Currently there are ~140 approved drugs being used to treat cancer and many more are in clinical trials. Unfortunately, most of these drugs induce partial responses at best. One of the underlying reasons for treatment failure is poor penetrability of solid tumours; drugs do not achieve a therapeutic dose at the tumour site. High extracellular matrix (ECM) content of desmoplastic tumours manifests as tumour stiffness and presents a major obstacle to drug delivery.
We have developed a novel approach that improves tumour perfusion and drug uptake by bringing about degradation of tumour ECM. This is achieved by incorporating two biomolecules; (i) a novel peptide ligand that has specific binding affinity to tumour ECM in murine and human carcinomas, and (ii) an immune modulating cytokine, tumour necrosis factor alpha (TNFα) which attracts immune cells that secrete multiple ECM degrading proteases.
Systemic injection of ECM-targeted TNFα in tumour-bearing mice triggers robust immune cell infiltration into otherwise impenetrable tumours. The immune cell infiltration is accompanied by extensive degradation of tumour ECM and reduction in tumour stiffness. Tumour blood vessels become wider, better perfused, and more accessible for various imaging and therapeutic agents. Treatment with ECM-targeted TNFα also suppresses tumour growth and prolongs survival, with no toxic effects detectable in normal tissues. Moreover, this compound is usable across a wide spectrum of tumour types.