Using an engineered common cold virus, UCLA researchers delivered a genetic payload to prostate cancer cells that allowed them, using Positron Emission Tomography (PET), to locate the diseased cells as they spread to the lymph nodes, the first place prostate cancer goes before invading other organs.

The tiny cancer metastases in the pelvic lymph nodes are very difficult to find using conventional imaging tools such as CT scanning. This discovery could aid oncologists in finding the cancer’s spread earlier, when it’s more treatable, and before it invades distant organs, said Lily Wu, a researcher at UCLA’s Jonsson Cancer Center and the senior author of the study.

The next step for Wu and her colleagues is linking the non-invasive imaging advance with a treatment component, activating a toxic agent in the genetic payload to kill the spreading cancer cells. Wu hopes one day to be able to find tiny prostate cancer metastases in patients and kill them at the same time, watching it all on a PET scanner. She currently is refining this image-guided therapy in her lab in mouse models.

“I think this is very exciting for many reasons,” said Wu, who also is an associate professor of pharmacology and urology. “We now know we can reach these prostate cancer metastases at an earlier stage than before, and we know we can deliver genes to those cancer cells that produce proteins that can be imaged by PET. Now we will find out how effective this genetic toxic payload is in preventing further spread of the cancer to other vital organs.”

The study appears July 11, 2008 in the early, online edition of the peer-reviewed journal Nature Medicine.

The spread of prostate cancer to the pelvic lymph nodes is the most reliable indicator that the patient will have a poor prognosis, with disease recurrence and progression likely. Accurately assessing pelvic lymph node involvement in patients is critical in planning their treatment, Wu said.

Currently, physicians don’t know if a treatment is attacking cancer cells until, using traditional imaging, they see a decrease in tumor size, an insensitive approach that can take weeks and months. And if the treatment isn’t working, the patient is exposed to a toxic therapy that isn’t helping them. If Wu is successful, an oncologist would know within days if the cancer has spread and whether the treatment is killing the cancer.

Using mouse models, Wu and her team engineered a virus to travel to the lymph nodes, using a prostate cancer-specific vector that dictates s its protein payload be expressed only in prostate cells. The payload in this case is a protein that can be imaged by PET scanning. The virus was introduced into the tumor in the mouse and Wu and her team were able to detect PET signals only from the lymph nodes with cancer cell involvement, indicating the virus reached and infected the prostate cancer cells and produced the imaging protein.

As part of this study, Wu co-developed TSTA, a two-step transcriptional amplification method, which increased the expression of the genetic payload inside the cancer cells – in effect boosting the imaging signals and potential killing activity of the engineered virus.

Wu believes this type of image-guided therapy has the potential to improve the way advanced prostate cancer is treated.

“It would represent a treatment advance in patients for whom outcome is not good,” Wu said. “This would help improve the prognosis for these patients by letting us find and treat these metastases early. If we can catch the cancer before it invades other organs, we have a better chance to change the outcomes for these patients.”

This type of approach was pioneered in the field of breast cancer with testing of the sentinel lymph node, the first place breast cancer goes when it spreads. A biopsy can determine if the cancer is in the sentinel node, therefore spreading, and oncologists base their treatment decisions on that information. In prostate cancer, the lymph nodes are much more difficult to access for biopsy, so Wu’s method provides a much needed, non-invasive alternative.

Among patients with castration-resistant prostate cancer, the addition of hormone therapy following vaccine treatment improved overall survival compared with either treatment alone or when the vaccine followed hormone treatment, according to recent data published in the July 15 Clinical Cancer Research, a journal of the American Association for Cancer Research.

Philip M. Arlen, M.D., director of the Clinical Research Group for the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, at the National Cancer Institute, said the findings have important implications for guiding treatment decisions for prostate cancer patients.

“Vaccines, if and when they are approved, can be safely and effectively combined with other therapies, including hormones,” said Arlen.  “There appears to be an advantage in overall survival.”

Arlen and colleagues enrolled 42 patients who had castration-resistant prostate cancer.  These patients were randomly assigned to receive either a poxvirus-based prostate-specific antigen vaccine or hormone therapy with nilutamide.  At progression, patients received the other therapy and continued to receive their original therapy.

For all the patients enrolled in the study, the three-year survival probability was 71 percent and the median overall survival was 4.4 years.  Patients randomized to the vaccine had a three-year survival probability of 81 percent and an overall survival of 5.1 years, while patients taking nilutamide had a three-year survival probability of 62 percent and an overall survival of 3.4 years.

Of the 42 patients in the study, 12 patients who were originally assigned to vaccine switched to nilutamide plus vaccine and eight patients who were originally assigned to nilutamide switched to vaccine plus hormone, due to rising levels of prostate-specific antigen with no evidence of metastasis.  For patients who received vaccine and then nilutamide, the three-year survival probability was 100 percent with a median overall survival of 6.2 years.  For patients who switched to the vaccine after hormone, the three-year survival probability was 75 percent with a median overall survival of 3.7 years.

Arlen said the hormone therapy in combination with the vaccine works in two ways.

“By using hormone therapy in prostate cancer you can help enhance your T-cell response to where the cancer is in the prostate gland, and you are also more likely to achieve a better immune response,” said Arlen.

Building on the results of this phase II study, researchers have developed another generation of this vaccine by adding molecules which boost T-cell responses.

Based on the current pace of vaccine research overall, Arlen predicts that men with prostate cancer could potentially see an effective, new treatment vaccine within the next several years.

“Phase II trials such as this one are adding to our knowledge, and other phase III trials are getting ready to publish their data,” said Arlen.  “If the phase II data hold up in phase III trials, we could see a new treatment vaccine within a few years.”

Although prostate cancer is the second most common cause of death from cancer in the US, it is not the tumor in the prostate that usually causes death.  Rather, death mainly occurs as a result of the tumor spreading to the bones, where it is known as an osteoblastic bone metastasis.  Treatments that deprive the tumor of male sex hormones (androgens) are usually effective, but only briefly as the tumors typically develop the ability to grow in the absence of androgens and the diseases progresses.  New data, generated using two prostate cancer cell lines that lack expression of androgen receptors and that were derived from the bones of an individual with osteoblastic bone metastases, by Nora Navone and colleagues, at The University of Texas MD Anderson Cancer Center, Houston, have provided new insight into the mechanisms by which prostate cancer osteoblastic bone metastases progress.

The androgen receptor–negative prostate cancer cell lines generated by the authors grew when transplanted into immunocompromised mice and generated osteoblastic bone metastases.  A protein known as FGF9 was found to be expressed at higher levels in these cells lines than in other bone-derived prostate cancer cells and induced bone formation in an in vitro organ culture assay.  Further, as blocking FGF9 reduced the osteoblastic bone metastases in mice transplanted with the cell lines and FGF9 was found to be expressed in all human prostate cancer osteoblastic bone metastases analyzed, the authors suggest that FGF9 has an important role in prostate cancer progression to osteoblastic bone metastases.  The cells lines generated are also likely to be an important preclinical model for researchers developing therapeutics for osteoblastic bone metastases in individuals with prostate cancer.

Genetic changes during the initiation and progression of prostate cancer have eluded scientists to date. Now for the first time researchers have identified a specific gene expression profile of prostate cancer stem cells, with important implications for future treatments. The findings, published in BioMed Central’s open access journal Genome Biology, revealed 581 genes that are differentially expressed in certain prostate cancer cells, highlighting several pathways important in the cancer stem-cells biology, and offering targets for new chemopreventative and chemotherapeutic approaches.

The cells in the study represent less than 0.1% of prostate cancer tumors, and have properties that mark them out as cancer stem cells. The cells renew themselves, are highly invasive, and have a longer lifetime than normal stem cells. They also feature a primitive epithelial phenotype and can differentiate to recapitulate phenotypes seen in prostate tumors. The cells are found in all stages and types of prostate cancer.

Expression profiling of prostate cancers typically uses tumor cell mass samples to identify individual genes. In this study, researchers harnessed advances in microarray and target labelling technologies to produce a functionally annotated expression profile of these prostate cancer stem cells.

The team, from the YCR Cancer Research Unit at the University of York and Pro-cure Therapeutics Ltd, created a malignant stem cell signature by combining genes significantly overexpressed in stem cells with those significantly overexpressed in malignant stem cells. Quantitative RT-PCR, flow cytometry and immunocytochemistry were used to validate the gene expression changes.

Genes associated with inflammation were prominent in the cancer stem cell expression profile. Potential therapeutic target NFκB is known to promote cell survival. The researchers showed that an NFκB inhibitor triggered programmed cell death in cancer stem cells, but spared normal stem cells. This provides a potential therapeutic target for this rare group of cells, which are unlikely to be affected by current chemotherapy regimens.

“For the first time we are looking at the subpopulation of cancer cells which actually initiate new tumors” explains Anne Collins, who coordinated the study. “The genetic profiling we have carried out should stimulate new lines of research directed towards stem cell treatments for cancer”

New research suggests that the form of tomato product one eats could be the key to unlocking its prostate cancer-fighting potential, according to a report in the June 1 issue of Cancer Research, a journal of the American Association for Cancer Research.“Processing of many edible plants through heating, grinding, mixing or drying dramatically increases their nutrition value, including their cancer prevention potential. It appears that the greatest protective effect from tomatoes comes by rehydrating tomato powder into tomato paste,” said Valeri V. Mossine, Ph.D., research assistant professor of biochemistry at the University of Missouri.

The protective effect of tomato products against prostate cancer has been suggested in many studies, but researchers remain uncertain about the exact mechanisms. Mossine and colleagues demonstrated that FruHis, an organic carbohydrate present in dehydrated tomato products, exerts a strong protective effect.

Researchers divided rats into groups of 20 and fed them a control diet or a diet that included tomato paste, tomato powder or tomato paste plus additional FruHis. All animals were then injected with prostate cancer-causing chemicals.

Animals fed the tomato paste plus FruHis diet had the longest survival from cancer at 51 weeks compared with 50 weeks in the tomato powder group, 45 weeks in the tomato paste alone group and 40 weeks in the control group.

On post-mortem exam, prostate tumors were found in 10 percent of the rats that had been given a combination of tomato paste and FruHis, compared with 30 percent of animals in the tomato powder group, 25 percent in the tomato paste alone group and 60 percent in the control group.

Mossine said the protective effect of tomato-based products was restricted to prostate tumors, which is consistent with other research on tomatoes and cancer. Incidence of other tumors was too small to examine.

In vitro, Mossine and colleagues evaluated the anti-cancer properties of FruHis and 14 other D-fructose amino acids and found that FruHis in a concentrated form protected against DNA damage known to lead to prostate cancer. When combined with lycopene, FruHis stopped cancerous cell growth more than 98 percent of the time.

“Before this study, researchers attributed the protective effect of tomatoes to ascorbic acid, carotenoids, or phenolic compounds,” Mossine said. “FruHis may represent a novel type of potential dietary antioxidant. Experiments like these suggest that a combination of FruHis and lycopene should be investigated as a potential therapeutic anti-tumor agent, not just a prevention strategy.”

Although Mossine cautioned against drawing broad conclusions from this animal study, he said, “the result may introduce an additional intrigue into an ongoing dispute over the beneficial effects of dietary lycopene and tomato products in lowering the risk of prostate cancer. Human trials are certainly warranted.”