Characterizing PAFAH1B3 as a Novel Metabolic Target for Breast Cancer Therapy
Abstract
Cancer cells have fundamentally altered cellular metabolism that not only involves fundamental rewiring of biochemical pathways (e.g., an addiction to glucose and glycolysis) or retasking of enzymes to perform novel pathological roles, but also alterations in the levels and activities of enzymes that regulate them. Although metabolic changes in common and well-understood metabolic pathways during cancer development have been well recognized, much less is understood about the majority of both characterized and uncharacterized metabolic networks. Even less is understood about the altered metabolic pathways that drive breast cancer progression and metastasis. We believe that by identifying and targeting key nodal control points in these rewired and reorganized biochemical pathways in cancer cells, it may be possible to perturb entire metabolic networks, leading to effective treatments for malignant breast cancers. We have performed studies in a breast cancer progression model that incorporate both cellular transformation as well as the acquisition of malignant features that are often associated with highly metaplastic human breast cancer with poor prognosis and chemotherapy resistance. We utilized an innovative chemical approach coupled to advanced proteomic technologies, called activity-based protein profiling, to identify platelet activating factor acetyl hydrolase 1B3 (PAFAH1B3) as a critical metabolic driver of breast cancer. We show that this enzyme is upregulated in primary human breast tumors and correlated with poor prognosis. We show that blocking this enzyme significantly impairs breast cancer pathogenicity and eliminates tumor growth in mice. Using innovative technologies for broadly and comprehensively measuring metabolite levels in breast cancer cells, we have found that PAFAH1B3 inactivation leads to elevations in the levels of several lipids that act as tumor-suppressing signaling lipids that we believe are important in mediating breast cancer pathogenicity. This proposal will focus on investigating both the pathophysiological and metabolic roles of PAFAH1B3 enzymes in breast cancer and developing PAFAH1B3 inhibitors for future breast cancer therapy. In this proposal, we will investigate the biochemical and pathophysiological mechanisms through which PAFAH1B3 coordinately regulate metabolic and signaling pathways that underlie breast cancer progression, using cancer biology approaches coupled with innovative functional metabolomic technologies, and innovative chemical strategies for developing PAFAH1B3 inhibitors for future breast cancer therapy. Collectively, this proposal will determine the therapeutic potential of PAFAH1B3 as a breast cancer therapy target and will provide a PAFAH1B3 inhibitor that can serve as a lead for future (pre)clinical development by pharmaceutical companies to advance PAFAH1B3 inhibitors as breast cancer therapeutics. This proposal will directly address several of the Breast Cancer Research Program overarching challenges by (1) identifying what drives breast cancer growth and metastasis; (2) developing treatments to eliminate the mortality associated with metastatic breast cancer; and (3) revolutionizing treatment regimens by replacing drugs that have life-threatening toxicities with safe, effective interventions. There is currently a fundamental lack of therapies for metastatic breast cancer. Metastatic breast cancer is responsible for the majority of breast cancer deaths, with this type of cancer especially affecting African American women. Here, we propose PAFAH1B3 as a novel and unique metabolic target to cure metastatic breast cancer by heightening the levels of multiple tumor-suppressing lipid signals that attenuate breast tumor growth and metastasis. We propose to not only research the basic biology around this target, but also to develop small-molecule PAFAH1B3 inhibitors for translational development. Our discoveries will particularly help women, especia
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510051
Entities
People
- Kunxin Luo
Organizations
- United States Army
- University of California, Berkeley