Mentor: Richard Cerione
Contact Information: firstname.lastname@example.org; Phone: 607-253-3878
Sponsor: American Cancer Society
Grant Number: PF-10-238-01-CCE
Title: Glutaminase Inhibition as a Method of Breast Cancer Control
Annual Direct Cost: $48,000
Project Period: 07/01/10-06/30/13
DESCRIPTION (provided by applicant): Members of a family of proteins called Rho GTPases act as molecular switches in cells that control many aspects of cell growth and movement. A number of members of this family have been linked to cancer, and particularly cancer metastasis, due to their roles in stimulating cell movement and the ability of cells to invade other tissues. However, recently we have discovered a novel signaling endpoint for Rho GTPases, whereby they influence the fundamental metabolism of cells. This occurs through their ability to cause the activation of an enzyme (called glutaminase), which is responsible for elevating the metabolism of glutamine and helping to fulfill the energy requirements of cancer cells. Cancer cells have significantly different energy requirements than healthy, non-cancerous cells, making the actions of the metabolic enzyme, glutaminase, much more important to cancer cells than healthy cells. This then makes the enzyme glutaminase an intriguing target for drug discovery efforts.
Our laboratory has identified a small molecule, designated 968, which inhibits the activity of glutaminase in cancer cells, and is thus able to block their aberrant growth. We have demonstrated the inhibitory actions of 968 in two different breast cancer cell lines as well as in normal cells that are transformed into cancer-like cells due to over-activation of Rho GTPases. We have also found that the activity of the enzyme glutaminase is signficiantly elevated in cancer cells and that the increased enzyme activity can be directly linked to the activity of the Rho GTPases in these cells. Importantly, we have also shown that while the small molecule 968 inhibits cancer cell growth, it has little or no effect on the growth of healthy breast cells, implying that it may be a non-toxic cancer chemotherapeutic.
I propose studies that will further investigate how the small molecule 968 inhibits cancer cell growth. This will be done by examining a number of additional cancer cell lines so that we may learn which types of cancer are most vulnerable to 968 treatment. We hypothesize that those cells with the most demanding glutaminase-based energy requirements will be most responsive to treatment with 968. Additionally, I will set out to better understand how the hyper-activation of Rho GTPases that occurs in cancer cells initiates signals that culminate in the activation of the metabolic enzyme. Finally, I will work to develop a more active and more drug-like adaptation of the small molecule 968. While 968 shows reasonable potency, and a negligible toxicity, in early tests, it is not particularly soluble in water, and would not yet be an ideal drug candidate. Improving the various properties associated might yield a truly drug-like molecule, which would be of great benefit to cancer sufferers.