Hypoxia-activated DNA-PK inhibitor
Categories for this Technology
Novel DNA-PK inhibitor prodrug which is hypoxia-activated and radiosensitizes tumour cells more potently and specifically, increasing response rate to radiation by blocking the DNA-PK pathway.
DNA-PK and Cancer
Radiotherapy, in combination with chemotherapy, is used with curative intent for the treatment of advanced head and neck squamous cell carcinoma (HNSCC). However, local control within the radiation field is often unsuccessful, causing undesired off-target effects in normal cells. The problem is heightened by radiation resistance in tumour cells. Radiation resistant tumour cells require more potent radiation doses, but doses are limited to avoid undesired off-target effects, compromising efficacy. A major source of this resistance is non-homologous end-joining (NHEJ) repair, which repairs broken tumor DNA, leading to poor prognosis / disease progression. DNA-dependent protein kinase (DNA-PK) plays a key role in the activation of canonical NHEJ repair of DNA double strand breaks.
Issues with other radio-sensitizing cancer drugs
Inhibiting DNA-PK is proven to prevent NHEJ repair, preventing radiation resistance in tumour cells and increasing their sensitivity to radiation therapy. However, current inhibitors of DNA-PK are poorly selective. This lack of selectivity contributes to toxicities observed in preclinical studies with these agents, maintaining the need for dose-limitation of therapy, compromising efficacy.
A novel, potent, and highly selective DNA-PK inhibitors which radiosensitise HNSCC cells in vitro and in vivo has been indentified. The plan to use hypoxia activated prodrugs of these DNA-PK inhibitors to deliver them selectively to tumours to improve the therapeutic index. This approach provides a clear opportunity to capitalise on the burgeoning investment in DNA damage response inhibitors for cancer therapy.
• HPV-ve HNSCC
• NSCLC patients with stage IIB/III disease
• Pancreatic ductal adenocarcinoma
• Prostate carcinoma.
• Combinations of DNA-PK HAPs with cytotoxic chemotherapy
• The use of HAP-mediated tumour selective drug delivery would provide a considerably broader context for application of DNA-PK inhibitors
• Greater Selectivity: Novel hypoxia-activated prodrug approach reduces off-target effects in normal cells compared to other inhibitors of DNA-PK.
• Tumour selectivity: HNSCC tumours are hypoxic. Hypoxia reduces effectiveness of standard treatment (radiotherepy + chemotherapy). Hypoxia-activated prodrug selectively targets HNSCC tumours, increasing efficacy of standard therapy.
• More Potent that other DNA-PK inhibitors.
Questions about this Technology?
Contact Dr Sandhya Badrinarayanan