Targeting the Mevalonate Pathway and Its Restorative Feedback Loop in Breast Cancer
Abstract
The diagnosis and treatment of breast cancer has improved, in part, through synergistic partnerships in basic and clinical research; however, a crucial remaining challenge is to ensure cancer does not return, after seemingly going away following initial treatment. Many of these recurrent cancers are found in places other than the breast and are called metastasis. There are currently few options to prevent metastasis, and once metastasis has occurred, there are rarely options to cure this disease. The majority of breast cancer deaths are caused by metastasis. Identifying ways to prevent metastasis would have great benefit. Statins are common drugs used worldwide to lower cholesterol. We have recently shown that statins can kill breast cancer cells that are undergoing changes associated with metastasis and do so without harming normal cells. Statins inhibit a metabolic process found in all cells of the body, called the mevalonate pathway. The job of the mevalonate pathway is to generate many products needed by the cell, including cholesterol and small lipid tags called isoprenoids. We, and others, have shown that when statins inhibit the mevalonate pathway, it is the depletion of the lipid tags that kills the tumor cells. In fact, breast tumor cells depend on these lipid tags for growth and survival. This evidence suggests that statins can be used not only for cholesterol control, but also to treat breast cancer. Women taking statins to lower cholesterol have a decreased risk of breast cancer, and two recent clinical trials have shown that statins can decrease breast cancer growth and increase death of the cancer itself. Because statins are Food and Drug Administration (FDA)-approved agents that are made by generic drug companies, they are immediately available and affordable drugs that can be mobilized for the prevention of breast cancer metastasis without delay. Why are metastatic breast cancer cells particularly sensitive to statin-induced tumor cell death? For breast cancer cells to undergo metastasis, they must: (i) become mobile and leave the breast, (ii) survive as they travel throughout the body, and (iii) settle and grow in a new location. Many of these actions require specific molecules that are dependent on the small lipid tags produced exclusively by the mevalonate pathway. For example, we show that the first step of metastasis, called epithelial-to-mesenchymal transition (EMT), is dependent on the production of these small lipid tags. This is a breast cancer cell vulnerability that we can exploit with statins. By treating patients with statins, tumor cells are deprived of their lipid tags and cannot metastasize. Thus, we think that statin treatment will cause tumor cells to die instead of undergoing metastasis. Statin activity can be reduced by a feedback loop that restores the mevalonate pathway. To increase the efficacy of statins, we recently discovered a way to inhibit this feedback loop with another FDA-approved drug, called dipyridamole (DP). DP has been used for decades for stroke prevention and, like statins, is produced by generic drug companies, making both agents available and affordable as anti-breast cancer agents. Statins and DP have been safely prescribed together for cardiac disease. Our hypothesis is that statins, with or without DP, can prevent breast cancer recurrence and metastasis without side effects. To evaluate this hypothesis we aim to: (1) Develop new assays to monitor statin + DP-induced death of pre-metastatic EMT breast cancer cells. (2) Determine how DP blocks statin-induced feedback to develop new drugs that work with statins to kill breast cancer cells. (3) Evaluate the effectiveness of statins +/- DP at inhibiting primary and metastatic breast cancers in relevant model systems that mimic the patient experience and identify patients that will benefit from the addition of statins +/- DP to their treatment protocol. Upon completion of this Breast Ca
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1610069
Entities
People
- David Cescon
Organizations
- United States Army
- University Health Network