SLIDES & TRANSCRIPTS
Saturday, December 6, 2003

Highlights of GU SPORES

Kenneth Pienta, M.D.

Evan Keller with David Smith are leading a project on osteoclastogenesis as a target for prostate cancer metastasis therapy which includes a clinical trial with taxotere, zometa and estramustine. Project two is my project, with a co-investigator from internal medicine, Alvin Schmaier, who has developed a thrombin receptor inhibitor that actually targets protease activated receptor one in prostate cancer metastasis.

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Project three, you saw Raul yesterday talking about signature lethal biomarkers. He continues to work with Mark Rubin at the Dana-Farber to develop these in especially advanced prostate cancer as well as prognostic markers.

Kathy Cooney and her co-investigators are looking at defining genetic risk factors for brothers of men with prostate cancer, and they have continued to establish a large cohort of men at high risk for prostate cancer. D.V. Robbins is looking at androgen resistance in prostate cancer progression.

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Our core consists of myself, Kathy Cooney and Jim Montie. We have a new clinical applications committee to help us push the transaction on the SPORE, and this is part of our renewal. Jeremy Taylor runs our biostatistics, and Arul and Rajai run our tissue core.

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One of the things that has been instrumental in our SPORE, and I just wanted to bring it up again, copying Hopkins and Bob Vesella's group and Paul Lange's group at Washington, we continue to have the rapid autopsy program, where we collect information in tissue on patients dying of prostate cancer. We have now done 30 autopsies. We are averaging about five per year and have 100 samples stored from these patients, and we consider it one of the most valuable resources that we could possibly have. For example, I think it goes without saying that Raul couldn't have discovered many of the things he did without this kind of tissue.

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We have multiple research development projects. I'm not going to go through them all, except to say that we fund these on a yearly basis, and many of them have developed into R0-1 type projects, as well as projects on the current SPORE.

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We have one current career development person, Mike Ray, who is a new faculty member in radiation oncology, looking at predictive biomarkers for radiation therapy outcomes in prostate cancer. We are very pleased about this, because this is the first time in the several year history of the SPORE that we have actually incorporated a radiation oncologist to join our urology and medical oncology efforts.

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I wanted to just briefly mention some science related to what has really developed into another core aspect of the SPORE here. That is a preclinical model to test compounds based on a luceriferase model. We have developed several cell lines, including the VCAP cell line that we developed from the rapid autopsies, LNCAP C42B as well as PC3 cells, and stably transvected them with a retrovirus that includes luciferase. Luciferase is what makes fireflies glow by interacting with luciferin, and we have stably transfected the luciferase in. If we then inject these cells into a mouse and let them grow, we can then inject luciferin into their belly and put them under an IVIS camera system and count how much -- by counting photons, how much cancer is there. It is directly proportional to the number of living cells.

Typically we do this, inject the cells as an intracardiac injection of 200,000 cells. We can also do this as a direct injection to the tibia, to the prostate, to the renal capsule, or just under the skin.

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This is an example of what these mice look like. Here we are using SKD mice. You can see that a mouse is being rotated here, and you can see lesions in their tibia and snout. Then if you take these bones out, the leg out here, you can see the hot lesion here in the femur. You can't really see it from the back, but there is a lytic lesion, since this was a PC3.

This is an adrenal metastasis. Here is another adrenal metastasis. These are lymph nodes, and this is mandibular metastasis.

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We have looked at many something cell lines. This is the VCaP cell line, ten out of 12 animals had adrenal metastases, five out of 12 give what amounts to a lacrimal gland with metastasis that in the mouse is androgen receptor positive, and is for some reason sensitive to androgens. The lungs, three out of 12 mandibular, 11 out of 12, we believe this is because of high turnover, in limbs seven out of 12 and seven out of 12 nodes. You can see that we have good histology to back this up.

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What is nice about this is that you can have growth kinetics over time. You can see the tumors as early as one week after injection, then you can follow as they get hotter and hotter over time. You can either measure the entire mouse or you can put a circle around regions of interest and just measure the amount of cancer in that one spot.

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We looked at as examples the total tumor burden over time in young versus old mice, and found that growth kinetics in young mice were slightly faster than old mice. This has allowed us to now use all young mice in our experiments.

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You can see that it is pretty reproducible. If you look at individual bone metastases between different mice, they grow at very similar rates.

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This has allowed us to also do a wide variety of therapeutic experiments. Here is just one experiment where we allowed different animals to get their tumors grow, and then we treated them with various doses of standard chemotherapy agents, docetaxel or mitoxantrone or some combination, and we can follow how the tumor responds, how quickly they die back, how quickly they start to grow back. This allows us then to look at everything from chemotherapeutic agents to agents that might stop metastasis to agents that can stop adhesion.

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So I was deciding whether this was going to be my model for our SPORE, but I decided maybe we are a little better than this.

Thank you.

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