Therapeutic Targeting of Lipid Synthesis Pathway in Advanced Prostate Cancer
Abstract
This proposal will address the Fiscal Year 2014 Prostate Cancer Research Program overarching challenge of developing effective treatments for men with high-risk or metastatic prostate cancer as we will identify how a subclass of benzodiazepines rapidly block FASN activity (fatty acid synthase is an enzyme for biosynthesis of fatty acids). We will identify and develop compounds to block FASN based on the structure of the benzodiazepine, diazepam, but avoids the sedative affects acting through binding on receptors in the central nervous system (CNS). The focus area of this proposal will be therapy as it will identify new targets, pathways, and therapeutic modalities to develop new ways of treating men with advanced prostate cancer. Prostate cancer remains the most common cancer among men in the United States, accounting for approximately 28% of cancer-related diagnoses and 11% of deaths. A substantial portion of patients with localized disease have a favorable prognosis and high cure rates are observed in this patient population with currently available treatment modalities. However, for many men, the disease gradually develops resistance to these therapies and progresses to castration-resistant prostate cancer (CRPC). Current treatment options for patients with CRPC are limited and include secondary hormonal therapy (e.g., oral antiandrogens, estrogens, and adrenolytics), cytotoxic chemotherapy (docetaxel- or cabazitaxel-based), palliative radiation therapy, and, more recently, immunotherapy with sipuleucel-T. Advances in our understanding of the prostate cancer microenvironment and mechanisms that underlie progression of this disease have led to the identification of novel targets for anticancer therapy beyond the androgen pathway. In particular, mounting evidence suggests that the fatty acid synthase (FASN) pathway becomes dysregulated in prostate cancer, with FASN becoming increasingly elevated as the disease progresses. In prostate cancer, FASN is upregulated and has been shown to be closely associated to progression as well as aggressiveness of the disease. The role of FASN under normal conditions is minor due to the intake of dietary fatty acids. Inhibitors of this pathway induce cell death in cancer cells; however, no compounds have been developed that have sufficient bioavailability or acceptable toxicity. We found by serendipity that a subset of benzodiazepines currently used in the clinic effectively and rapidly block FASN pathway activity in a mouse model of prostate cancer and induce tumor cell death. Benzodiazepines are psychoactive drugs with sedative effects whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The CNS binding site for benzodiazepines (GABAA) modulates neuron hyperpolarization and levels of benzodiazepines needed to kill tumor cells would have significant sedation effects on patients. Recently, the binding mode of diazepam to the GABAA receptor has been modeled, and we will use this information to develop a compound that will not bind to the CNS site but will block FASN activity. As our preliminary experiments have found a novel mechanism of FASN inhibition and induces tumor cell death, the objective of this proposal is to develop this innovative idea to precisely understand the mechanism of FASN pathway inhibition by benzodiazepines in prostate cancer and develop a FASN inhibitor based on diazepam but without the sedative effects via the GABAA receptor in the brain. The near-term utility of this work is clear, as benzodiazepines are currently used in the clinic for other indications and a modified compound could be translated into the oncology field rapidly.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510465
Entities
People
- Beth Pflug
Organizations
- United States Army