The Coffey Lecture: Steroidogenic enzyme inhibitors and hormone dependent cancer

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Urologic Oncology (Impact Factor: 3.36). 01/2009; 27(1):53-63. DOI: 10.1016/j.urolonc.2008.07.036
Source: PubMed

ABSTRACT To improve treatment for patients with breast and prostate cancer.
A number of novel inhibitors of steroidogenic enzymes have been developed. Their biological effects have been evaluated in a variety of preclinical models. Aromatase (estrogen synthetase) inhibitors have now been extensively tested in clinical trials in breast cancer patients. Inhibitors of 17alpha-hydroxylase/lyase have also been studied in preclinical models and are beginning trials in prostate cancer patients.
The enzyme aromatase (CYP19) has proven to be an important therapeutic target. Inhibitors of aromatase (AIs) are showing greater benefit than antiestrogens in the treatment of breast cancer. Although effective in other conditions in both women and men, AIs have not been useful in benign prostatic hypertrophy or prostate cancer. However inhibitors of 17alphahydroxylase/lyase (CYP17) to block synthesis of androgens may be effective for prostate cancer. Recent clinical trials with abiraterone and preclinical studies with other novel CYP17 inhibitors, which also interact with the androgen receptor and cause its down-regulation, could provide a new approach for treating this disease. In further studies, we optimized treatment with aromatase inhibitors and antiestrogens utilizing an intratumoral aromatase xenograft model. AIs were more effective and sustained growth inhibition was longer than antiestrogens. However, inevitably tumors eventually began to grow despite continued treatment. Analysis of breast tumors from mice treated with letrozole revealed up-regulation of HER-2 and MAP Kinase signaling proteins and down-regulation of the estrogen receptor. Our studies showed that tumors adapt to AI treatment by activating alternate signaling pathways, thus enabling them to proliferate in the absence of estrogen. When mice bearing resistant tumors were treated with trastuzumab, the anti-HER-2 antibody (herceptin), HER-2 was decreased in the tumor but the estrogen receptor and aromatase were restored. Tumor growth was significantly inhibited by treatment with trastuzumab in addition to letrozole.
Aromatase inhibitors are proving to be an effective new class of agents for the treatment of breast cancer. Compounds inhibiting 17alphahydroxylase/lyase have potential for the treatment of prostate cancer. Our results suggest that strategies to overcome resistance to these types of agents can restore sensitivity of the tumors to hormone therapy.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: CYP, a ubiquitous superfamily of enzymes expressed in major organs in humans, plays a key role in biosynthesis of steroids and metabolism of xenobiotics. Inhibitors of these vital enzymes provide, as tools, the opportunity to gain an insight to their role in a myriad of bioactivity and to intervene as therapeutics in disease. Areas covered: This article reviews granted patents for human CYP inhibitors from the US and European territories within the past decade. Expert opinion: Granted patents, albeit mostly embodying evidence from in vitro and limited preclinical trials, demonstrate good potential for use in industry and the clinic following future human trials. Indeed, only a handful is on the market or under clinical evaluation. Diagnostic monoclonal antibodies (mAbs) show high specificity for CYP families 1, 2, and 3, while potent inhibitors of CYPs 17, 19, 24, 26, 3A4 activities, in use with or without other drugs, display potential in treating prostate and breast cancers, dermatology, and improved retroviral therapy, although some may have challenges in delivery to target tissues. The involvement of this superfamily of enzymes in cellular functions, a multitude of disease states, and pharmacogenetics make them ideal candidates to better understand contemporary human health issues and identification of targeted, specific, and potent inhibitors is a useful strategy to employ, toward achieving that wider goal.
    Expert Opinion on Therapeutic Patents 03/2014; 24(6). DOI:10.1517/13543776.2014.899583 · 3.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The importance of the microenvironment in breast cancer growth and progression is becoming increasingly clear. Adipocytes are abundant in the mammary microenvironment, and recent studies show that adipocytes produce endocrine, inflammatory, and angiogenic factors that have tremendous potential to affect adjacent breast cancer cells. Yet, the extent to which local adipocyte function contributes to the pathogenesis of breast cancer is largely unexplored. Here we describe a unique animal model to study interactions between adipocytes and breast cancer cells in the tumor microenvironment. Our results suggest that local interactions between adipocytes and tumor cells are sufficient to promote the growth of hormone-dependent breast cancer. We also demonstrate that leptin signaling in adipocytes induces aromatase expression, expected to result in higher estrogen in the microenvironment thus enabling mammary tumorigenesis.
    07/2013; 2(3):165-9. DOI:10.4161/adip.23645
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In most populations, gastric cancer (GC) incidence is higher in men than in women, which may suggest the role of sex steroid hormones in gastric cancerogenesis. Both, androgens and estrogens can be synthetised in peripherial tissues. This process is controlled by expression of steroidogenic enzymes. Therefore, we evaluate the 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) transcript and protein levels in gastric tumoral and nontumoral tissue. We also determined the association between HSD17B2 transcript and protein levels and some clinicopathological features in GC. We found significantly decreased levels of HSD17B2 transcript (P=0.00072) and protein (P=0.00017) in primary tumoral tissues of GC patients, as compared to nontumoral tissues. In patients above 60years of age the amounts of HSD17B2 transcript (P=0.00044) and protein (P=0.00027) were significantly lower in tumoral than nontumoral tissues. Similarly, lower HSD17B2 levels, both in terms of the transcript and protein, were observed in tumoral tissues of male (P=0.013, P=0.0014), patients stomach (P=0.0062, P=0.045) and cardia (P=0.02, P=0.02) site of tumor, T3 (P=0.018, P=0.014) depth of invasion, N0 (P=0.017, P=0.045) lymph node metastasis, G3 (P=0.0027, P=0.014) malignancy grade. We also observed significantly reduced level of HSD17B2 transcript in tumoral tissue specimens of females (P=0.014), T4 depth of invasion (P=0.02), N3 lymph node metastasis (P=0.037) and G2 malignancy grade (P=0.045). Furthermore, diffuse GC histological types were associated with lower HSD17B2 protein level (P=0.024) than nontumoral tissues. We demonstrated that HSD17B2 transcript and protein levels are linked to some clinicopathological features in GC. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Biomedecine [?] Pharmacotherapy 03/2015; 70. DOI:10.1016/j.biopha.2014.12.042 · 2.11 Impact Factor

Full-text (2 Sources)

Available from
Aug 14, 2014