|GPCC Scientific Retreat at Robert Wood Johnson Medical School / UniversityMedicine and Dentistry of New Jersey, Center for Advanced Biotechnology and Medicine - 8 December 2001|
This meeting of scientists to shared what each was doing in prostate cancer research . Each speaker was given 7 minutes to speak, 1 minute to sum up, and then 4 - 5 minutes Q & A. They really stuck to this schedule, using a kitchen timer to keep it going. With this tight schedule, they got through 12 speakers and the introduction and the conclusion starting at 0830 and ending at 1135 hrs.
The introduction was given by Cory Abate-Shen, who laid down the ground rules as outlined above. She then introduced the first speaker Dr. Robert DiPaola whose subject was "Translational Research in Prostate Cancer".
In his talk he said that in 2000 180,000 men were diagnosed with prostate cancer (CaP). He pointed out that many patients experienced a recurrence with advanced disease in spite of initial treatment. This failure is treated with androgen ablation therapy which works for a while, and then chemo therapy which will only work for so long before the cancer learns how to avoid it.
Molecular changes occur in the cancer and affect the programmed cell death pathways of the cancer cells which bring on this resistance to chemotherapy. These changes include mutations in p53 and over expression of bcl-2. They may be able to improve treatment by altering the expression and/or function of these proteins.
The next speaker was Parvesh Kumar whose subject was titled "A Novel Therapeutic Strategy Testing the Safety and Feasibility of Concurrent Docetaxel and 3-D Conformal Radiation Therapy in Patients With High Risk Localized Adenocarcinoma of the Prostate: Progress Report of an Ongoing Phase I/II Trial".
Parvesh told us about a trial with 15 high risk patients enrolled in the trial between January 2000 and August 2001. These men were given radiation and escalating doses of docetaxel. Nine patients have finished their treatment, 3 are undergoing treatment at 16 mg/m2 docetaxel dose level and 3 are pending to start their next dose level. They have not encountered dose limiting toxicities in the 9 patients who have completed their chemo/radiation therapy treatments. In conclusion weekly docetaxel up to 12 mg/m2 is very well tolerated with concurrent 3-D conformal RT with minimal to no significant acute side effects. The maximally tolerated dose (MTD) has not yet been reached and the phase I/II trial is ongoing. This treatment looks promising as a new treatment strategy for high risk localized prostate cancer patients.
The next presenter was Tamara Minko, Ph.D., Assistant Professor Department of Pharmaceutics, College of Pharmacy, Rutgers, The State University of New Jersey. Dr. Minko's topic was "Enhancing the Efficacy of Chemotherapeutic Drugs by the Suppression of Antiapoptotic Cellular Defense".
This was a test tube study on prostate cancer and ovarian cancer cells using doxorubicin (DOX) and a synthetic BCL-2 peptide (BH3). The DOX was used to cause cell apoptosis, and (BH3) peptide was used to suppress the cellular antiapoptotic defense mechanism of the cells. With the DOX alone both the pro and antiapoptotic functions of the BCL-2 family were over expressed. This in turn produced multidrug resistance in the cancer cells.The BH3 alone inhibited most antiapoptotic members of the BCL-2 family proteins. It was limited in it's ability to induce apoptosis of the cancer cells. The combination of the two suppressed the cells defenses and caused an increase in the cytotoxicity of the DOX. The conclusion was that the combination of the DOX and the BH3 caused a significant increase in the efficacy of the chemotherapy and might be used for cancer treatment and prevention of multidrug resistance during chemotherapy.
Stephen Marcella, M.D., M.P.H. spoke on the subject "PSA Screening and Prostate Cancer Mortality: Preliminary Evidence of Increased Incidence of Prostatism in Clinically Aggressive Prostate Cancer". They have beeninvestigating the hypothesis that PSA testing results in a decrease inmortality from prostate cancer. The study is also suggesting that there may be an increased incidence of BPH in men with clinically aggressive prostate cancer.
The next presenter was Carlos A. Molina Ph.D. Department of Obstetrics, Gynecology and Women's Health and Department of Biochemistry and Molecular Biology, New Jersey Medical School. His topic was "Regulation of the Transcriptional Repressor Inducible cAMP Early Repressor in Prostate Cancer Cells". Inducible cAMP Early Repressor (ICER) is a tumor suppressor gene product.
They are studying several forms of cancer including prostate cancer and finding that there is either no ICER or very little present in the cancer cells. By forcing expression of ICER in prostate cancer cells the cells growth was inhibited and they would not form tumors in nude mice. They now have to look further to find what causes the cell to turn off production of the ICER product.
Keith Bupp Department of Biochemistry, Robert Wood Johnson Medical School/UMDNJ presented a report on "Targeting Retroviruses Using Random Display Envelope Libraries". He told about using feline leukemia virus and changing the envelope of the virus so that it would be attracted to specific cell types. They are producing a whole library of these virus envelopes and testing them to see which cells they will fit in with. So far most of the testing has been in animal models. The only human testing is with the 293T kidney cell line. They will soon begin screening to find envelope variants that will go to prostate cancer.
Arnold B. Rabson of the Center for Advanced Biotechnology and Medicine and the Cancer Institute of New Jersey presented a talk on "Mechanisms of Constitutive NF-kB Activation in Human Prostate Cancer Cells". Constitutive activation of NF-kB has been observed in prostate cancer and is thought to play a part in the resistance to apoptosis and in metastasis of the cancer. The highest binding activity of the constitutive NF-kB DNA was detected in the most aggressive prostate cancer cell lines.
Zui Pan presented a talk on "Ca2+ signaling and Bax translocation in Apoptosis of Prostate Cancer Cell Lines". He told us that apoptosis is a normal and fundamental function of cells. Bax is a pro-apoptotic member of the Bcl-2 family and its translocation from cytosol to mitochondrial outer membrane induces cell death. They have found that the prostate cancer cell line (NRP-154) could resist an over expression of Bax (up to 10 fold over the normal level). They are investigating the relationship between Ca2+ and Bax translocation in the initiation of apoptosis in the NRP-154 cells. They are also looking for the genes involved in this process and they hope to provide potential targets for prostate cancer therapy.
The next topic was "Molecular Determinants of Response to Therapy in Patients with Prostate Cancer" presented by William N. Hait departments of Medicine and Pharmacology, UMDNJ-Robert Wood Johnson Medical School, The Cancer Institute of N J.
Prostate cancer has a poor response rate to chemotherapy even when treatment is started early. They studied the expression of six genes known to produce drug resistance, and then based on those results studied the influence of p53 on the expression of multidrug resistance protein.
Using the results from the medical records of 96 prostate cancer patients they found that several drug resistance genes were present at the time of diagnosis including bcl-2 and MRP. As the stage of the cancer increased they found an increasing number of cancers with both mutant p53 and MRP expression. They created a new prostate cancer cell line based on the LNCaP cell line that was used to further their studies. Their studies show that the p53 does over express the MRP and this in turn leads to multidrug resistance.
In conclusion they believe that these studies suggest drug resistance occurs during the development of the prostate cancer independent of treatment, and P53 may play a central role through the regulation of MRP, bcl-2 and other p53 regulated genes.
"Molecular Genetics of Mouse Prostate Development" was presented by Michael M. Shen, of the Center for Advanced Biotechnology and Medicine, UMDNJ-Robert Wood Johnson Medical School. Michael described his groups study of the development of the prostate in mouse models and the application of this work to the human prostate. They are identifying the signaling pathways in the embryo that promote the development of the mouse's prostate.
Cory Abate-Shen presented her talk entitled "Cooperativity of Tissue-specific and Broad-spectrum Tumor Suppressor Genes in a Mouse Model of Prostate Cancer". This study is being done by Center for Advanced Biotechnology and Medicine, Departments of Neuroscience and Pediatrics, UMDNJ-Robert Wood Johnson Medical School and the Department of Pathology, College of Physicians and Surgeons, Columbia University, New York.
They are studying the Nkx3.1 homeobox gene which displays restricted expression in the developing and adult prostate. The loss of the function of this gene in mice results in defects of prostate differentiation and function. The Nkx3.1 gene maps to the human chromosomal region 8p21 which undergoes loss of heterozygosity in 80% of prostate tumors. This also occurs in prostatic intraepithelial neoplasia, the precursor lesion of cancer, which suggest 8p21 deletion is a key initiating event in carcinogenesis. They have found that Nkx3.1 displays tumor suppressor activities in cell culture and in nude mice, which suggest that epigenetic inactivation of Nkx3.1 is a critical event in prostate cancer initiation.
last reviewed December 2005
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