Threshold is developing drugs that target tumor hypoxia, a common characteristic of the tumor microenvironment that is associated with tumor progression, metastasis, resistance to radiotherapy and standard chemotherapy, and ultimately treatment failure.

Regions of tumor hypoxia, or low-oxygen conditions, is a common feature of the microenvironment of many solid tumors.1 The network of blood vessels supplying solid tumors is known to be highly irregular and disordered, failing to deliver sufficient oxygen and nutrients to the rapidly dividing cancer cells. Compromised oxygen delivery results in the development of regions of tumors that are chronically and transiently hypoxic.2,3 Hypoxia is associated with increased tumor resistance to chemotherapy and radiation treatment.1 Many conventional reactive chemotherapies are not able to penetrate into the hypoxic zones that are located at a distance from the blood vessels.4,5 Moreover, chronic hypoxia limits cancer cell proliferation, rendering the quiescent tumor cells in the hypoxic region of the tumor less susceptible to conventional antiproliferative agents, which typically target actively dividing cells in close proximity to the blood vessels. Under conditions of cell hypoxia, genomic instability can lead to tumor cell variants that can survive in an oxygen depleted environment through clonal selection and expansion.6 This clonal expansion leads to tumor progression, metastasis, acquired resistance to chemotherapy, and treatment failure, ultimately resulting in compromised clinical outcomes.6,7

Given the role of hypoxia in tumor progression, metastasis, and resistance to radiotherapy and standard chemotherapy, and ultimately treatment failure, specific targeting of hypoxic tumor regions is emerging as a significant, high-priority target for effective and durable cancer therapy.7

Threshold is currently developing evofosfamide based on hypoxia-activated prodrug technology. Scientists at Threshold designed evofosfamide as a prodrug such that it is selectively activated under hypoxic conditions, which are found in cancer tissue. Upon activation, evofosfamide releases a cytotoxic DNA-alkylating agent.


References

  1. Bertout JA, et al. Nat Rev Cancer 2008;8:967-75.
  2. Coleman CN. J Natl Cancer Inst 1988;80:310-317. 
  3. Vaupel P, et al. Cancer Res 1989; 49:6449-6465. 
  4. Minchinton AI and Tannock IF. Nat Rev Cancer 2006;6:583-92. 
  5. Phillips RM, et al. Br J Cancer 1998;77:2112-9. 
  6. Vaupel, P. Exp Oncol 2010;32:125-127. 
  7. Wilson WR and Hay MP. Nat Rev Cancer 2011;11(6):393-410.