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School of Medicine
Promise and Progress - Steming Cancer
Special Commemorative Issue: The Abeloff Era - Building Upon a Tradition of Excellence
Date: April 1, 2007
At Johns Hopkins, researchers and clinicians believe thatcancer stem cells may be a new therapeutic target for cancer.
MULTIPLE MYELOMA PATIENT PAMELA JOSEPH IS making history. She is one of the first people to get a cancer stem cell-directed therapy. She is aware that the drug trickling through her IV is part of an experimental mission. Her participation will help prove if therapies that target cancer stem cells cure cancer. What she doesn’t know is that this new therapy she’s getting is rootedin more than 50 years of research.
One would think that cancer stem cells, with their recent notoriety, were just discovered. In truth, it is really only the name that is new. The study of these mysterious cells, the malignant counterparts to those cells that grow and heal damaged organs and tissue, dates back as early as 1950. It was then thatresearchers first observed that a minute fraction of cells maintained tumor growth. Today, these obscure subpopulations of cells have been found in leukemia, multiple myeloma, and head and neck, pancreas, colon, and other cancers and are now usually referred to as cancer stem cells.
From Obscurity to Mainstream
So what exactly is a 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 dark and crucial difference, says cancer stem cell expert Rick Jones.One makes normal, mature tissue, while the other makes tumors.
In the 1970s, investigators used these rare colonies of cells to grow tumors in test tubes. These lab-grown cancers were used to screen for potential cancerfighting drugs. Researchers would throw different drugs in with the growing cells, hoping that if a drug killed the cancer cells in the test tube, it would also kill cancer cells in people. The work didn’t pan out, and without the technology to do any more with these cells, researchers stopped looking at them.
“I guess you could say cancer stem cells are an old concept made new with technology,” says Jones. What scientists now know is that many, if not most, cancers contain these colonies of cells that make them grow and spread.What we don’t know yet is the clinical significance of this finding.
Many investigators remain skeptical,” explains William Matsui, who is collaborating with Jones on this research. “Currently we have a disconnect between what we have proven in the lab and what may or may not work for patients,” he says, “and let’s face it, there is a big difference between finding something in the lab and having it do any good for humanity.”
Still, Jones, Matsui, and clinical collaborators Carol Ann Huff and Doug Smith remain optimistic, or at least willing to explore the possibility that targeting cancer stem cells may have a therapeutic benefit for patients. Together, they have made the Kimmel Cancer Center the site of the first clinical trials to test the theory.
“If you look at plants, the flowers all look very different,” says Jones. “An ivy looks different from a ficus,” says Jones. “But, if you look at the roots, they all look very much alike.” Similarly, he and his colleagues believe that while colon cancer looks very different from, say, a prostate cancer or breast cancer, the cancer stem cells may look very much the same. As a result, they wonder if cancer stem cells may be a commonality among all cancers. If they are right about that, cancer stem cell therapies could be the broad-based cure for cancer that the world has been waiting for.
The First Cancer Stem Cell Clinical Trial
The group’s laboratory findings in 2005 on a multiple myeloma stem cell have led them to believe that many current cancer therapies miss the mark, and it is the reason that drug resistance and recurrence are so common in cancer.“We’ve been studying the bulk of the tumor instead of the cell responsible for the tumor,” says Jones. He likens it to weeding a garden of dandelions. If a gardener pulls the tops off of all of the weeds, it will look, for a while, like the weeds are gone, he says. But, with the root intact, the weed will almost always grow back. “The root is the cancer stem cell,” says Jones.
In multiple myeloma, a cancer of the blood plasma cells that has a high recurrence rate, Jones says mainstream therapies are misguided. Current therapies target only the plasma cells. That seems to make sense, as the plasma cells make up 99 percent of the malignant cells in this cancer. But, in 2004, Jones and his team’s research revealed another culprit blood cell, the B cell.
It is infinitely fewer in number, but they say it is what drives the cancer and is responsible for its high recurrence rates. They call the B cell the multiple myeloma cancer stem cell. “Standard therapies get rid of the malignant plasma cells,” Jones says, “so it looks like the cancer is gone. But in time, the B cells, which escaped treatment, start producing more malignant plasma cells, and the cancer comes back.
”It is a theory that most treating oncologists are not yet willing to accept but Jones, Matsui, and team hope to win them over with their clinical trial, which strikes a compromise by both treating the plasma cells—the cancer that can be seen—as well as the nearly invisible cancer stem cells. In the short term, laboratory examinations of B cells taken from patients enrolled in the trial, will reveal if investigators are actually hitting their target. Once they confirm that they have the right drug—one that will seek out and destroy the B cells—only time will tell if setting their sights on the cancer stem cell truly is the key to preventing the cancer from coming back. This, Matsui, says, is what a skeptical cancer ommunity is waiting to see.
Another Stem Cell Story
Jones is not deterred by skepticism. He’s been in this position before. In 1996, he asked then-new faculty member Robert Brodsky to look through the decades-old patient notes and files of aplastic anemia expert Lyle Sensenbrenner, who had left Hopkins in 1987. At that time, bone marrow transplant was the only known cure for severe aplastic anemia (SAA), a rare disease in which the body’s immune system turns off blood-forming stem cells, causing them to stop producing redcells, white cells and platelets and leaving patients at the brink of death. In a lastditch effort to save the lives of 10 SAA patients who had exhausted all other treatment options, Sensenbrenner treated the patients with high doses of the drug cyclophosphamide.
Sensenbrenner had observed in the 1970s and ’80s, and documented in his files, that some patients undergoing bone marrow transplant (a procedure in which a patient’s own marrow is destroyed with drugs like cyclocphosphamide and replaced with the healthy bone marrow of a donor) recovered some of their own bone marrow function instead of that of their donors’.
Nearly a decade later, when Brodsky began to investigate what had happened to Sensenbrenner’s 10 patients, he found that seven were alive and completely disease free. The high doses of cyclophosphamide had cured them, but no one knew why until Brodsky opened up a trial of his own, following Sensenbrenner’s earlier work to at. He began seeing similar results.
The reason, Brodsky found, was that the very high doses of cyclophosphamide wiped out the abnormal blood cells that were attacking the bone marrow and reprogrammed the immune system but had no affect on blood stem cells, the factory for the production of all new blood cells. The recovery takes longer than bone marrow transplant, but in time, the stem cells rebuild a new, disease-free immune system, Brodsky learned.
Like Jones, Brodsky was not without his critics, who worried because it took longer for his blood stem-cell directed therapy to repopulate blood and bone marrow.
Brodsky, now director of hematology, has since used this therapy to successfully treat over 60 SAA patients as well as patients with other autoimmune diseases, including lupus, severe rheumatoid arthritis, scleroderma, and myasthenia gravis.
Shifting the Long-Held Cancer Paradigm
Jones is willing to accept that some of the criticism surrounding cancer stem cells is based in science, or the lack thereof. But much of it, he believes, is based on long-held perceptions about cancers that may be incorrect. Separating what is psychologically based from what is physiologically based is the challenge.
In cancer, says Matsui, we have been trained to relate treatment success to how quickly a tumor responds to a drug and how much the visible tumor shrinks. In terms of cancer stem cell-based therapies, this whole belief system is turned upside down.
“Cancer stem cells make up less than 1 percent of most tumors, so by killing them, you won’t necessarily shrink the tumor,” says Matsui. “But you may be getting the cell causing it and the one that will eventually cause the cancer to die and fade away”—eventually being the controversial word. “Our mindset is not one of waiting when it comes to cancer.It is contradictory to current practice to leave the bulk of the tumor.”
Current practice, however, may not be best practice. The team believes that the cells that start any epithelial cancer— cancers that start in the lining or ducts of an organ, like breast, colon and most solid tumors—are not just any breast or colon cells that have gone amok. They hypothesize that genetic alterations and mutations linked to cancer must occur in one of these specialized cancer stem cells to set the cancer process in motion.
“Even in solid tumors, unless you catch it very early, cutting it out doesn’t necessarily cure it,” says Jones. “With cancer, the cell of origin often goes somewhere else, and we know this as metastasis.”This going somewhere else, the team says, is a hallmark of the cancer stem cell. He believes that stem cells remain dormant in safe harbors known as niches until they are called on to fix damaged tissues and organs. Jones and his group are trying to learn more about this environment and the signals stem cells receive that set them into action. By nature, Matsui explains, stem cells migrate, traveling to areas of the body that need repair. Once there, they grow and fix the damage. If one of these specialized cells becomes altered, it doesn’t stop growing after the damage is repaired; it continues to grow and grow and grow. This is a cancer, and it may explain why a person can get breast cancer in the lung, lung cancer in the brain, and colon cancer in the liver.
The Past Leaves Clues to Future Cures
Jones, Matsui, Huff, and Smith are turning to the past to find more clues about the future of cancer stem cell therapies. They are taking a closer look at drugs that have successfully cured cancers while also exploring those that were shelved because they did not work quickly enough.
Since the early 1970s, cisplatin has been a known anticancer drug. It almost always cures testicular cancer, one of the earliest victories in the war against cancer. However, while clinicians knew it worked, as with many of the early anticancer drugs, they didn’t know why.
More recent research points to cisplatin as a telomere poison. Telomeres are a protective cap of sorts on the ends of chromosomes. As cells age, these protective caps begin to shorten, causing most cells to stop dividing or die. Others, however, undergo a chromosome rearrangement that can lead to cancer.
In 1984, Johns Hopkins researcher and telomere expert Carol Greider discovered that an enzyme called telomerase maintains the length and integrity of telomeres. Telomerase plays a critical role in the endless cell proliferation that normal stem cells use to regenerate and repair tissue and organs. Many investigators believe it may also be what gives cancer stem cells their edge. It may be the fountain of youth to the cancer cell.Knocking out telomerase, as drugs like cisplatin appear to do, seems to shut down cancer stem cells, explaining why this and other known anticancer drugs work against cancer.
For example, agents like the lymphoma drug rituxan, which was shelved because it did not kill the bulk of multiple myeloma quickly enough, and taxol, first used against ovarian cancer in the 1980s and now used to treat lung, breast and other cancers, are being re-examined as potential cancer stem cell targets for their telomerase-poisoning capabilities.
Waiting for Proof
Jones, Matsui, Huff and Smith understand that the scientific community, and particularly patients, are not ready to abandon the philosophy of getting all of the tumor and getting it quickly. “Right now, people are not of the mindset to sit and wait while we target the stem cells and see if they impact the tumor,” says Huff. “It would cause too much anxiety for patients. Frankly, most oncologists are reluctant, without any clinical proof, to get too excited about cancer stem cell therapies.
”It’s no wonder. The list of experimental cancer therapies that have worked in mice and test tubes is much longer than the list of those that have worked in humans.
So, for now, oncologists are looking to the Kimmel Cancer Center, awaiting the results of Huff’s multiple myeloma trial, and looking to Smith’s newly opened chronic myelogenous leukemia study to change their minds.
They are also looking to people like 56-year-old Pamela Joseph, who sits casually knitting in her recliner in the outpatient clinic as cancer stem cell-targeting drugs course through her veins. Joseph is receiving the last treatment in a 12-month course of therapy. She says the new treatment has fewer symptoms than the chemotherapy she got to destroy the diseased plasma cells. She feels more energetic and hopeful that she will be cured. Whether or not the drugs she is getting are actually targeting her stem cells, and even if they are, if it will make a difference, remains to be seen. That’s what everyone—doctors and patients alike—are waiting to find out.