Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 10/29/07 → 10/28/09 |
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