Prodrug TH-302 Plus Radiation Targets Tumor Hypoxia in Patient-Derived Pancreatic Xenografts
“The tumor selective hypoxia-activated cytotoxic prodrug TH-302 specifically and selectively targets extreme hypoxia found in solid tumors and is therefore believed to not only increase the treatment response of the primary tumor but also prevent tumor recurrence and metastasis,” noted Ines Lohse, PhD, of Ontario Cancer Institute at the Princess Margaret Hospital, Toronto, Canada. “The clinically validated warhead functions as an alkylator that kills dividing as well as non-dividing tumor cells while designed to be inactive and non-toxic in normal tissues.
The investigators used 7 patient-derived xenograft models to examine the efficacy of TH-302 in pancreatic tumors. Mice received chronic treatment with TH-302 alone, ionizing radiation alone, or both treatments combined: TH-302 treated mice received 3 doses of 50mg/kg TH-302 and mice treated with ionizing radiation received 2Gy on 3 consecutive days.
“TH-302 specifically targeted the hypoxic zone in the xenograft models,” Dr. Lohse reported. “Additionally, TH-302 treatment induced DNA damage in tumor tissue adjacent to the hypoxic zone, which is consistent with the previously demonstrated bystander effect of TH-302.”
In the primary patient-derived xenograft models, treatment with TH-302 in combination with ionizing radiation reduced tumor growth in high and medium hypoxic xenograft models; however, little impact on tumor growth in low or non-hypoxic models was observed.
Response depended on the extent of tumor hypoxia and the tumor growth rate. While showing high treatment efficacy even as a single agent in fast-growing hypoxic models, TH-302 treatment had little effect on tumor growth in a hypoxic model that displayed slow growth rates.
“Our results strongly support the ongoing clinical trials of TH-302,” said Dr. 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.”