Human Pancreatic Tumor Growth In Hypoxic Xenografts Reduced By A Combination Of TH-302 And Radiation
A combination of the prodrug TH-302 and radiation may provide an effective treatment strategy for pancreatic cancer, according to preclinical results presented at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges conference, being held here June 18-21.
“We found that the combination of TH-302 and ionizing radiation reduced pancreatic tumor growth in hypoxic xenografts,” said Ines Lohse, Ph.D., a postdoctoral fellow at the Ontario Cancer Institute at the Princess Margaret Hospital in Toronto, Canada. “The response we observed depended on the magnitude of tumor hypoxia and the tumor growth rate.
“We have previously shown that hypoxia in our patient-derived pancreatic tumor models correlates with aggressive growth and a high metastatic potential, meaning if a tumor shows high levels of hypoxia, it will grow faster and is more likely to metastasize,” Lohse said.
All solid tumors contain areas of low oxygen tension (that is, regions of hypoxia). Cancer cells in these areas are less responsive to standard cancer chemo- and radiotherapy. Researchers hypothesize that drugs that can specifically target these regions will increase primary tumor treatment responses and prevent tumor recurrence and metastasis. One strategy under investigation is to use therapies that are toxic only under hypoxic conditions, for example, prodrugs that are converted to their active form by hypoxia.
In preclinical models of pancreatic cancer, Lohse and colleagues tested TH-302, a tumor-selective, hypoxia-activated, cytotoxic prodrug that specifically targets the areas of extreme hypoxia found in solid tumors. Using seven patient-derived pancreatic tumor models grown in immune-compromised mice, they assessed the efficacy of treatment with TH-302 alone, ionizing radiation alone or a combination of the two, wherein the mice received three 50 mg/kg doses of the drug and ionizing radiation on three consecutive days.
The combination treatment reduced tumor growth in high and medium hypoxic xenografts; however, the combination had little effect on tumor growth in low- or nonhypoxic implants. Treatment efficacy depended on the extent of tumor hypoxia and tumor growth rate.
“We were expecting that hypoxia would be a strong predictor of treatment efficacy,” Lohse said. “But in our models, we actually showed that hypoxia is not the only predictor. Tumor growth rates are equally important in predicting treatment efficacy.
“Our results strongly support the ongoing clinical trials of TH-302,” said Lohse. “In these trials, TH-302 is being tested in combination with chemotherapy, and one combination has, in fact, been recently reported to prolong progression-free survival in patients with advanced pancreatic cancer. We hope that our data might lead to TH-302 being tested in combination with ionizing radiation as an alternative treatment option for pancreatic cancer.”
Abstract: Targeting Tumor Hypoxia in Patient-Derived Pancreatic Xenografts Using TH-302. Ines Lohse, Joanna Rasowski, PinJiang Cao, Emin Ibrahimov, Melania Pintille, Ming S. Tsao, Richard Hill, David W. Hedley. Ontario Cancer Institute / Princess Margaret Hospital, Toronto, ON, Canada.
American Association for Cancer Research