2010 Annual Report - Cancer Research Center

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Current Research On Ta r g e T: DevelOping a c a n c e r T r e a T m e n T T h a T h i T s T h e m a r k Let’s face it. The current gold standards of cancer treatment, chemotherapy and radiation, are really bad shots. Yes, they kill cancer cells but they also hit all of the other living, normal cells and tissues in range. If these treatments were police academy recruits they would never see graduation day. At the Cancer Research Center we think it’s high time for some new recruits. So, we started our search from the beginning and found that the idea of recruiting bacteria as a cancer treatment has been steadily gaining momentum for sometime. Way back in the early 1900’s William B. Coley for example observed that sarcoma patients who acquired a severe Clostridium infection fared better after surgery than patients who did not. In the years that followed Dr. Coley developed a cancer treatment regimen involving bacteria cell walls at what is now Memorial Sloan-Kettering Cancer Center (Coley, 1929). Fast forward sixty years and treatment with a non-pathogenic strain of Bacillus bacteria is being used to treat superficial bladder carcinoma in patients with complete tumor responses in more than 60% of the patients treated (Friberg, 1993). Early in the new millennia prostate cancer research joined the scene when researchers at Yale developed a strain of Salmonella typhimurium dubbed VNP20009 that preferentially killed prostate cancer cells. Initial results were promising but Yale researchers ran into toxicity issues with the strain in phase 1 clinical trials. Even stalemated the proposition is exciting. If Yale researchers had made it to phase 1 trials with a tempered pathogenic strain we were likely sitting on the answer. The Cancer Research Center is fortunate to possess a very unique resource in the form of several thousand non-pathogenic archival Salmonella strains all slightly different genetically. These strains have been stored so long (50+ years) they have naturally lost the ability to cause disease. In near starvation conditions and with no mammalian host in sight, these strains dumped their pathogenic genes in an effort to streamline themselves for survival. Their genetic losses are our gain. ca n c e r Th e r a p y i n T h e ma k i n g (2004-p r e s e n T) In 2004, we began combing our archival Salmonella collection for star recruits. Each selected Salmonella strain was tested for tumor targeting talent by incubating the strain with cancer cells. We found that within 30 minutes the non-toxic Salmonella attached to the cancer cells and did not let go. Even better was that the Salmonella seemed to know the difference between a normal and a cancerous cell and only attached to and killed the cancerous cells. This was the first promise of a smart, targeted cancer treatment using bacteria from the CRC. In 2005, we upped the ante and started running time course experiments to gauge the behavior and tumor destruction talents of the Salmonella over time. These studies revealed a unique advantage over Yale’s VNP20009. Unlike VNP20009, our naturally mellowed Salmonella did not break open the cell while destroying it. A small but crucial detail as loose cell contents are a major “red flag” in the body and get the immune system working overtime. While activation of the immune system is desirable in cancer treatment, too zealous of a response can be disastrous for the patient. 2006 began the painstaking process of fine-tuning the therapeutic strain to further enhance the strain’s nontoxic nature and natural tumor targeting talent. During this time one of the several strains we initially investigated became a clear frontrunner for the therapeutic Salmonella title. This strain became known as CRC 2631. 2007 brought hard-won approval to test CRC2631 for toxicity and tumor targeting ability in mice.
Current Research Deeming our research worthy to procede beyond lab-cultured cells, this approval was a major victory and milestone on the way to human clinical trials. We acquired mouse facilities at the University of Missouri Columbia and determined safe and effective dosage levels to treat the primary and secondary tumors TRAMP mice develop. We were excited to find that the TRAMP mice easily tolerated doses of over 100 million therapeutic CRC2631 bacteria. In contrast, just 10 non-therapeutic or Salmonella as found in the wild will kill a mouse within three days. Following promising toxicity trials we turned our attention to tracking the bacteria in the mouse. Testing which carried over into 2008 repeatedly showed that within 24-48 hours our therapeutic Salmonella was eliminated from the body of TRAMP mice and only retained in the tumor. We also continued to see CRC2631 target cancer cells 1,000 times over normal cells in the mouse even as we made genetic changes to fine-tune the bacteria’s performance. In 2009, we developed dosage protocols and conducted therapeutic studies to determine the dosage of CRC2631 therapeutic Salmonella to give to the TRAMP mice to inhibit, reduce, and/or eliminate their tumors. Normally, TRAMP mice do not make it to one year of age due to their predisposition to produce large prostate tumors at a young age (3-6 months). The goal is to have them live to a ripe old age, which for this species of mice is about two years. These studies continued into 2010. A second critical objective was reached in 2009 with the development of a quantitative assay to measure the number and type of cancerous cells that our therapeutic Salmonella preferentially attack. Using a Fluorescence Activated Cell Sorting (FACS) system we are able to count individual cancer cells and determine how effectively our bacterial therapy attaches and destroys them. This new assay helps us identify bacterial strains with improved cancer-targeting capabilities and to determine exactly how proficient the bacteria are at targeting different types of cancer. We now use this system to identify strains with enhanced cancertargeting capabilities and will use it to screen for strains attracted to other cancer types such as melanoma, pancreatic, breast and colon. Senior Investigator Dr. Robert Kazmierczak and Senior Technician & Laboratory Manager Alison Fea A year in review 2010 11
Page 2 and 3: The Cancer Research Center At CRC,
Page 4 and 5: Meet the CRC Staff A braham Eisenst
Page 6 and 7: Reaching out to the Community Sam
Page 8 and 9: From Scholars to Scientists Buildin
Page 12 and 13: Current Research TargeTeD Ba c T e
Page 14 and 15: 2010 Gala Committee 2010 Jim Kidwel
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2010 Annual Report - Cancer Research Center

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