Combination Therapy to Treat Gemcitabine-Resistant Cancers

Unmet Need: Gemcitabine resistance is a widespread problem. A large proportion of cancer patients end up receiving gemcitabine at some point of their care (as is approved in lung, pancreatic, breast and ovarian cancer), and although efficacious in a third of the cases, most do not respond, and even those who respond eventually develop resistance. Plk1 is a key step in cell cycle progression, and there is preclinical evidence suggesting that after cytotoxic damage cells are particularly sensitive to Plk1 inhibition. Here we provide in vitro and in vivo evidence of that hypothesis. With this combination, a two-step approach can increment the antitumor efficacy and turn growth arrest into cell death by interfering with the cell cycle. Advantages include:
 

• Combination of cell cycle modulator ON 01910.Na with nucleotide analog chemotherapeutic gemcitabine
• Synergistic anti-tumor effect that induces tumor regression in gemcitabine-resistant pancreatic cancer
• Combination therapy for any diseases where gemcitabine is indicated 

Technical Details: Johns Hopkins researchers have developed a combinatorial approach with gemcitabine and ON 01910.Na, a cell cycle modulator that interacts at the polo-like 1-controlled G2/M checkpoint. Plk1 knock-down in gemcitabine-resistant pancreatic cancer cell lines caused a modest growth inhibitory effect; yet, treatment with combinations gemcitabine and ON 01910.Na induced synergy. Similar synergy was observed in in vivo xenograft models where the combination resulted in tumor regression, which was more pronounced the higher the gemcitabine resistance was in vivo. This combination may be useful in any disease where gemcitabine is indicated, including pancreatic, lung, breast and ovarian cancer. 
 
Patent Status: Granted Patents in USA 8,962,614, and South Korea 10-2010-0137570
 
Associated Publications: Oncogene. 2009 Jan 29;28(4):610-8.

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