Novel Small Molecules that Target Cancer Stem Cells for the Treatment of Cancer
BACKGROUND
Lung cancer is the leading cause of cancer related death in the United States. In 2012, it is estimated that approximately 230,000 patients will be newly diagnosed, and since more than 160,000 individuals will succumb to this disease, there exists an urgent need for improved therapeutics. In the past, natural products have served as the basis for the development of a number of anti-cancer agents approved for clinical use; examples include the plant derivatives taxol and camptothecin.
Interestingly, anti-tumor activity of parthenolide (PTL) - a natural substance that can be isolated from a plant known as feverfew (Tanacetum parthenium) - has also been demonstrated. However, feverfew extract and native PTL exhibit poor bioavailability. Analogs with increased solubility and bioavailability have recently been synthesized and show promise as anti-cancer agents. One of these analogs, dimethylaminoparthenolide (DMAPT), has recently entered early phase clinical testing for the treatment of leukemia.
INNOVATION
Professor Michael Jung from the Department of Chemistry and Biochemistry, Professor Richard Pietras from the Department of Medicine, and colleagues at UCLA have recently synthesized and evaluated a series of unique PTL derivatives. A number of these compounds exhibit (i) improved aqueous solubility as well as (ii) improved in vitro cell killing relative to the native forms of PTL and DMAPT. Furthermore, these new derivatives exhibit a synergistic cell killing effect when combined with existing approved chemotherapeutic agents.
Perhaps one of the most intriguing characteristics of the PTL analogs is their ability to inhibit the growth of lung cancer stem cells as demonstrated by the UCLA team in their preliminary studies. Given the significant role that cancer stem cells purportedly play in both metastatic spread as well as in patient relapse, these compounds hold strong promise to reduce the mortality associated with advanced stage lung cancer.
APPLICATIONS
- PTL analogs exhibit strong promise for use in the therapeutic treatment of advanced stage lung cancer
- Although the investigators have focused on lung cancer, it is possible that PTL analogs may have activity against other cancers
ADVANTAGES
- PTL analogs exhibit improved solubility as well as an enhanced cell killing ability in vitro
- PTL and its analogs are thought to kill and sensitize cells to DNA damaging agents by inhibiting NFκB