Abstract LB-129: NDAT and P-bi-TAT formulations of tetraiodothyroacetic acid (tetrac) induce devascularization, necrosis and apoptosis in glioblastoma xenografts

Abstract

Abstract Thyroid hormone as L-thyroxine (T4) has been reported to stimulate proliferation of multiple glioma cell lines in vitro and there is clinical evidence that medical induction of hypothyroidism slows growth of glioblastoma multiforme (GBM). The proliferative action of T4 on glioma cells is initiated at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone (T4) derivative that blocks T4 action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) or to two polyethylene glycol (PEG) molecules (P-bi-TAT) that increase the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of U87 MG GBM xenografts, NDAT administered daily for 10 days s.c. as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p <0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p <0.001). There was no intratumoral hemorrhage. There was extensive cellular necrosis in treated tumors attributable to devascularization. Cells not necrotic in treated xenografts exhibited apoptosis, so that 80% of cells were either necrotic or apoptotic, compared to controls (p <0.001). Induction of apoptosis in cancer cells is a well-described quality of NDAT. P-bi-TAT treatment resulted in similar results after 20 days of treatment, but included a 21-day off-treatment follow-up after therapy. Xenografts achieved a 95% volume loss in the off-treatment, follow-up phase (P < 0.001). In summary, systemic NDAT and P-bi-TAT have been shown to be effective by multiple mechanisms in treatment of GBM xenografts. Citation Format: Paul J. Davis, Sudha Thangirala, Stewart Sell, Aleck Hercbergs, Shaker A. Mousa. NDAT and P-bi-TAT formulations of tetraiodothyroacetic acid (tetrac) induce devascularization, necrosis and apoptosis in glioblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-129. doi:10.1158/1538-7445.AM2017-LB-129