The Coffey Lecture: steroidogenic enzyme inhibitors and hormone dependent cancer.
OBJECTIVE
To improve treatment for patients with breast and prostate cancer.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Brodie
Angela
A
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA. abrodie@umaryland.edu
Njar
Vincent
V
Macedo
Luciana Furtado
LF
Vasaitis
T Sean
TS
Sabnis
Gauri
G
D000077384:Anastrozole; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001943:Breast Neoplasms / Q000628:therapy; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*; D000068878:Trastuzumab; D014230:Triazoles / Q000494:pharmacology
D000077384:Anastrozole; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001141:Aromatase; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013256:Steroids; D000068878:Trastuzumab; D014230:Triazoles; C508053:ERBB2 protein, human