Tarloxotinib: Targeting hypoxia-induced, wild-type EGFR signaling.

Tarloxotinib bromide*, or "tarloxotinib" (TH-4000), is a clinical-stage Hypoxia-Activated Prodrug (HAP) that is designed to release an irreversible, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) under hypoxic conditions. Threshold holds a license to exclusive worldwide rights for tarloxotinib from the University of Auckland, New Zealand.

Aberrant EGFR signaling is implicated in the growth and spread of certain tumor types including non-small cell lung cancer (NSCLC) and head and neck cancer. Current EGFR-TKI therapies are ineffective in shutting down aberrant EGFR signaling due to dose-limiting toxicities of rash and diarrhea. At the same time, these tumors are hypoxic, and hypoxia drives the overexpression of wild-type EGFR. Clinical studies indicate that mutant EGFR-positive NSCLC with wild-type EGFR present (heterozygous) is associated with reduced response rates, progression-free survival and overall survival outcomes on conventional EGFR-TKIs.

Therefore, a molecularly-targeted, hypoxia-activated, irreversible EGFR-TKI is expected to deliver greater efficacy with fewer side effects than currently available treatments.

Leveraging knowledge that the hypoxic tumor microenvironment enhances aberrant, wild-type EGFR signaling, tarloxotinib is designed to selectively release an irreversible EGFR inhibitor upon encountering tumor hypoxia.

[18F]-HX4: An imaging agent for hypoxia

Positron Emission Tomography, or PET, is a non-invasive nuclear medical imaging technique that produces three-dimensional images of certain functional processes in the entire body or selected organs and tissues. [18F]-HX4 contains a short-lived radioisotope, 18F, which can be detected in a PET scanner. PET imaging is used to help physicians diagnose and treat cancer and is routinely performed in cancer treatment centers globally. [18F]-HX4 has a 2-nitroimidazole “trigger” that is designed to be activated under the extreme hypoxic conditions generally found in tumors but not typically in normal healthy tissue, therefore it will accumulate more in these hypoxic regions.1 Clinical data has demonstrated the potential of [18F]-HX4 to quantify the degree of hypoxia within different tumors.2-4

Patient with high uptake of [18F]-HX4 in left lung mass with mediastinal adenopathy (CT image top right, PET image bottom right, superimposed image on the left)


1. Dubois, L.J. et al. Preclinical evaluation and validation of [18F]-HX4, a promising hypoxia marker for PET imaging. Proc Natl Acad Sci USA 108: 14620–14625, 2011.
2. van Loon, J. et al. PET imaging of hypoxia using [18F]-HX4: a phase I trial. Eur J Nucl Med Mol Imaging 37: 1663-1668, 2010. 
3. Doss, M. et al. Biodistribution and radiation dosimetry of the hypoxia marker [18F]-HX4 in monkeys and humans determined by using whole-body PET/CT. Nucl Med Commun 31: 1016-1024, 2010.
4. Chen, L. et al. 18F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with 18F-FMISO. Nucl Med Commun 33: 1096-1102, 2012.