Anti-Cancer Therapy: Targeting the Mevalonate Pathway

Abstract

The mevalonate pathway has become an important target for anti-cancer therapy. Manipulation of this pathway results in alteration of malignant cell growth and survival in cell culture and animal models, with promising potential for application in human cancers. Mevalonate is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). Mevalonate is further metabolized to farnesyl pyrophosphate (FPP), which is the precursor for sterols. In addition, the farnesyl moiety from FPP is utilized for post-translational modification of proteins including small GTPases, such as Ras and Ras related proteins, which play a role in malignant transformation of cells. FPP is a precursor for geranylgeranyl pyrophosphate (GGPP), which is similarly involved in post-translational modification of proteins. There has been intense interest in manipulating the pathway through HMG-CoA reductase inhibition. More recently, the focus has been on manipulating the pathway by post-translational modification of key regulatory proteins through farnesyl prenyl transferase (FPTase) or geranylgeranyl prenyl transferase (GGPTase) inhibition. This review focuses on the mevalonate pathway and the application of rational drug therapies to manipulate this pathway. Included in the review are a summary of agents demonstrating success in preclinical investigations such as; farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors, dual inhibitors, statins, bisphosphonates, histone deacetylase inhibitors and other compounds. While these agents have shown preclinical success, translation to success in clinical trials has been more difficult. These clinical trials are reviewed along with evaluation of some of the potential problems with these agents in their clinical application.

Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells

“…These drugs inhibit the sterol-specific portion of the pathway and do not interfere with isoprenoid synthesis. Blocking isoprenoid synthesis is known to inhibit cell growth by preventing isoprenylation of important growth-regulatory proteins (28). If sterol supplementation can reverse the effects of ZGA and TPL, it would suggest that these drugs inhibit MB cell growth by blocking the synthesis of a critical downstream sterol product rather than by causing accumulation of a growth-inhibiting upstream intermediate.…”

“…The role of SSPIs as therapeutic agents for human cancer has primarily focused on statins (28). The activity of these agents is mainly due to inhibition of isoprenoid synthesis, blocking isoprenylation of key growth-regulatory proteins like Ras and Rho.…”

Molecular pathology of breast apocrine carcinomas: A protein expression signature specific for benign apocrine metaplasia

“…Some of the biomarkers we identified as being expressed by apocrine metaplasias such as 15-PGDH, HMGCoA reductase, and COX-2, are well known therapeutic targets [74][75][76][77][78] with pharmacological agents already available (e.g. pravastatin, lovastatin, Ph CL 28A, nafazatrom, celecoxib, and rofecoxib).…”

Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better

“…to be candidate cancer genes (CAN-genes). The average number of mutant CAN-genes was 12 (range, 4 -23) for breast cancers and 9 (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] for colorectal cancers with a distinct CAN-gene signature found for each cancer. Furthermore, the mutation spectrum was markedly different between breast and colon cancers with all the differences highly significant (p Ͻ .0001).…”