Technologies

Challenge

One of the many challenges in treating cancer lies in the fact that not all cancer cells are identical to each other within a single patient. In tumors, some cells are glutamine addictive and some are glutamine independent. Glutamine addictive cells require glutamine for the TCA cycle, balancing redox in cells, activating signaling, and serving as building blocks for cell proliferation and metastasis. Glutamine independent cells use the enzyme glutamine synthetase to generate necessary glutamine. Specifically, low-invasive ovarian cancer (OVCA) cells are glutamine independent while high-invasive ovarian cancer (OVCA) are glutamine dependent. Because of the different metabolic nature of the cells, simply using one drug to inhibit one of the pathways will not have a prominent effect on clinical outcomes.

Solution

This invention is a method of targeting ovarian cancer cells with a combinational drug therapy. The cancer prognosis is first determined using the ratio of glutamine catabolism over anabolism, a novel biomarker. Then, a glutaminase inhibitor, a glutamine synthetase inhibitor, and a STAT3 inhibitor are administered in combination. The administration of the glutaminase inhibitor and glutamine synthetase inhibitor may be an effective therapy for heterogenous tumors, those containing both high-invasive OVCA and low-invasive OVCA. STAT3 signaling, which can be activated by glutamine, is important for cell invasion and is a malignant state marker. Therefore, to further inhibit cancer cells’ metastasis, a STAT3 inhibitor is combined along with the targets of glutamine pathways to block glutamine’s effect on metastasis, signaling, and tumor growth.

Technology Relevant Papers and Web Links

http://nagrathlab.rice.edu/

Yang L, Moss T, Mangala LS, Marini J, Zhao H, Wahlig S, Armaiz-Pena G, Jiang D, Achreja A, Win J, Roopaimoole R, Rodriguez-Aguayo C, Mercado-Uribe I, Lopez-Berestein G, Liu J, Tsukamoto T, Sood AK, Ram PT, Nagrath D. Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer.Mol. Syst. Biol. 2014 , 12(5), 1-23.