Innovative research set to push boundaries of cancer care
PHILADELPHIA − Cancer researchers wielding opportunistic bacteria, vaccines, electric pulses, nano buckeyballs, and designer agents that enter the brain are being featured in a "Novel Approaches" press conference at the Molecular Targets and Cancer Therapeutics International Conference.
The November 14-18 meeting is being sponsored by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This press conference features research designed to expand the medical kit now used to treat cancer. Investigators have found that:
Soil-based bacteria that naturally attack cancer cells in order to protect itself could be used as an agent to fight tumors.
Use of electric pulses to force a gene into melanoma tumor cells that then stimulates an immune system attack.
An experimental agent that, for the first time, seems to cross the blood-brain barrier to treat the most dangerous brain tumors, representing a potential treatment for tumors that originate in the brain or metastasize there.
A novel vaccine designed to boost the immune system of pancreatic cancer patients, when used before and after traditional chemotherapy and radiation.
A small soccerball-shaped nanoparticle may sop up dangerous oxygen radicals produced as a result of radiation and chemotherapy treatment, thus protecting normal tissue and reducing side effects.
Bacterial Protein Azurin as a Novel Anticancer Agent (Abstract 3335)
For more than 100 years, scientists have reported that bacterial infections can sometimes elicit remission in certain forms of cancer. Much effort, therefore, has been spent over the years in developing wild-type or modified bacterial and viral strains to treat the disease. But the results have been mixed, due to the significant toxicity associated with giving patients live microbes, which often induces an immune response. In fact, the only widely used bacterial treatment to date is bacillus Calmette Guérin (BCG) for superficial bladder cancer.
Researchers at the University of Illinois at Chicago, however, have found that an opportunistic bacterium, Pseudomonas aeruginosa, that grows in the soil and marshes but is often found in the lungs of cystic fibrosis patients, may offer a new route to cancer therapy. A series of studies they have developed has shown that this bacterium produces a protein, azurin, which it uses as a weapon, possibly to defend itself against cancer cells that might end up harming the microbe.
Based on this novel and surprising discovery, a team of researchers has shown that P. aeruginosa preferentially enters human melanoma and breast cancer cells, triggering apoptotic cell death. They further discovered that azurin sets off this death sequence by forming a complex with the well-known tumor suppressor protein p53, stabilizing it, and activating caspases that induces apoptosis in cancer cells. P53 normally stops cells that are damaged from reproducing and encourages them to commit apoptosis, but a majority of cancer cells have damaged or missing p53.
To test the therapeutic power of azurin to damage cancer cells, the researchers have used it in mouse models of melanoma and breast cancer and found it led to significant regression of these cancers, says Tohru Yamada, Ph.D., a visiting research assistant professor in the Department of Surgical Oncology.
Now, they demonstrate that a smaller, 28 amino-acid fragment of azurin also enters cancer cells selectively, but not in any of the normal cells tested. This small molecule could potentially be used as a vehicle for cancer-targeted chemotherapy, Yamada says. The researchers are continuing to reduce the size of azurin to make the protein easier to enter cancer cells without losing its cancer-killing activity.
First Human Phase I Trial of Plasmid IL-12 Electro Gene Therapy in Patients with Malignant Melanoma (Abstract 3701)
In a bid to turn the human immune system against cancer, researchers have tried a number of different strategies to deliver the powerful immune system stimulant interleukin 12 (IL-12) to tumor cells. But an optimal anti-tumor effect has not been achieved. When injected as a recombinant protein, IL-12 produced toxic side effects, and varied attempts at gene therapy have show only limited success.
Now, however, researchers at the H. Lee Moffitt Cancer Center and Research Institute and the University of South Florida are almost mid-way through a human clinical trial that uses pulses of electricity to deliver a plasmid encoding for IL-12 to melanoma tumor cells. This phase I trial will enroll approximately 18-30 patients with advanced melanoma at five dose levels. The current dose (3rd dose level) being tested is five times higher than the first dose tested. Thus far there has been no toxicity to date in the six patients who have participated at the first two dose levels.
The clinical trial is the first to test "electroporation," or electrical stimulation, to deliver to humans a plasmid that contains all the genetic material necessary to tell a cancer cell to produce IL-12. In less than a minute after the plasmid is applied to melanoma on the skin, an electrode delivers six brief pulses to the tumor. This strategy briefly increases the permeability of the membrane of tumor cells, allowing the very large plasmid molecule to enter, according to principal investigator Richard Heller, Ph.D., co-director of the Center for Molecular Delivery at the University of South Florida.
Once inside the cell, the plasmid makes its way to the nucleus and the cell machinery transcribes IL-12 DNA, and produces and secretes the cytokine, which can stimulate the immune system to attack the tumor.
A series of preclinical studies by Heller and his team found that the technique resulted in an 80 percent complete response in mice models of a very aggressive mouse melanoma. They also noted that the mice did not develop new tumors, suggesting that the therapy induced a systemic immune response against new cancers.
While the strategy appears to be ideal for accessible cancers, such as those on the skin, the USF team and other research teams have used electroporation delivery of plasmids encoding various molecules to the liver, spleen and kidneys of animals.
The Discovery and Development of Blood-Brain Barrier (BBB) Penetrating Anthracyclines for the Treatment of Brain Tumors (Abstract 3384)
A major deterrent in treating malignant brain tumors is that systemic chemotherapy effective against other types of tumors is limited because most drugs can not penetrate the blood-brain barrier effectively. But now, researchers at The University of Texas M. D. Anderson Cancer Center have developed an agent that not only gains entry into the brain, but also targets topoisomerase II , a protein associated with malignant gliomas, the most aggressive form of brain tumors. The drug, WP744, has entered a phase I clinical trial, which will enroll up to 30 patients with advanced brain cancer.
A research team led by Waldemar Priebe, Ph.D., professor of Medicinal Chemistry in the Department of Experimental Therapeutics, developed the dual-purpose agent, which targets topoisomerase II and avoids transport proteins found in both the blood-brain barrier and glioma tumor cells. These proteins,known as ABC-binding cassette transporters like MRP1, LRP, and P-gp, control which molecules can pass through a membrane (such as the "blood-brain barrier") and are also part of a cellular defense that is associated with a cancer cell's ability to become resistant to multiple drugs.
Priebe, working with, Charles Conrad, M.D., associate professor of Neuro-Oncology, Timothy Madden, Pharm.D., associate professor of Pharmacology, and Izabela Fokt, Ph.D., Instructor of Medicinal Chemistry, designed and synthesized DNA-binding agents using a modular approach and searched for topoisomerase II poisons that could circumvent transport proteins efflux, hypothesizing that this will allow entry into both the blood-brain barrier and glioma tumor cells.
Out of 400 DNA binding agents, they selected two compounds for evaluation in vivo. Both of these compounds resemble the well-known anticancer chemotherapy drug doxorubicin, but have properties that are also unique, according to Priebe. In mice studies, one of the compounds, WP744 entered the brain and effectively treated cancer, increasing the survival time of the animals. This compound, now called RTA744, was licensed by Reata Pharmaceuticals in Dallas and is undergoing phase I studies at the M. D. Anderson Cancer Center.
The researchers say the agent may prove to be effective in treating brain tumor patients because, in contrast to doxorubicin, it can cross the blood-brain barrier and hone in on these cancers when delivered systemically. RTA744 (WP744) may represent a treatment not only for tumors that originate in the brain, but also for other cancers that tend to metastasize to the brain as well, the researchers say.
A Safety and Efficacy Trial of Lethally Irradiated Allogeneic Pancreatic Tumor Cells Transfected with the GM-CSF Gene in Combination with Adjuvant Chemoradiotherapy for the Treatment of Adenocarcinoma of the Pancreas (Abstract 2229)
A novel vaccine for pancreatic cancer appears to be nudging survival rates higher, say researchers at Johns Hopkins University School of Medicine. Their study, the first reported phase II study of a vaccine to treat this often lethal disease following surgery, has found in an early analysis that 88 percent of 56 patients tested are alive a year after treatment, and that two year survival is 76 percent. Researchers say that represents a significant bump over historical survival statistics, which are approximately 60 and 40 percent, respectively.
And if the Phase II trial mirrors results from its phase I predecessor, some patients may defy survival projections altogether, they say. In that study of 14 patients, three patients remain cancer free more than seven years after use of the experimental vaccine. Pancreatic cancer is the fourth leading cause of cancer death, and only about three percent of all pancreatic cancer patients are expected to survive beyond five years, according to Daniel Laheru, M.D., assistant professor of medical oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
In this study, the vaccine was added to the standard treatment for patients whose cancer is confined to the pancreas. The first vaccine was delivered eight weeks after surgery, and that was followed a month later by a six-month course of chemotherapy and chemo-radiation. Three more vaccines were given every month thereafter, and the final dose was delivered after six months.
The vaccine is designed to boost a patient's immune response to pancreatic cancer cells that may still exist despite surgery and chemo-radiation treatment. It was derived from cancer cells extracted from two patients, which were genetically modified to secrete the immune stimulatory protein granulocyte-macrophage colony stimulating factor (GM-CSF). Because the vaccine is made up of cancer cells, it was irradiated to disarm any growth potential before being delivered to patients.
Researchers believe that once in the body, the vaccine cells produce GM-CSF for about five days, which is within the critical time period required to attract antigen presenting cells. This sets off an immune system response that may result in recognition of protein tags on the tumor cells, which are subsequently attacked, Laheru says. With an analysis of long-term responders in both of these clinical trials, the research team may be able to identify cancer-associated proteins that the immune system specifically reacts to, and modify the vaccine to display those antigens, he says. A phase III trial might also test use of the vaccine against traditional chemo-radiation treatment, he adds.
In vivo Evaluation of Radioprotection by the Fullerene CD60_DF1 Using a Zebrafish Model (Abstract 3381)
As beneficial as chemotherapy and radiotherapy are in managing cancer, these treatments can cause harm to normal tissue by producing stress on cells. One particularly harmful result is the production of hydroxyl radicals, in which water atoms in a cell exposed to radiation split apart, creating high reactive oxygen free radicals capable of damaging cellular molecules. Radiation can damage epithelial cells and lead to permanent hair loss, among other effects, and certain types of systemic chemotherapy can produce hearing loss and damage to a number of organs, including the heart and kidneys.
For those reasons, researchers have been seeking an agent that protects normal tissue against these effects. Although one such drug, Amifostine, is now on the market, it carries toxicities of its own which has limited its use.
Now, researchers have studied how a nanoparticle, a soccer ball-shaped hollow carbon structure known as a fullerene, acts like an "oxygen sink." The 60-carbon structure, known as CD60_DF1, is a technology that is currently patented and under development by a Houston based drug company, C Sixty. To test how well it works, researchers at Thomas Jefferson University used tiny zebrafish embryos, which are transparent and allow scientists to closely observe damage produced by cancer treatments to organs.
They gave the embryos different doses of ionizing radiation as well as treatment by either Amifostine, which acted as a control agent, or CD60_DF1. Then the research team used a novel organ specific "read-out," which they developed, to calculate damage to organs. They found that CD60_DF1 given before exposure to X-rays reduced organ damage by 2/3rds, a level of protection that was as good as that provided by Amifostine.
The fullerene nanoparticle effectively and efficiently bound to, and thus inactivated, loose oxygen radicals produced by cancer treatment, but appeared to have no other effects in normal tissue, and were quickly excreted, say the study's principal investigator, radiation oncologist Adam Dicker, M.D., Ph.D. and his collaborator Dr. Ulrich Rodeck.
Not only does the biopharmaceutical fullerene potentially represent a new class of radioprotective drugs, which might be modifiable to protect specific organs and tissues, but the agents might also provide general protection against radiation poisoning from a "dirty bomb" that might be used in an attack, Dicker says. Still, he adds, there is much work to be done, including determining how to target the agent to normal tissues only.
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