Summary of Invention
This invention relates to the treatment of solid tumors with a triple combination therapy of maximum tolerated dose (MTD) chemotherapy, Continuous low dose (CLD) chemotherapy, and a cathepsin inhibitor. Both the Hi-Lo chemotherapy as well as the triple combination therapy are novel concepts.
With MTD chemotherapy alone, some tumors may regress but others may become resistant to the therapy. When MTD (cyclophosphamide) was given to mice with pancreatic tumors, average tumor size decreased but there was a large variation in tumor volume since some tumors rebounded. When the MTD chemotherapy was combined with CLD (cyclophosphamide) chemotherapy (CLD alone does not have a significant effect on tumor volume), established tumors regressed. This combined treatment had no effect, however, on the prevalence of invasive carcinomas and only a modest effect on survival. This combination treatment was termed Hi-Lo chemotherapy. When the Hi-Lo chemotherapy was combined with the cathepsin inhibitor (JPM-OEt), there was:
- Decreased tumor proliferation
- Increased tumor apoptosis
- Decreased tumor vascularity
- Reduced tumor invasion
- Increased survival of the mice
The cysteine cathepsin proteases are primarily intracellular proteases that function in terminal protein degradation in lysosomes and protein processing in other intracellular organelles. Gene expression profiling of pancreatic islet tumors in a mouse model of cancer revealed upregulation of cathepsin cysteine proteases. A broad-spectrum cysteine cathepsin inhibitor (JPM-OEt) was used to pharmacologically knock out cathepsin function at different stages of tumorigenesis. This resulted in impairment of angiogenic switching in progenitor lesions, as well as reduction of tumor growth, vascularity, and invasiveness. There was, however, no increase in tumor apoptosis. It was hypothesized that if the cathepsin inhibitor treatment was combined with chemotherapy (which causes tumor apoptosis), tumor growth could be stabilized or regressed and survival could be increased.
The triple combination therapy potentially may be used in cases of breast cancer, prostate cancer, and other solid tumors. Revenue figures for existing treatments are one indication of the scope of this potential market: for example, Taxol had worldwide revenues of $385 million in 2008; Abraxane, $299 million (2008); Paclitaxel, $67 million (2007); and Gemzar $1.7 billion (2008).
The triple combination therapy results in the regression of established tumors and a significant increase in survival. The regression of tumors and the increase in survival is significantly higher than seen with the Hi-Lo therapy alone.
Areas of Application
Solid tumor therapy
Stage of Development
Johanna Joyce, PhD
Yashodhara Dash, MBBS, PhD, MBA, CLP
Senior Licensing Manager
Tel. 646-888-1073; Fax: 646-888-1120