EndoRelatedCancer

Division of Endocrinology

University of Virginia

Rob McPherson, PhD
Assistant Professor of Research
ram2b@virginia.edu

Breast Cancer

There are about 176,000 new diagnoses of breast cancer every year in the United States. One-third of breast cancers are hormone dependent at the time of initial presentation of the patient. So a reduction in circulating Estrogen (E2) levels, either by surgical oophorectomy or through the use of anti-estrogens, aromatase inhibitors or GnRH analogues, causes tumor regression in this subset of patients. During the course of hormone deprivation the majority of tumors will adapt to this hormonally deprived milieux (1-6). The tumor cells gradually lose their dependence on E2 and eventually become independent of hormonal requirements for growth. As tumors develop the ability to grow in the absence of E2, they usually become more aggressive requiring harsh chemotherapy.

Questions:
1) What are the mechanisms of resistance to hormone deprivation?
2) How can we use our knowledge of resistance mechanisms to develop therapies?

See our Breast Cancer projects here

Prostate Cancer

There are 179,000 new diagnoses of Prostate Cancer (PCa) annually in the United States. Localized PCa diagnosed early is very curable, but advanced PCa requires more stringent treatments. Prostate tissue is dependent on the male steroid, androgen, for growth so a standard treatment of advanced PCa is Androgen Deprivation Therapy (ADT). ADT involves reduction of circulating androgen by either surgical or chemical castration, sometimes in combination with radiation or brachytherapy (7). A large proportion of patients respond to ADT, reflected by pain reduction, Prostate Specific Antigen (PSA) lowering and tumor shrinkage when measurable. The tumor will adapt to the lowered androgen environment after 12 to 18 months in up to 85% of initial responders. Of these recurrent tumors, some 20 to 60% will regress again in response to further reduction of adrenal-derived androgens or chemotherapy (8), extending median survival (9).

Questions:
1) What are the mechanisms of resistance to ADT?
2) How can we use our knowledge of resistance mechanisms to develop therapies?

See our Prostate Cancer projects here

REFERENCES FOR THIS PAGE

(1) Dorssers, L. C. and van Agthoven, T. Genetic mechanisms of estrogen-independence in breast cancer, Pathol Res Pract. 192: 743-51, 1996.
(2) Leonessa, F., Boulay, V., Wright, A., Thompson, E. W., Brunner, N., and Clarke, R. The biology of breast tumor progression. Acquisition of hormone independence and resistance to cytotoxic drugs, Acta Oncol. 31: 115-23, 1992.
(3) Miller, W. R. Oestrogens and breast cancer: biological considerations, Br Med Bull. 47: 470-83, 1991.
(4) Nicholson, R. I. and Gee, J. M. Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer, Br J Cancer. 82: 501-13, 2000.
(5) Buzdar, A.I. Endocrine therapy in the treatment of metastatic breast cancer, Sem. Oncol. 28, 291-305, 2001.
(6) Buzdar AU, Come SE, Brodie A, Ellis M, Goss PE, Ingle JN, Johnston SR, Lee AV, Osborne CK, Vogel VG, Hart CS. Proceedings of the First International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer: summary consensus statement. Clin Cancer Res. 7 (12 Suppl), 4335s-4337s, 2001.
(7) D'Amico, A. Radiation and hormonal therapy for locally advanced and clinically localized prostate cancer, Urology. 58: 78-82., 2001.
(8) Santen, R. J. Treatment of Hormone Dependent Malignancies: Breast , Endometrium, Prostate, Williams Textbook of Endocrinology, Larsen PR, Kronenberg H, Melmed S, and Polonsky K editors. tenth edition: In Press, 2002.
(9) Rubben, H., Bex, A., and Otto, T. Systemic treatment of hormone refractory prostate cancer, World J Urol. 19: 99-110., 2001.