A Common Good - The Commonwealth Foundation
Date: November 11, 2010
Turning Research into Results—and Results into Reality
While all research expands knowledge, in medicine, true value is measured by the ability of research to mediate human suffering. In the cancer world, we call this translational research.
The Commonwealth Foundation for Cancer Research, under the direction of Board Chairman William Goodwin, has been a leading supporter of translational research at the Kimmel Cancer Center, donating more than $42 million and funding research projects that are being directly applied to patient care.
Tough cases require innovative medicine, and for colon cancer patients whose cancers have not relented to other treatments, a new therapy called COBALT (combined bacteriolytic therapy), has shown promise. At the center of the therapy is the bacteria Clostridium novyi-NT, a germ that causes gas gangrene when it gets into wounds. For their purposes, researchers led by Bert Vogelstein, have genetically modified the bacteria creating a strain without a lethal toxin.
Delivered via a single intravenous injection, the bacteria work within the oxygen-starved core of tumors. Researchers use the bacterialytic therapy in combination with chemotherapy with the goal of selectively attacking tumors from the inside with bacteria and from the outside with chemotherapy. Anticancer drugs cannot reach places where blood does not circulate, so this is where Clostridium novyi-NT goes to work. The investigators use mitomycin C, a well-known chemotherapy agent, to attack dividing cells by entangling their DNA strands with chemical cross-links. With mitomycin eroding the surface of tumors and the bacteria chewing away inside, a final blow comes from another drug, dolastatin-10, which closes down the tumor's blood vessels.
In animal studies, this combined germ/chemo approach temporarily wiped out both large and small tumors in almost 100 percent of mice and permanently cured more than two-thirds of them. The reined-in bacteria selectively targeted colon cancer cells and showed no interest in normal cells. Clinical trials in a limited number of patients are ongoing.
However, in human studies, the use of live bacteria calls for extreme caution, and so our clinicians and investigators are moving ahead slowly. Patients who develop fevers following treatment must be given antibiotics which, of course, eliminate the bacteria and prevent it from doing its job. As the team demonstrates control over the bacteria, they look forward to less stringent FDA controls, including scaled-back use of antibiotics, to allow the bacteria to finish its job against the cancer.
Tracking the Ghost in Lung Cancer Cells
Epigenetic alterations have been referred to as a ghost in our genes because unlike mutations which leave their mark directly on a gene, epigenetic alterations affect the development and progression of cancer without changing a cell’s DNA.
Researchers Stephen Baylin, James Herman, and team have figured out how to track these stealth alterations and use them to determine whether a cancer is likely to recur. Their work has initiated the era of molecular staging of cancers, a form of cancer detection that reveals a trail of evidence that cannot be seen through the pathologist’s microscope. “This is DNA forensics for cancer,” says surgeon Malcolm Brock, a member of the Baylin/Herman team. “While there may be no visible trace of cancer after surgery, DNA evidence of tumor cells is left at the scene, hiding in tissues such as lymph nodes.”
The team recently reported findings in the New England Journal of Medicine from a study of 167 patients with early stage non-small cell lung cancer, an aggressive and treatment-resistant form of lung cancer. All of the patients had small tumors that were surgically removed. Within about three years, the cancer returned in 51 of the patients, while the other 116 remained cancer free. The team set out to find, on the molecular level, what the microscope did not—what was different about the cancers that returned.
The culprit, they found, was in the methylation patterns of four genes already linked to lung cancer. Methylation is a normal cellular process that often goes awry in cancer resulting in the over- or hypermethylation of genes. This alteration to the environment of genes renders them invisible to cells, often shutting down key tumor suppressing functions. Depending upon the combination of genes abnormally methylated, the risk of a lung cancer returning increased two- to 25-fold. The worst scenario proved to be the overmethylation of two particular genes, p16 and H-cadherin, which foreshadowed a swift return of the lung cancer. Moreover, methylation patterns appeared to be more predictive of a cancer’s return than tumor size. In fact, the investigators found that tiny tumors, even those as small as a pea, could harbor epigenetic alterations that can make them very dangerous and aggressive.
If these findings are confirmed in additional studies, molecular staging of non-small cell lung cancer may become the standard. Identifying patients, whose cancers have the epigenetic alterations the research team uncovered, could allow them to be treated more aggressively with chemotherapy and surgery. Working toward this goal, the team has already developed a new and ultrasensitive nanotechnology-based assay to further enhance the power of their biomarker approach. (Nanotechnology involves the extension of the existing sciences into the study of ultra-tiny structures, materials, and devices.)
Moreover, these marks of aggressive disease that are driving the molecular staging also can be targets for treatment. Therapies that block methylation of genes have worked in other cancers. Baylin and Herman worked with clinical investigator Stephen Gore to lead multicenter trials of the demethylating agent 5-aza-cytidine in patients with a pre-leukemia condition known as myelodysplastic syndrome (MDS). The experimental treatment resulted in complete remissions in up to half of patients with MDS and leukemia, resulting in the first FDA approval of demethylating agent.
Researchers are now taking a similar approach in non-small cell lung cancer in clinical trials led by Charles Rudin and Rosalyn Juergens, and early results give cause for optimism with robust responses seen in at least two patients—one with a complete response and one with a high partial response, in both the primary tumor and metastatic sites. “These results are particularly exciting since all of these patients treated to date have advanced lung cancer which has proven refractory to three or more prior therapies,” says Baylin.
These above responses are supported by laboratory studies that show that very low, non-toxic, doses of the demethylating therapy agents truly reverse suppressor gene silencing and reprogram cancer cells.
Therapeutic Vaccines for Pancreatic Cancer
The Johns Hopkins Kimmel Cancer Center receives more than 60 calls each month, and even more emails, from patients wanting to receive our pancreatic cancer vaccine. When the vaccine makes the news, the calls and emails increase. With pancreatic cancer being one of the deadliest cancers and few treatments making any real gains in long-term survival, the vaccine has garnered attention because it is providing new hope for survival.
Until recently, most studies have shown pancreatic cancer survival rates at about 63 percent one year after diagnosis and about 42 percent at two years. The long-term outlook has been grim, with just 15 to 20 percent of patients with local disease alive at five years. Early on, results of our pancreatic cancer therapeutic vaccine studies were hopeful, finding 88 percent survival at one year with 76 percent alive after two years in a study of 60 patients.
Training the immune system to react to cancer has proven to be a huge challenge. Developing therapeutic vaccines is more difficult than developing vaccines aimed at prevention. The immune system is naturally equipped to recognize things it has not seen before, but cancer cells are enough like our own normal cells that they do not solicit an immune response. And, as cancers progress, our immune system grows even more comfortable with the cancer’s presence developing a dialog with cellular pathways that keep the immune system turned off.
The pancreatic cancer vaccine, spearheaded in the clinic by cancer immunology experts Elizabeth Jaffee and Daniel Laheru, uses irradiated pancreatic cancer cells incapable of growing, but genetically altered to secrete a molecule called GM-CSF. The molecule acts as a lure to attract immune cells to the site of the tumor vaccine, where they encounter antigens on the surface of the irradiated cells. These newly-armed immune cells patrol the patient’s body destroying circulating pancreatic cancer cells with the same antigen profile. As a result, the immune system, typically blind to cancer, attacks cancer cells in the pancreas and throughout the body.
In the newest vaccine study, patients are given the vaccine two weeks before surgery. Jaffee says it gets the immune system juiced up, and she has the evidence to support it. When the pancreas is removed as part of the therapy two weeks later, the group can see that the immune cells are already in the pancreas and ready to fight the cancer. Jaffee and Laheru take advantage of the two-month recuperation time patients have after undergoing cancer surgery. Without additional therapy, this lag time, gives any remaining microscopic cancer cells time to travel, spreading the cancer. Laheru says pancreatic cancer is notorious for being in areas outside of the pancreas. Giving the vaccine before surgery may allow them to get ahead of the disease and attack microscopic renegades before they gain traction.
With promising results from early vaccine studies, including a modest but real improvement in survival time, the vaccine is now about to undergo testing by many cancer centers throughout the U.S. In addition, the investigators continue to tweak the vaccine, including a chemotherapy-vaccine combo. They alter the tumor’s environment by treating patients with the drug cyclophosphamide before giving the vaccine. The chemotherapy seems to make the tumor more responsive to the vaccine. Other studies have confirmed that giving radiation therapy sequentially to vaccination, improves the vaccine’s effectiveness. Using these approaches before surgery not only gives clinicians an advance attack on the cancer but also allows them to see, at the time of surgery, what impact the treatment has had on the tumor.
More recently, Jaffee and Laheru have begun working with new faculty recruit Dung Le in an approach that combines targeted therapy with vaccine therapy. The protein mesothelin is believed to play a role in causing pancreatic cancer to grow and spread. Researchers have found high levels of the protein on the surface of tumor cells in many patients. Investigators believe that shutting down mesothelin may slow the growth of tumors and give the vaccine an advantage against cancer cells.
Other work to strengthen the vaccine enlists the bacterium listeria. In general, it is considered a pretty wimpy germ. If a person has eaten bleu cheese, he has been exposed to listeria. In fact, listeria is almost everywhere and resides throughout the gastrointestinal tract. For most people, it is harmless, and this is especially true of the version being used by the pancreatic cancer team as it has been genetically engineered to remove its toxins. Listeria thrives within immune cells known as antigen presenting cells (APCs). APCs consume foreign invaders and instruct the immune system to attack them. To date, nine patients have been treated with no adverse effects. Two patients whose cancers had not responded to other therapies saw declining biomarkers of pancreatic cancer, and many of the patients treated for the first time with this vaccine are still alive more than a year later, even though they were thought to have just a few months to live. Investigators are now studying whether the vaccine can prevent cancer in high risk patients and if it could benefit colon cancer patients with liver metastases.
“Our philosophy is to attack the disease on all fronts,” says Jaffee. “We want to get the disease to a point where we are controlling it, not it controlling us.”
A Similar Approach for Breast Cancer
Like Jaffee and Laheru with their pancreatic cancer work, Leisha Emens is going after breast cancer via the immune system. Emens vaccine is constructed much like Jaffee and Laheru’s pancreatic cancer vaccine. It uses GM-CSF to boost the immune system and irradiated cells to deliver them.
The vaccine is injected under the skin, 12 doses at time, and four times over six months. It draws the attention of immune cells known as dendritic cells to the vaccine site. Dendritic cells are the ones that send out the critical danger signal that arouses an immune response. Tumor cells have learned to manipulate them, hijacking the same process that keeps our immune system from attacking our own cells. The breast cancer vaccine teaches dendritic cells to recognize the difference between tumor cells and normal cells so that they enlist the help of another kind of immune regulatory cells known as T cells. T cells patrol the body looking for foreign invaders, and the vaccine—and subsequent dendritic cell alert—sends them on a seek-and-destroy mission for breast cancer cells.
Like Jaffee and Laheru, Emens is tweaking the effectiveness of the vaccine by combining it with chemotherapy and targeted therapies. At once, researchers must be able to suppress and excite the immune system. It is a delicate balance. For the vaccine to work, Emens must use just the right dose of the drug cyclophosphamide to ratchet down regulatory T-cells that recognize the tumor as part of the body and therefore want to protect it, but too much of the drug would bring the immune system to a screeching halt and render the vaccine useless against the cancer. Clinical studies have helped her determine the precise dose, and in newer studies, she has added a targeted therapy, combining the vaccine with Herceptin, a drug that specifically interacts with HER-2, a genetic alteration that can make for a particularly aggressive breast cancer.
The pancreatic cancer and breast cancer vaccines used in clinical trials are made in a FDA-approved GMP (good manufacturing practices) facility run by Jaffee. It was the first of its kind in a university setting.
What exactly is a cancer stem cell? Very simply, a stem cell is a parent cell from which other cells arise. Normal stem cells and cancer stem cells are really very similar, say experts. They use the same pathways and biological mechanisms, with one crucial difference. Normal stem cells make normal, mature tissue, and cancer stem cells make tumors.
Researcher Richard Jones says that cancer stems cells are similar to the roots of plants. While flowers all look different, their roots appear very much the same. Jones believes that the same is true of cancers. While a prostate cancer may look different from breast cancer, their cancer stem cells may look the same. Investigators like Jones and William Matsui wonder if cancer stem cells may be a commonality among all cancers, and if that’s the case, could therapies directed at these cancer stem cells hold the key to a broad-based cure for cancer.
Research in 2005 by Jones and Matsui led them to believe that many cancer therapies could be missing the mark. “We’ve been studying the bulk of the tumor instead of the cell responsible for the tumor,” says Jones. He illustrates with a weed. “If you pull the top off of a weed, it will look like it’s gone for awhile. But, at some point, the root still intact, it will almost always grow back.” In cancer, if drugs destroy the bulk of the tumor, but miss the cancer stem cells, the cancer will get smaller and seem to go away, but will eventually come back. The researchers believe that cancer stem cells are behind the common problem of treatment-resistance and cancer recurrence.
In earlier work, Jones and Matsui revealed the B cell as the multiple myeloma stem cell and the cause for high recurrence rates for this cancer of the blood plasma cells. The B-cell is infinitely fewer in number--plasma cells make up 99 percent of the malignant cells in this cancer—but the rarer B-cell drives the cancer. Standard therapies are successful at getting rid of the plasma cells, so it looks like the cancer is gone, for a time. However, the B-cells, which escape therapy, start producing more malignant plasma cells, and the cancer comes back.
Jones, Matsui, and Carol Ann Huff became the first investigators to study the therapeutic benefits of targeting cancer stem cells. In what is believed to be the first clinical trial of a cancer stem-cell targeting therapy, the team tested the drug rituximab in combination with cyclophosphamide against multiple myeloma stem cells—cyclophosphamide to target the plasma cells, or the bulk of the tumor, and rituximab to go after the cancer stem cells, smaller in numbers but the driver of the growth and spread of tumor cells. While the therapy did not prolong survival of patients, rituximab’s ability to suppress cancer stem cells was impressive enough to send investigators looking for a better drug. It reduced cancer stem cells by up to 1000-fold during the initial treatment, but stem cell quantities eventually crept back up. In fact, the investigators were able to predict when a patient’s cancer would recur by monitoring and tracking rising numbers of cancer stem cells. “We found cancer stem cells coated with rituximab, but the drug wasn’t killing them,” says Huff. “We think the idea is the right one, but the drug is not.”
They are now looking to hedgehog pathway inhibitors. Laboratory evidence points to drugs that block the hedgehog pathway as toxic to B-cells, and the team is testing this theory in the clinic. In laboratory studies by another Kimmel Cancer Center research team, blocking the Hedgehog pathway resulted in the death of brain cancer stem cells.
Investigators are also taking a closer look at drugs that have successfully cured cancers as well as those that have been shelved because they didn’t work quickly enough.
One example is cisplatin. Since the early 1970s, cisplatin has been used to treat cancer. While doctors knew it worked, as with many of the early anticancer drugs, they didn’t know why. More recent research has pointed to cisplatin as a telomere poison. Telomeres are the protective end caps of sorts on the ends of chromosomes. As cells age, these protective caps begin to shorten, causing most cells to stop dividing or die. Johns Hopkins researcher Carol Greider discovered that an enzyme called telomerase maintains the length and integrity of telomeres. The work earned her a Nobel Prize in 2009. Many investigators believe that telomerase also is what give cancer stem cells their edge, and shutting down telomerase could shut down cancer stem cells. Investigators are now evaluating potential new targets for cancer stem cells in the form of telomerase-blocking drugs.
Targeting Small Cell Lung Cancer
Lung cancer tops all cancers in terms of the number of lives it claims. Small cell lung cancer represents 15 percent of all lung cancers. While up to 85 percent of patients’ cancers initially respond to anticancer drugs, almost all patients die of recurrent disease within one year of diagnosis. This has been the case for nearly two decades underscoring the critical need for new therapies.
Charles Rudin and Christine Hann are studying a gene called Bcl-2 that inhibits cell death and is over-expressed in the majority of small cell lung cancer cases. Abnormal expression of this protein has been linked to therapy resistance, making it a promising target for new therapies.
Hann and Rudin are studying a drug that directly inhibits Bcl-2 and has been proven effective in laboratory models. Clinical trials of the drug and other combined approaches using Bcl-2 inhibitors with anticancer drugs are now underway.
The researchers are also studying lung cancer stem cells. Cancer stem cell populations have been identified in several solid tumors, including breast, brain, pancreas, and prostate cancers, and are thought to play a role in therapy resistance and tumor recurrence. Because cancer stem cells are small in numbers, they are difficult to isolate, and Hann and Rudin are taking a unique approach to bring them out of hiding. In laboratory studies, they are using Bcl-2 inhibitors to kill the bulk of the tumor, so that they can reveal and define the rare, treatment-resistant cancer stem cells.
Viruses Used to Self Destruct Tumor Cells
In a study led by Richard Ambinder, viruses naturally associated with certain kinds of cancers could be activated by treatment with a cancer drug bortezomib. Activation leads to expression of a viral enzyme in the cancer cells allowing them to act as a sponge to soak up a radioactive drug. The cancer cells are then killed by the radiation. Any radioactive drug that is not soaked up by the sponge is rapidly eliminated from the body in the urine. This approach has the promise of targeting radiation very specifically to cancer cells and avoiding injury to normal tissues. Lymphomas and AIDS-associated cancers are predominantly virus associated and in the investigators recent research they showed that the viruses linked to two different kinds of AIDS cancers (lymphoma and Kaposi's sarcoma) could be activated to soak up the radiation and kill tumor cells.
Checking Out Cancer Drugs at a Johns Hopkins Library
The Johns Hopkins Drug Library research goes to the heart of translational research. It was born out of investigators’ frustration over the lengthy time it took to move a new targeted therapy from the laboratory to the clinic. Much of the delay is directly related to regulatory issues, so the researchers, led by Jun Lui, are focusing their attention on the FDA-approved drugs being used to treat other diseases. These drugs have already been subjected to safety and dosage studies, so if they were used in cancer clinical trials researchers could skip the earliest stage of clinical trials, shaving months or years off the time it takes for therapeutic advances.
To date, they have accumulated approximately half of the 11,500 FDA-approved drugs in the Johns Hopkins Drug Library and have begun screening them for their activity against cancer cells. A search of drugs that have antiangiogenesis properties—can cut off the nourishing blood supply to tumors—revealed the antifungal agent itroconazole and led to Phase II clinical trials in lung cancer. Other drugs and combinations of drugs that work together to block the growth of blood vessels that sustain tumors also are being identified.
In another breakthrough discovery, researcher Gregg Semenza used Lui’s library, screening more than 3,000 drugs for their ability to block the HIF-1 protein, a gene crucial to cancer cell survival. While they found 20 drugs that shut HIF-1 down by as much as 88 percent, Semenza and team focused on Digoxin, a drug used for decades to treat heart failure, for its already well-established clinical use. It is now being tested in clinical trials for prostate cancer. Population studies indicate that it may not only have therapeutic benefit for prostate cancer but may also be able to prevent the disease.
Researcher Elizabeth Platz collaborated with investigators at Harvard University to study a group of 47,759 men who have been followed since 1986. The men, age 40 to 75 and all cancer free when they began participating, were asked every two years about the medications they take. At the start of the study, two percent of men said that they regularly used digoxin. By 2006, 5,008 of the men had been diagnosed with prostate cancer.
"We found that men who regularly used digoxin at the start of the study had about a 25-percent lower risk of getting prostate cancer than men who were not using the drug," says Platz. "This was true whether they used the drug to treat congestive heart failure or arrhythmia." Because men who have many health problems may be less likely to be screened for prostate cancer, the team also looked among men who had taken a PSA test. Again, they found that men on digoxin had a lower risk of prostate cancer. "There was even evidence that men who took digoxin for 10 or more years had the lowest risk of prostate cancer," Platz adds. "Their risk was 40 percent lower than that of men who had never used digoxin."
With these exciting early findings, this new resource for cancer researchers promises to speed the pace of clinical research as agents that act against newly-identified gene targets are identified and expedited in clinical trials.
Articles in this Issue
Cover Story: Personalized Medicine is Here, The Time is Now
- Personalized Medicine is Here: The Time is Now
- Cover Story Sidebar: Our Cancer Reasearch is Curing Other Diseases Too
- Cover Story Sidebar: A New Paradigm for Cancer Drug Discovery
- Cover Story Sidebar: Personalized Approaches in Pediatric Cancer
- Cover Story Sidebar: The Frankenstein Project
- Cover Story Sidebar: The Serendipitous Discovery of a Cancer Starter
- Cover Story Sidebar: The Mathematics of Curing Cancer
- Immune Cell Commander
- A Personalized Genetic Profile for Brain Cancer
- A New "Twist" in Breast Cancer
- JHU Engineering Student Invents Melanoma Screening Device
- Special Delivery: Biodegradable Particles Transport Drugs to Diseased Tissues and Organs
- Targeting Brain Cancer Stem Cells
- Vaccine Clears Out Leukemia Cells
- Does Low Cholesterol Equal Lower Risk of High-Grade Prostate Cancer?
- A Common Good - The Commonwealth Foundation
- Helping Us Solve The Cancer Puzzle
- The Skip Viragh Center
- Making Waves to Fight Cancer
- Gift Brings Complementary Care to Cancer Patients
- A Major Gift for Kidney Cancer Research
- Giant Food Supports Childhood Cancer Research
- Wawa Cares About Cancer Patients
- Young Lacrosse Players Faced Off Against Childhood Cancer