. We hypothesize that the down-regulation of thiamine uptake in breast cancer may expose a metabolic vulnerability in these tumors that could be exploited by thiaminase I treatment. Our specific aims are: 1) To produce and purify adequate amounts of thiaminase I enzyme for cell culture experiments; 2) To compare the effect of thiaminase I exposure to thiamine starvation in breast cancer cells; and 3) To determine whether thiaminase I exposure enhances the effectiveness of chemotherapy in a representative panel of breast cancer cells. We hypothesize that acute thiamine starvation will provide a completely new avenue for the therapeutic exploitation of a nutritional vulnerability, altered glucose metabolism, of breast cancer cells. In acute lymphoblastic leukemia, the metabolic vulnerability of the cancer cell is the down-regulation of asparagine synthase, the essential nutrient is asparagine, and the therapeutic agent to exploit the vulnerability is the bacterial enzyme asparaginase, which digests asparagine. In this proposal for breast cancer, the metabolic vulnerability is the down-regulation of the thiamine transporter gene, the essential nutrient is thiamine, and the therapeutic agent to exploit the vulnerability is the bacterial enzyme thiaminase, which digests thiamine.
Effective start/end date10/29/0710/28/09


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