Clinical research performed by our group at Washington University School of Medicine has defined an essential role for pre-treatment and post-treatment 18F-fluoro-deoxy-glucose (FDG)-PET scanning for patients with cervical cancer.  We have found that cervical tumors with increased FDG uptake on pretreatment PET scans have inferior outcomes after primary radiation.  FDG uptake in human tumors decreases rapidly during the course of radiation treatments, and tumors with residual FDG uptake after treatment are likely to recur.  In the laboratory we have found that alterations in expression of genes from the PI3K pathway are associated with residual FDG uptake in human cervical tumors after radiation.

Radiation oncologist Julie Schwarz, MD, PhD, (right) and staff scientist Ramachandran Rashmi, PhD, and their colleagues exploit cancer cell metabolism to kill cervical tumors that are resistant to standard chemotherapy and radiation. Photo by Matt Miller.

Recently, we have been evaluating the sensitivity of cervix cancer to inhibition of glycolysis using preclinical models both in vitro and in vivo. Similar to what we see in our patients, some cervical cancer cell lines take up large quantities of glucose, and these cell line are resistant to radiation therapy. 2-DG, similar to FDG, is taken up by glucose transporters and phosphorylated by hexokinase, but cannot transition further down the glycolytic pathway.  2-DG enhances the effects of cisplatin only minimally, and sensitizes highly glycolytic cells to irradiation.  Interestingly, when 2-DG is combined with inhibitors of glutathione (BSO) and thioredoxin metabolism (AUR), 2 key pathways necessary for maintenance of intracellular redox homeostasis, highly glycolytic cell lines are unable to form colonies in vitro and significant tumor growth delay is observed in vivo.  For cervical cancer tumor lines that display intermediate levels of glucose uptake, simultaneous treatment with 2-DG, BSO and AUR can be used to radio-sensitize cervical cancer tumor lines at clinically relevant radiation doses both in vitro and in vivo

Most recently we have found that cervical cancers that are resistant to radiation are very sensitive to inhibition of glutamine metabolism, as this amino acid is used in cervical cancer cells to generate intermediates needed for the tricarboxylic acid cycle  and reduced glutathione for the maintenance of redox balance.  Inhibition of glutamine metabolism is appealing clinically as inhibition is less toxic to normal tissues.  We have recently completed a series of preclinical studies combining inhibition of glutamine metabolism with radiation in cells and animal models of cervical cancer (figures from this paper are copied below and link is first paper link).  This data is now being used to form the basis of new clinical trials for patients with locally advanced cervical cancer.

Read more about Ramachandran Rashmi, PhD, and her research in the Schwarz lab here. Her recent papers are published here and here.