Collaborative Efforts Relating to Mayo's Prostate SPORE

In addition to the SPORE research projects there are other ongoing research activities at Mayo that focus on other aspects of prostate cancer, including:

• The Biology and Genetics of Prostate Cancer
• Detection and Prognosis of Prostate Cancer
• Molecular Epidemiology and Susceptibility of Prostate Cancer
• The Prevention of Prostate Cancer
• Novel Treatments of Prostate Cancer
• Prostate and Prostate Cancer Imaging

The Biology and Genetics of Prostate Cancer

Jose D. Debes, M.D.; Thomas J. Sebo, M.D.; and Donald J. Tindall, Ph.D.; are studying alterations in the nuclear structure, including morphologic changes, in cancer cells and non-cancer cells. Their findings reveal a new insight in the transcriptional and structural regulation of prostate cancer.

Haojie Huang, Ph.D.; and Dr. Tindall are studying androgen regulation of homeostasis of the normal prostate and growth of prostate cancer. Their findings suggest that androgen-induced down regulation of Skp2 is mediated through both transcriptional and post-transcriptional mechanisms. Further studies on the molecular mechanism of androgen regulation of Skp2 should enhance their understanding of the androgen action on prostate cancer and may provide new targets for the treatment of this disease.

Robert B. Jenkins, M.D., Ph.D.; and Dr. Tindall are studying the expression of the early growth response gene-1 (EGR-1 in prostate cancer as it is correlated with tumor progression. Their findings suggest that EGR-1 expression and activity is differentially regulated in PC-3 and BPH-1 cell lines.

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Detection and Prognosis of Prostate Cancer

Thomas J. Sebo, M.D.; and John C. Cheville, M.D.; are studying the usefulness of a p63/P504S immunostain "cocktail" in evaluation of prostate biopsy specimens. They found that the p63/P504S immunohistochemical stain is a sensitive, specific marker for prostatic adenocarcinoma and HPIN and useful in the evaluation of AASA in biopsy specimens.

Horst Zincke, M.D., Ph.D.; Eric J. Bergstralh and Michael L. Blute, M.D.; are studying prostate specific antigen doubling time following radical prostatectomy for prostate cancer. Salvage radiotherapy is commonly used because of its relatively low morbidity. They found that prostate specific antigen doubling time is an independent predictor of biochemical and clinical disease recurrence following salvage radiotherapy.

Brian J. Davis, M.D., Ph.D.; Dr. Blute and Torrence M. Wilson, M.D. are studying PSA definitions of biochemical failure in cohorts of men with low risk prostate cancer undergoing radical prostatectomy or brachytherapy at our institution which are well matched with respect to prognostic factors and year of treatment. Their findings emphasize the need to investigate and develop other biomarkers for the management of prostate cancer.

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Molecular Epidemiology and Susceptibility of Prostate Cancer

Michael L. Blute, M.D.; Daniel J. Schaid, Ph.D.; and Steven N. Thibodeau, Ph.D.; have used a genome linkage scan to study prostate cancer families using micro satellite markers. Their studies are providing important clues into the chromosomal regions that contribute to familial prostate cancer and suggest candidate genes that should be further studies.

Drs. Schaid, Blute, and Thibodeau compared genome linkage scans using micro satellites with those using single-nucleotide polymorphisms, in men with a familial history of prostate cancer. Their findings are providing better analytical tools for assessing linkage of genes with prostate cancer.

Rosebud O. Roberts, Michael M. Lieber, M.D.; Donald J. Tindall, Ph.D.; and Steven J. Jacobsen, M.D.; investigated the association between daily use of calcium channel blockers and prostate cancer. Their findings suggest an association between prostate cancer and daily use of calcium channel blockers that varies by family history of prostate cancer.

Drs. Jacobsen, Tindall, Schaid, and Thibodeau and Wangao Liu, Ph.D.; assessed the correlation of the GSTP1 I105V polymorphism with familial and sporadic PCa in an American population. Their findings suggest that although GSTP1 expression may be an early event in sporadic prostate cancer, the I105V polymorphism is not associated with familial prostate cancer.

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The Prevention of Prostate Cancer

Zhiguo Zhang, Ph.D.; and Charles Y. F. Young, Ph.D.; investigated the effects of nonsteroidal anti-inflammatory drugs on androgen receptor-mediated functions in prostate cancer cells. Their findings provide a strong rationale for targeting the COX-2 signaling pathway for prostate cancer prevention and/or treatment.

Huiqing Yuan and Dr. Young demonstrated that quercetin and resveratrol inhibit the function of androgen receptor (AR). Their results support a mechanism in which over expressed c-Jun mediates inhibitory effect on the function of AR. These polyphenols might potentially be useful in prostate cancer prevention.

Lucy J. Schmidt and Donald J. Tindall, Ph.D.; are studying a dual 5-alpha reductase inhibitor dutasteride. Their findings delineate the cellular and molecular effects of dutasteride in androgen-responsive prostate cancer cells in vitro in a manner which should facilitate an improved therapeutic and chemopreventive use in prostate cancer.

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Novel Treatments of Prostate Cancer

Michael E. Grossmann, Ph.D.; and Charles Y. F. Young, Ph.D.; found that forced over secretion of Hsp70 could protect against prostate tumor growth. These results may provide a novel approach for treating prostate cancer.

Brian J. Davis, M.D., Ph.D.; Thomas M. Pisansky, M.D.; Torrence M. Wilson, M.D.; and Lance A. Mynderse, M.D.; quantified prostate volume changes with transrectal ultrasound immediately after permanent prostate brachytherapy and correlated these changes with post implant computed tomography volumetrics. Their data and methods are also very applicable to research in vibro-acoustic imaging and ultrasound-guided in situ gene therapy being studied in the Prostate SPORE.

Horst Zincke, M.D.,Ph.D.; Eric J. Bergstralh; Robert P. Myers, M.D.; and Michael L. Blute, M.D.; examined whether neurovascular bundle preservation during radical prostatectomy is a risk factor for positive surgical margins and progression-free survival after adjusting for disease severity. Their studies suggest that all patients with organ confined prostate cancer should be considered candidates for a nerve sparing operation.

Matthew T. Gettman, M.D.; and George K. Chow, M.D.; are pioneering the use of robotic surgery. Clinical and basic science research for robotic and pure laparoscopic radical prostatectomy at Mayo continues to improve patient selection, surgical approaches, optimal dissection methods, and novel hemostatic techniques.

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Prostate and Prostate Cancer Imaging

Akira Kawashima, M.D.; Kiaran P. McGee, Ph.D.; and Thomas J. Sebo, M.D.; were key investigators in an NCI funded American College of Radiology Imaging Network (ACRIN) trial with six other institutions in the evaluation of 1.5T MR spectroscopic imaging of the prostate in patients with known prostate cancer undergoing radical prostatectomy. This is the first multicenter evaluation of this new technology.

Michael G. Herman, Ph.D.; Thomas M. Pisansky, M.D.; and Bernard F. King, M.D.; have coordinated new research and subsequently an innovative practice change incorporating ultrasound guided prostate gold seed placement for external beam radiotherapy (EBRT) in prostate cancer patients. Initial published work demonstrated more accurate targeting for EBRT in these patients.

Val J. Lowe, M.D.; Dr. Kawashima and Brian J. Davis, M.D., Ph.D.; have performed preliminary research comparing PET/CT Imaging using C11-choline and C11-acetate to MRI/MR Spectroscopic imaging. This work revealed promising information regarding the capabilities of PET/CT choline and acetate imaging in comparison to MR in prostate cancer.

Drs. Kawashima, King and Sebo have studied the ability of MR perfusion imaging to detect recurrent prostate cancer after radical prostatectomy. This new MR perfusion technique allows for more directed radiation therapy to the prostate bed in post prostatectomy patients who have demonstrated a small rise in their PSA after surgery.

Drs. Kawashima, King and McGee; along with Robert P. Hartman, M.D.; have studied the benefits of 3T MR imaging of the prostate gland utilizing a prostate phantom in a 3T and 1.5T MR imaging environment with a variety of receiver coils including a body coil, 4-channel phased array coil and endorectal coils. Current efforts are underway to study the imaging advantages of 3T MR in patients with known prostate cancer.

Richard L. Ehman, M.D.; Dr. King and others have coordinated NIH funded research efforts evaluating MR Elastography of the prostate gland in patients with known prostate cancer. Current work is centered on developing in-vivo MR Elastography devices to perform on patients with known prostate cancer.

Robert P. Myers, M.D.; Matthew T. Gettman, M.D.; along with Drs. King, Kawashima and Hartman, have studied the value of 2D and 3D MR imaging to elucidate the surgical anatomy of the pelvic floor in relation to the prostate gland for prostatectomy since considerable individual variation exists in the anatomy of the male pelvis. Applications to both conventional radical prostatectomy as well as robotic laparoscopic prostatectomy are evident.

Bradley C. Leibovich, M.D.; Michael L. Blute, M.D.; and Horst Zincke, M.D., Ph.D.; are conducting a prospective controlled Phase II study of preoperative exisulind therapy initiated prior to radical prostatectomy. Therapy is being initiated 4 weeks prior to radical prostatectomy. Markers of apoptosis are being assessed in both the pretreatment biopsy specimen and the radical prostatectomy specimen after four weeks of treatment.

Henry C. Pitot, M.D.; and Patrick A. Burch, M.D.; are conducting a Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) in patients with hormone-refractory metastatic prostate cancer to assess the PSA response to 17-AAG in patients with metastatic hormone-refractory prostate cancer.

Drs. Pitot and Burch are conducting a Phase II, Open-Label, Randomized Trial of Zoledronic Acid (Zometa™) and BMS-275291 in patients with hormone refractory prostate cancer.

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