Studies presented at the 2007 meeting of the American Association for Cancer Research show how researchers are using the new, as well as the natural, to help design and test new drugs to treat cancer.
For example, researchers are marrying the latest technologies and drug design together to figure out if a drug is having a biological impact, what the effect is, when it stops working and what can be done about it. They have "watched" as an experimental angiogenesis inhibitor shrank deadly brain tumors and when it began to fail. By reading blood proteins they discovered why that happened, and how a combination of therapies might work better.
Scientists are also turning to existing "natural" biological systems to help them design next era cancer therapies. Several research groups are making progress in turning viruses into smart search-and-destroy tumor busters that will leave normal cells alone, and others are finding that marijuana?s active ingredient can tweak receptors on the most common form of lung cancer and reduce cancer growth.
Eradication of resistant prostate cancer by a novel gene therapy approach: Abstract 4182
A research team at Columbia University has designed a novel viral-based gene therapy they say blasts through a body, targeting both primary and distant tumors, while leaving normal cells untouched. In the 15 mice they tested, injections of the therapy in tumors on one side of the mouse eliminated those cancers as well as tumors on the other side of the animal?s body, producing a cure in all of the mice.
This study tested this "dual cancer-specific targeting strategy" with aggressive therapy resistant prostate cancer. The researchers have also shown it works in animals with breast, and melanoma tumors.
An earlier version of the therapy showed powerful effects in a phase I clinical trial, said Paul B. Fisher, M.Ph., Ph.D., professor clinical pathology at Columbia. This improved treatment appears to be a much "smarter bomb with potential of treating metastatic and therapy-resistant cancers," he said.
"The beauty of this approach is that two methods are being used to destroy a tumor," said Devanand Sarkar, M.B.B.S, Ph.D., the study?s primary author, associate research scientist at Columbia. "The virus we designed replicates within a tumor, and at the same time produces a massive amount of a cancer killing compound. Either action alone is damaging and potentially deadly, but together they are lethal."
Columbia researchers built the therapy around their earlier, pivotal discovery of a cytokine (a signaling protein) called melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). A technology developed in the Fisher laboratory, "subtraction hybridization," applied to human melanoma, induced the cancer to revert to a more normal state, allowing comparison of genes expressed in both states. They discovered mda-7/IL-24 was progressively down-regulated as melanoma developed. In its normal state, the cytokine may affect growth and immune regulation, whereas expression at high levels kills cancer cells.
The investigators altered an adenovirus to carry the mda-7/IL-24 into tumors that normally did not express the gene, and based on successful animal studies, this cytokine was tested for safety in patients with advanced melanoma and other solid cancers. "Interestingly, this phase I clinical trial produced a significant clinical response," Fisher said.
To make the treatment more potent, they then paired the mda-7/IL-24 gene with a "replication competent" adenovirus, a virus that can multiply within cells. After such a microbe enters a cell, it can reproduce and cause the cell to burst, releasing more viral particles. During replication, the mda/IL-24 gene is also reproduced and then expressed, delivering huge quantities of active mda/IL-24 locally and systemically.
Finally, the researchers worked out a strategy to ensure that the loaded virus would only replicate within cancer cells. They manipulated the viral genome again, and substituted its normal promoter (E1A) with a promoter (PEG-3) that they discovered could only be activated by transcription factors found in cancer cells. That means that if the virus may enter a normal cell, it won?t replicate and the cell will not die, the researchers say. It also suggests that the therapy will work in a variety of cancers "because virtually all cancers we have tested contain the necessary transcription factors that activate the PEG-3 promoter," Fisher said.
When the viral gene therapy was injected into tumors growing in the mice, the virus replicated and produced mda-7/IL-24, which then killed the tumors, releasing millions of newly produced, loaded viral particles throughout the blood circulation to settle into distant tumors where the process was repeated. It also worked on prostate cancer resistant to other therapy because the two-pronged attack "overwhelmed their defense mechanisms," Sarker said.
Although Sarkar and Fisher say the results are exciting, they stress that additional research is needed prior to testing the therapy in humans, including experiment in mice with an intact immune system. While a primary immune system response against the virus may eliminate some of the loaded particles, the researchers say that the mda-7/IL-24 will likely heighten a secondary therapeutic immune response, offering a much stronger cancer-killing potential.
AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients: Abstract 2118
A phase II clinical trial of an angiogenesis inhibitor to treat glioblastoma has shown promise in a majority of patients tested, say researchers at Massachusetts General Hospital and Harvard Medical School. But they also say that the novel imaging and biomarker studies they performed as treatment was underway have revealed why the treatment, AZD2171, ultimately failed, and what might improve the response.
The imaging studies, which used specially adapted Magnetic Resonance Imaging (MRI) scans, exposed a "window" during which the blood system feeding the tumor reverted to a more normal state, before morphing again into the leaky, dilated vessels that make drug treatment difficult.
The blood biomarker studies showed that as tumors stopped relying on vascular endothelial growth factors (VEGF) to pump up blood flow to them -and VEGF is what AZD2171 targets-they started using two other growth factors, neither of which had previously been recognized as important for human tumor blood vessel growth.
The study is unique because it is the first to test AZD2171 in glioblastoma patients, and to find that it "offered promising benefits such as tumor shrinkage and reduction of brain swelling," said Tracy Batchelor, M.D., chief of neuro-oncology at Massachusetts General Hospital.
Of 31 patients who participated, more than half experienced tumor shrinkage of 50 percent or more, and median time to tumor regrowth was 111 days. "This was not a randomized study, but compared to historical benchmarks, in which response to conventional therapies is approximately 10 percent and progression is usually 63 days, these results are encouraging," Dr. Batchelor said.
The agent, which has been tested in other tumor types but is not yet approved, also reduced edema, or swelling, in the brain, he said. Because of that, some patients were able to stop using steroids, which can cause debilitating side effects.
The clinical trial also provided insights into how AZD2171 functions and how the therapy might be improved, the researchers say. MRI scans taken before, during, and after treatment provided a timeline picture of AZD2171?s effectiveness, and then loss of function as tumors began to resist the agent.
"This was beautiful," said Rakesh Jain, Ph.D., professor of tumor biology at Harvard Medical School. "We were able to see changes within 24 hours of taking a single dose."
Jain and his colleagues have spent years documenting how developing cancers promote blood growth factor signaling, which causes blood vessel architecture to go seriously awry: vessels loop back on each other, send blood in the wrong direction, and become enlarged as well as leaky due to holes that develop. They have found regions in solid tumors in which blood flows briskly, and others in which there is little or none. "If we try to deliver drugs to those latter areas, they do not arrive," Jain said.
Still, cancer cells are alive in those hypoxic regions, and, in fact, they morph into much more aggressive cells, he said. It is also in these areas where cancer stem cells might hide. "Buried deep in this hostile environment are the cells responsible for invasion and metastasis," Jain said.
The blood biomarker studies allowed them to track what was happening in the tumors. The researchers discovered that as expression of VEGF proteins decreased, levels of two other proteins increased as the tumor switched to other pathways. One of these proteins, fibroblast growth factor (FGF), was thought to be involved in angiogenesis, but the other, chemokine stroma-cell-derived factor 1 alpha (SDF1 alpha), was a new discovery, Jain said. "We threw a net up with the biomarker studies and found the involvement of FGF, which had never been documented in patients, and SDF1 alpha, which was not known to be one of several dozen pro-angiogenic molecules identified so far in such studies."
"We all recognize that what we need to do now is combine this therapy with other types of treatments, either existing or to be developed, and to deliver these drug combinations during the window we have identified," Dr. Batchelor said. "This might help us manage patients much more effectively."
Delta Tetrahydrocannabinol inhibits growth and metastasis of lung cancer: Abstract 4749
The active ingredient in marijuana cuts tumor growth in common lung cancer in half and significantly reduces the ability of the cancer to spread, say researchers at Harvard University who tested the chemical in both lab and mouse studies.
They say this is the first set of experiments to show that the compound, Delta-tetrahydrocannabinol (THC), inhibits EGF-induced growth and migration in epidermal growth factor receptor (EGFR) expressing non-small cell lung cancer cell lines. Lung cancers that over-express EGFR are usually highly aggressive and resistant to chemotherapy.
THC that targets cannabinoid receptors CB1 and CB2 is similar in function to endocannabinoids, which are cannabinoids that are naturally produced in the body and activate these receptors. The researchers suggest that THC or other designer agents that activate these receptors might be used in a targeted fashion to treat lung cancer.