Targeting FASN for Breast Cancer Treatment by Repositioning PPIs
Abstract
Fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo synthesis of long chain fatty acid palmitate. It was re-discovered as an independent prognostic molecule in breast cancer cells from patients with markedly worsened outcome. Breast cancers with high level of FASN are much more likely to recur and metastasize with significantly shorter disease-free and overall survival. It has also been shown that FASN causes resistance to multiple anticancer drugs including doxorubicin and cisplatin, commonly used breast cancer chemotherapeutic drugs. Due to sufficient dietary intake of free fatty acids in the Western diet, FASN is not required for normal cell function and, thus, its expression is very low in normal cells. However, many breast cancer cells have high level of FASN expression and require de novo fatty acid synthesis for survival. Inhibition of lipogenesis by targeting FASN induces cancer cell death selectively both in vitro and in vivo with minimal effect on normal cells. Thus, FASN drives breast cancer survival and poor outcome and is an ideal target for drug discovery to stop breast cancer cell growth. Proton pump inhibitors (PPIs) are Food and Drug Administration (FDA)-approved drugs for treatment of a variety of acid-related diseases that plague the digestive system. PPIs are chronically used and well tolerated in humans without apparent adverse effect. In preliminary studies, we show that PPIs also effectively inhibit human FASN and breast cancer cell survival as well as sensitize breast cancer cells to existing breast cancer chemotherapeutic drugs. In a preliminary study of a database containing electronic medical records of de-identified breast cancer patients, we show that breast cancer patients who used PPIs during chemotherapy had significantly improved overall survival and more so for triple-negative breast cancer patients who currently do not have any effective treatment strategies. Thus, PPIs may be repositioned as potentially safe therapeutics for treating breast cancers. In this application, we will overcome two Breast Cancer Research Program overarching challenges, namely, (1) to identify what drives breast cancer growth and determine how to stop it and (2) revolutionize treatment regimens with ones that are safe and effective. To do so, we plan to achieve three specific aims: (1) to understand how FASN drive breast cancer cell survival and drug resistance; (2) to test PPI efficacy using cell-based assay and patient-derived xenograft animal models and determine if PPIs work via inhibiting FASN; and (3) to associate PPI usage with breast cancer patient outcome by mining databases of electronic medical records. Because PPIs are FDA approved, affordable, and many breast cancer patients have already been using them and probably benefiting from the usage without knowing the benefits, the positive outcome of this study will likely lead to a randomized clinical trial that will have immediate and profound impact on breast cancer patients and improve their survival and life. From our preliminary studies, it appears that triple-negative patients, who do not have effective treatment strategies, will benefit the most from using PPIs. Finally, PPIs are available over the counter, very safe, and can be used chronically without major adverse effect. Thus, the risk of taking PPIs for breast cancer patients may be limited.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1610030
Entities
People
- Jian-Ting Zhang
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army