Optimizing the anti-cancer activity of thalidomide

Approximately 555,500 people die from cancer in the United States each year. The development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry (for a single source of key epidemiological, market and R&D data click here to access "The Cancer Market Outlook to 2008").

Prostate carcinoma is the most common malignancy and second leading cause of cancer death in men in the United States. Approximately 180,400 new cases of prostate cancer are diagnosed each year. Prostate cancers generally respond to androgen ablation therapy. However, such treatment is not curative, and the disease progresses to an androgen-independent stage. Effective treatment for advanced hormone-refractory cancers remains a significant challenge (click here for an overview of pharmaceutical approaches to prostate cancer).

Thalidomide (N-alpha-phthalimidoglutarimide), a glutamic acid derivative, is being increasingly used in the clinical management of a wide spectrum of immunologically mediated and infectious diseases. Cancer remains the primary off-label use of thalidomide and Celgene reports that 92% of thalidomide's $119 million in sales in 2002 came from this use.

The clinical value of thalidomide is, in part, as a result of its TNF-alpha inhibitory activity. Specifically, it inhibits TNF-alpha protein expression at the post-transcriptional level by facilitating turnover of the mRNA. More recent research has shown similar inhibitory action of COX2 protein expression and both actions are mediated post-transcriptionally via AU-rich elements found in the 3' untranslated regions (3'-UTRs) of each mRNA.

Further activity of clinical relevance includes the ability of thalidomide to inhibit the transcription factor, NFkB, to co-stimulate both CD8+ and CD4+ T cells and to reduce angiogenesis activity and thus in addition to having direct effects on proliferating cancer cells thalidomide also has indirect effects through the reduction of neovascularization and the stimulation of immune activity.

Tumor vascularization is key to the development of solid tumors and the vast majority of pharmaceutical activity surrounding angiogenesis relates to the development of therapeutic strategies to destroy existing tumor vasculature or to prevent neovascularization. Despite early enthusiasm for angiogenesis inhibitors as safe and effective anticancer drugs, several Phase III and Phase II trials have proved disappointing. Newer strategies are however being developed which will hopefully confer greater efficacy to this field (for an analysis of pharmaceutical activity surrounding the development of angiogenesis inhibitors click here).

The anti-angiogenic properties of thalidomide result from the inhibition of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). The action of thalidomide to inhibit angiogenesis is however not particularly potent and it therefore represents an interesting lead compound for medicinal chemistry. Lead optimization has especially high potential for the treatment of prostate cancer since thalidomide has demonstrated therapeutic activity, albeit modest, in patients with with androgen-independent metastatic prostate cancer.

In their recent Journal of Medicinal Chemistry paper researchers from the University of Virginia have reported the development of phthalimide analogues of thalidomide. In particular they have focused on substituting the four aromatic hydrogen atoms of phthalimide with fluorine.

In an initial screen Capitosti et al investigated the ability of their phthalimides to inhibit the proliferation of human microvascular endothelial cells (HMEC), both in the presence and absence of VEGF, and to reduce the proliferation of androgen receptor negative DU-145 and PC-3 prostate cancer cell lines.

Non-fluoro-substituted phthalimides as well as thalidomide had only modest activity against HMEC cells. Likewise, although thalidomide reduced the proliferation of androgen positive LNCaP prostate cancer cells, it had minimal activity against the androgen receptor negative DU-145 and PC-3 prostate cancer cell lines (generally thalidomide requires metabolic activation to be effective against these cell lines). Similarly the non-fluoro-substituted phthalimides were minimally active against DU-145 and PC-3 prostate cancer cell lines. In dramatic contrast the fluoro-substituted phthalimides prevented HMEC proliferation with potencies, in some cases, under 100nM (representing a 3000-fold improvement over thalidomide). In addition representatives from this class prevented the proliferation of LNCaP cells and furthermore the proliferation of DU-145 and PC-3 prostate cancer cell lines was also effectively reduced.

Thalidomide is commonly used off-label to treat cancer however analogues with improved efficacy and reduced adverse effects will eventually completely replace thalidomide. One example of a thalidomide analogue is Revlimid (CC-5013, known as Revimid in the US). This candidate shows great promise for the treatment of multiple myeloma after trials have shown no evidence of any side effects commonly sustained by the use of thalidomide.

Revlimid received orphan drug designation from the EC following the favorable opinion of the European Agency for the Evaluation of Medicinal Products and was granted orphan drug and fast track designations by the FDA in February 2003 for the treatment of myeloma, and in April 2003 for the treatment of myelodysplastic syndromes. Revlimid has been found to be 50 to 2000 times more potent than thalidomide in stimulating T-cell proliferation, but shows fewer side effects. Revlimid is currently only approved by the FDA for the treatment of leprosy. The company expects Revlimid to eventually replace thalidomide and overtake current sales, with anticipated annual sales of $1 billion a decade after approval is granted.

The present study further demonstrates the potential attached to the optimization of thalidomide and data comparing the efficacy of thalidomide, Revlimid and fluoro-substituted phthalimides in cancer models and their respective adverse effect profile are eagerly awaited.

Entry date Wednesday, April 14, 2004

Adapted from Capitosti et al, Bioorg Med Chem. 2004 Jan 15; 12(2): 327-36