Recent clinical trials have shown that antiangiogenesis drugs - those that inhibit blood vessel growth - can slow progression of colon and lung cancers. Now preliminary results from an NCI-sponsored study reveal that the antiangiogenesis drug bevacizumab (Avastin) has the same effect on recurrent or metastatic breast cancers when it is combined with the chemotherapy drug paclitaxel (Taxol).
These results come from the E2100 clinical trial, which is run by the Eastern Cooperative Oncology Group with the participation of 722 women. "This study is the first to find a benefit of antiangiogenic therapy in patients with breast cancer," said Dr. Kathy Miller, study chair and faculty member at Indiana University Medical Center.
Avastin is a humanized monoclonal antibody approved by FDA to treat metastatic colorectal cancer when combined with chemotherapy. It works by blocking a tumor-released molecule called vascular endothelial growth factor. The drug is manufactured by Genentech, Inc., and provided for use in this clinical trial through a Cooperative Research and Development Agreement with NCI.
Women in the E2100 trial were randomized to receive either paclitaxel alone or in combination with bevacizumab. On average, those who received the combination saw no worsening of their disease for 4 months longer than those who received only the paclitaxel.
The drug celecoxib (Celebrex), a COX-2 inhibitor, produces a distinct pattern of gene activity in the normal colons of patients at risk for an inherited form of colon cancer, according to results of a study reported at the AACR annual meeting.
The researchers identified a genetic "signature" based on 173 genes whose activity was altered by the drug, including many genes involved in the immune system and inflammatory response. Overall, celecoxib led to changes in more than 1,400 genes in the colon, according to Dr. Oleg Glebov, an NCI research fellow.
The signature may be the first indicator of whether the drug has effects in the colon. The researchers note that increasing the dose was associated with larger changes in gene activity, suggesting a dose-response effect.
"We can distinguish individuals who take celecoxib on a routine basis from those who do not," says Dr. Ilan Kirsch, Genetics Branch chief in NCI's Center for Cancer Research, who led the study. "The distinct pattern of gene activity implies that there could be a direct or indirect action of the drug on pathways of immune responsiveness, inflammation, and proliferation within the colon."
The researchers tested celecoxib in patients at risk for hereditary nonpoly-posis colon cancer. Also known as Lynch Syndrome, the disorder increases the risk of colorectal, ovarian, and endometrial cancers, among others.
The tumor suppressor gene DLC-1 (deleted in liver cancer-1) is often silenced in both prostate cancer and benign prostatic hyperplasia (BPH), according to a study presented at the AACR annual meeting. Dr. Nicholas Popescu and colleagues in NCI's CCR found that the DLC-1 promoter region was hypermethylated in a high number of prostate tumor and BPH samples, thus keeping the gene turned off and resulting in abnormal cell growth.
Loss of DLC-1 expression has been associated with liver, breast, and ovarian cancer, among others. Because the chromosome region that contains DLC-1 is often deleted in prostate tumors, DLC-1 might be associated with prostate cancer as well. DNA methylation is one way to keep genes turned off, and Dr. Popescu's lab identified DLC-1 hypermethylation in 11 of 20 prostate adenocarcinomas and 15 of 21 BPHs. In studies with two prostate cancer cell lines, the researchers found that histone deacetylation can also result in loss of DLC-1 expression. Increased DLC-1 methylation in BPH samples also correlated with increased levels of prostate-specific antigen in the blood.
"Because abnormal methylation is one of the earliest alterations in tumor development, the detection of DLC-1 promoter hypermethylation may have clinical application for early detection of prostate cancer," noted Dr. Popescu.
Combining the angiogenesis inhibitor bevacizumab (Avastin) with either of two investigational immunotoxins - genetically modified bacterial toxins that can penetrate cancer cells - provides superior tumor reduction in animal models when compared with bevacizumab alone, NCI researchers reported this week at the AACR meeting.
Bevacizumab was used in combination with SS1P and HA22, investigational immunotoxins being developed by Dr. Ira Pastan and colleagues in the Laboratory of Molecular Biology in NCI's CCR.
Mice were treated with a bevacizumab/immunotoxin combination, bevacizumab alone, or immunotoxin alone. The greatest reduction in tumor volume compared with untreated mice was seen with the bevacizumab/SS1P combination, but similar tumor volume reductions were seen with bevacizumab and with either immunotoxin when compared with bevacizumab alone.
According to Dr. Pastan, the rationale for the study came from work by Dr. Rakesh Jain from Harvard Medical School showing that antiangiogenic therapies can transiently "normalize" the abnormal structure and function of tumor vasculature, perhaps allowing for more effective delivery of antitumor agents.
SS1P is now in a phase 1 clinical trial at NCI and trials with HA22 will begin early in 2006. SS1P, which targets the protein mesothelin, has shown strong antitumor activity against mesothelin-expressing tumors in animal models and in tumor cells from patients with mesothelioma and ovarian cancer. HA22 targets the CD22 protein, which is overexpressed in several different B-cell malignancies.
According to a large observational study presented this week at the AACR meeting, the use of cholesterol-lowering drugs, such as statins, may significantly reduce the risk of advanced prostate cancer.
Researchers at NCI, Johns Hopkins University, and Harvard University followed 34,428 U.S. men for more than 10 years. They found that men who used cholesterol-lowering medications had half the risk of advanced prostate cancer and a third of the risk of metastatic or fatal prostate cancer, compared with nonusers. The study did not reveal any effects of cholesterol-lowering drugs on localized prostate cancer.
"This is a promising lead on a class of drugs that may be offering unanticipated benefits, but we need further studies to confirm these findings as well as figure out the mechanisms at work," says Dr. Elizabeth Platz, the study's lead investigator at Johns Hopkins. More than 90 percent of the men who were using cholesterol-lowering drugs reported using statins in particular.
"The next steps will be to examine the relationship between statin use and prostate cancer recurrence, and to conduct studies involving prostate tissue to try to understand how statins might be preventing the progression of early prostate cancer," adds study co-author Dr. Michael Leitzmann of NCI's Division of Cancer Epidemiology and Genetics (DCEG).
Another study by researchers from Rutgers University, the University of Oklahoma, and NCI's Division of Cancer Prevention and CCR showed that a combination of atorvastatin (Lipitor) and celecoxib was more effective at limiting colon cancer development than higher dosages of either agent alone in a rat model. A dosage of 300 ppm of celecoxib and 100 ppm of atorvastatin inhibited 95 percent of the invasive and noninvasive tumors that developed in the untreated rats. In contrast, twice the dosage of celecoxib given alone reduced tumor incidence and number by 80 percent; 150 ppm of atorvastatin alone reduced tumor incidence by 31 to 41 percent.
While some cancers spread slowly and respond to conventional therapy, others metastasize quickly and become fatal. Being able to determine which type of cancer a patient may have upon initial diagnosis would be invaluable in providing the best treatment possible, according to a pair of studies presented at the AACR annual meeting.
Dr. Gennadi Glinsky and colleagues at Sidney Kimmel Cancer Center used gene microarrays to identify a set of 11 genes known as the "death from cancer" signature. The 11 genes are part of the BMI-1 pathway, which normally is essential for the self-renewal of stem cells. This pathway can also increase renewal in cancer cells and promote tumor progression and metastasis. The researchers tested the predictive power of this gene set in 1,566 patients diagnosed with 10 different cancer types and found that positive expression of the BMI-1 pathway was a consistent predictor of rapid metastasis and poor patient outcome.
An NCI study led by Dr. Kent Hunter in NCI's CCR looked at the genetic make-up of normal cells, rather than which set of genes are turned on in a cancer cell. "Millions of polymorphisms exist between individuals in the population, and studies in mice have shown this genetic polymorphism can influence almost any measurable trait," said Dr. Hunter. "These observations suggest that even a process as complex as metastasis could be influenced by an organism's genetic background."
The researchers collected saliva samples from a panel of backcross transgenic mice - some that develop highly metastatic tumors and the others that do not - and ran protein expression profiles." They observed that the mice can be accurately classified as either low- or high-metastatic phenotypes according to their protein expression profiles. Using the protein classifiers developed in the training set of mice, the researchers were able to prospectively identify mice as high- or low-metastatic in a test set of 17 heterogenous mice.