Recent Discoveries Will Change The Direction of Treatment

By Beverly A. Caley

We live in the information age. The mapping of the human genome [the complete set of human DNA] has resulted in an exponential expansion of knowledge about genes as well as the potential to harness this knowledge and develop agents that halt the survival and spread of cancer cells. Advances in technology have enabled scientists to understand cancer on a new level. The challenge for oncology in the coming years is to manage that information and develop strategies to achieve real benefits for patients.

The Potential of Genomics Medicine

The reliance on traditional chemotherapy drugs to treat the majority of patients may become limited in the not-so-distant future, says John Nemunaitis, MD, executive director of the Mary Crowley Medical Research Center in Dallas. Since most traditional chemotherapy drugs affect normal cells as well as cancer cells, treatment strategies were designed with the goal that more cancer cells would be killed than normal cells. Now, with newer targeted therapies, the hope is that by identifying the genetic profile of a person’s cancer, doctors can individualize treatment for that patient.

Historically, finding the right drug for an individual has mostly been a process of trial and error. If the first treatment was ineffective or the patient had an adverse reaction, different drugs or dosages were tried until the right treatment was found. Currently, oncologists determine the best treatment based on a number of factors, such as the type of tumor, molecular and genetic markers, the stage of the cancer as well as patient characteristics, including age and general health status.

A rapidly emerging field is pharmacogenomics—the study of how individual genetic characteristics may predict one’s response to drugs. While this new approach is commonly labeled “personalized medicine,” Daniel Von Hoff, MD, director of drug development for the Translational Genomics Research Institute in Phoenix, says oncologists practice personalized medicine every day, and a more accurate description would be “genomics medicine.”

“Every month, researchers are identifying another genetic marker that says, treat here. If a patient is treated based on that target, the chance of having an anti-tumor response isn’t 5 percent but it’s 60 to 80 percent,” he says. Breast cancer patients with estrogen receptor-positive disease are already benefiting from genomics medicine with hormonal therapies. The same is true for women with HER2-positive breast cancer who receive Herceptin® (trastuzumab), and patients with c-kit-expressing gastrointestinal stromal tumors who benefit from Gleevec® (imatinib).

As more genetic markers are identified for certain cancers, scientists can then look across tumor types to see if a gene is expressed where it wouldn’t be anticipated. By examining a patient’s tumor cells for unexpected targets, researchers can study if the presence of HER2 in pancreatic cancer means Herceptin might work. Even when the right drug is identified, genomics medicine could potentially help physicians determine the correct dose by unraveling how the patient’s body would break down the drug—a crucial step in cancer treatment because the margin between the toxic dose and the therapeutic dose is narrow.

Although a number of cancer agents treat gene overexpression, one of the most common genetic abnormalities in tumors is deletions (missing genes). If a patient has too many tumor suppressor genes missing, the protective effect is gone. “Everybody started off with gene therapy to put the genes back in, but it’s really hard to replace a function,” says Dr. Von Hoff. “So at TGen, we’re looking for small molecules that preferentially kill cancer cells that have specific deletions.” The researchers take a normal cell and an identical cell that has a specific gene missing. Using a vast library of chemicals, they employ robotic technology to identify drugs that kill only those cells with deletions. So far, TGen’s scientists have been exploring a deletion that is present in 55 percent of pancreatic cancers, and of the first 200,000 chemicals tested, Dr. Von Hoff says they have isolated five candidates and are currently developing compounds to test in patients whose pancreatic cancers have that deletion.

In an undertaking that would greatly simplify treatment decisions, TGen is analyzing tumors for US Oncology in its effort to more precisely match patients to therapy. The so-called “Epiphany Project” will incorporate molecular and gene profiling with agents in clinical trials. “Let’s say we have six ongoing phase II trials with new agents. US Oncology wants to put a system in place so that when a patient walks in the door, their tumor can be characterized for all six of those targets to see which of those agents they would potentially benefit from,” says Dr. Von Hoff.

He predicts that in the future, cancer will be identified and treated not based on a patient’s type of cancer but on a patient’s specific tumor targets. “This is not for our grandchildren; this is for our children. In 25 years, the whole landscape should be hugely different.”

Vaccines: Activating Natural Defenses

An experiment by a New York physician more than a century ago led to the first connection between cancer and the immune system. After observing tumor regression in patients who contracted bacterial infections, Dr. William Coley injected live bacteria into a patient with inoperable cancer. The patient’s disease went into remission for eight years.

Recent breakthroughs in cancer vaccine development occurred as researchers made continued progress in identifying tumor antigens. Antigens are substances (usually proteins) that activate an immune response. All cells, including tumor cells, display antigens on their surfaces, and different cells have different antigens. Such individualized cell markers enable each person’s immune system to tell the difference between “self” (for example, skin cells and lung cells) and “non-self” (for example, a flu virus). A flu vaccine exposes the body to the antigens from several flu viruses, and stimulates the body to develop antibodies against these foreign cells. If an individual’s immune system cells encounter those flu antigens again, they will specifically attack those “foreign” cells. Because tumor cells develop from normal cells, they have a complicated system of avoidance that often results in the body tolerating these cells. The theory behind cancer vaccines is that we can stimulate our own immune system to specifically attack the tumor cells.

As the first responder to an invading pathogen, the innate immune system quarantines the intruder by activating antigen-presenting cells (APCs), such as dendritic cells and macrophages. APCs chew up the foreign cells, and the resulting fragments are presented on the APC’s surface. At this point, the adaptive immune system goes to work. While APCs and other members of the innate immune system attack without specificity, the adaptive immune system, composed of T cells and B cells, attacks only the particular cells it views as foreign. Though no cancer vaccines have been approved to date, more than 100 therapeutic cancer vaccine trials are currently under way in the United States.

Cancer vaccine research took a breakthrough turn after the recent discovery of a class of proteins called toll-like receptors. Of the 10 known toll-like receptors, cancer research has focused on toll-like receptor 9 (TLR9), which is found in dendritic cells of the innate immune system. TLR9 recognizes the DNA pattern of invading intracellular pathogens and sets the immune response in motion.

PF-3512676 (previously called ProMune™), a synthetic stimulator for TLR9, has entered phase III testing in lung cancer thanks to favorable phase II results. When added to chemotherapy, PF-3512676 almost doubled the median survival time to 12.8 months compared with 6.8 months for patients receiving chemotherapy alone. Side effects included myelosuppression and fever.

Antigen-targeted vaccines effectively treat tumors that are known to express that specific protein. For breast cancer patients whose tumors express the HER2 protein, results of a recent study found that a vaccine that targets HER2 effectively lessened breast cancer recurrence. After 22 months, only 8 percent of women in the vaccinated group experienced a recurrence compared with 21 percent in the control group.

While scientists continue to make progress in identifying additional tumor-specific antigens, the whole-cell vaccine approach provides another option. Doctors can take cancer cells directly from the patient, or create them in a laboratory, and manipulate any antigen found on a specific patient’s cancer cells in hopes of stimulating an immune response. Since whole-cell vaccines must be made individually for each patient, they are expensive and most drug companies have shifted their focus away from this area of vaccine research. But the failures and successes of this lesser-used approach helped researchers develop vaccines that can be used in entire patient populations.

In the spring of 1999, an X-ray showed that Connie West had a spot on her lung. Because she was 53 and had no history of smoking, her healthcare providers thought she had a respiratory infection. A couple of months later, further testing revealed she had stage 4 cancer in both lungs. After treatment in two clinical trials failed to significantly improve her prognosis, West entered a trial of GVAX®, led by Dr. Nemunaitis, in September 2000.

GVAX, which has shown effectiveness in prostate and pancreatic cancer, contains tumor cells that have been genetically modified to contain the gene for granulocyte macrophage colony-stimulating factor (GM-CSF), a growth factor that stimulates the body’s immune response to improve the vaccine’s activity. In creating the vaccine, the cancer cell lines are irradiated to prevent them from growing and dividing.

In West’s case, the vaccine was successful in treating the cancer. “I’m a miracle. I know I am,” she says. “The one thing I would say to anybody who has cancer is never give up. There are too many things to try, too many places to go, too many therapies. Never give up.”

So far, most patients do not get miraculous results from whole-cell vaccines. In the trial that West participated in, advanced non-small cell lung cancer was eliminated completely in just three of 33 patients. But Dr. Nemunaitis says advances in identifying and characterizing cancer will help doctors discover what therapy is best for each patient. “If you can correct the body’s systems to fight cancer, you are likely to have a much more durable effect, particularly when the therapy deals with enhancing the immune system.”

Able to successfully activate the immune system to attack cancer cells‚ researchers are now looking at ways to keep the immune system “on.” Currently in early-phase trials are two monoclonal antibodies that bind to and disable CTLA-4, a naturally occurring molecule that diminishes the immune response. MDX-010 is in phase III testing for advanced metastatic melanoma and has also shown the ability to shrink tumors in patients with advanced kidney cancer. Another CTLA-4 target is ticilimumab, which is being developed for kidney cancer and melanoma. The antibodies are being tested either alone or with cancer vaccines.

While experts are excited about the potential for genomics medicine and vaccines, some believe these advances will result in little net gain in survival, because localized primary tumors can be cured by surgery and local radiation. This school of thought argues that the real killer is metastasis and future research should be directed at understanding how cancer spreads and the role of so-called cancer stem cells.

The Cancer Stem Cell Hypothesis

New technology has allowed researchers to confirm an old proposition: that cancers derive from cancer stem cells. This was confirmed first in leukemia and more recently in solid tumors. The findings have led to the “cancer stem cell hypothesis,” the concept that a very small population of cancer cells are especially resistant to treatment and are responsible for regenerating tumors.
This is good news and bad news, says Michael Dean, PhD, head of the National Cancer Institute’s Human Genetics Section. “The bad news is that cancer is difficult to cure because cancer stem cells are closely related to normal stem cells and have evolved to be very hardy and survive adverse conditions. The good news is that this understanding completely refocuses the research effort.” If the hypothesis is correct, and if researchers find ways to target and kill these cells, cancer should become significantly easier to treat.

Stem cells of any origin share a characteristic of most cancer cells in that they can essentially live indefinitely. Normally, when a cell divides, one or both of the daughter cells alters its specific characteristics and functions in a process called differentiation. When a stem cell divides, however, at least one of the daughter cells does not differentiate further and remains a stem cell. The other copy can adopt a specialized role, such as a muscle, blood or brain cell, depending on the presence or absence of biochemical signals. In humans, a number of different types of stem cells exist, including the much-debated embryonic stem cells that can develop into any one of about 200 types of cells.

It is not yet clear how cancer stem cells originate. Some experts think they develop from mutations of normal stem cells, while others theorize some cancer cells undergo additional genetic changes and become cancer stem cells.

Max Wicha, MD, director of the University of Michigan Comprehensive Cancer Center in Ann Arbor, was on the team that discovered the presence of stem cells in human breast tumors. He explains that cancer stem cells can be identified by a protein on the cell surface, which varies according to the type of cancer. In the case of breast cancer, the protein marker is called CD44. “You can take as few as about 100 of these cells that have CD44 and put them in a mouse and it always forms a cancer,” he explains. “Whereas if you take 20,000 cells that don’t have CD44 and put them in a mouse, you get no cancers.”

Most current cancer therapies, particularly chemotherapy, seem to kill the more differentiated cells in a tumor while sparing the cancer stem cells that can then repopulate and grow. Cancer stem cells contain “transporter” proteins that literally pump out chemotherapy drugs before the drugs can kill them. “This may explain why many treatments cause cancer to shrink down but don’t necessarily make patients live longer,” Dr. Wicha says. “If we’re killing the wrong cells in the cancer, all we’re doing is reducing the number of non-stem cells. The root of the cancer is left behind and causes recurrence.” Another problem is that many therapies are directed to cancer cells that proliferate rapidly. However, cancer stem cells proliferate much more slowly than differentiated cancer cells, which renders traditional chemotherapies less effective.

One approach to killing cancer stem cells is to target the pathways (biochemical networks) that regulate their replication. Three key pathways have been identified: Hedgehog, Notch and Wnt. According to Dr. Wicha, studies in animals indicate drugs that inhibit these pathways have a more toxic effect on cancer stem cells than on normal stem cells. He expects clinical trials of inhibitors of these pathways to begin within the next year or two.

The cancer stem cell hypothesis also has implications for prevention and early detection of cancer. Dr. Wicha speculates that a woman’s risk of breast cancer may be related to the number of stem cells in her breast. In fact, tamoxifen may reduce stem cell populations, which would explain why it helps prevent recurrence of breast cancer. Theoretically, Dr. Wicha says, breast cancer could be prevented by eliminating mutated stem cells before they develop into cancer, or by forcing those cancer stem cells to differentiate so they can no longer self-renew. He adds it may be possible to develop blood tests to detect the proteins produced by cancer stem cells for very early detection of cancer.

Bringing It All Together

To collect and share all of the leading-edge research approaches that science is now exploring, what’s needed is an information platform that gives doctors and researchers real-time access to the most current information. Two years ago, the NCI launched the cancer Bioinformatics Grid (caBIG), which now links more than 50 cancer hospitals. Envisioned to become the World Wide Web of cancer research, caBIG is an open-access, voluntary network where cancer researchers can share tools, data, applications and technologies.

The NCI has also joined in the effort to make the proposed Human Cancer Genome Project a reality. The NCI and the National Human Genome Research Institute announced Dec. 13 that they have together committed $100 million for The Cancer Genome Atlas Pilot Project. The three-year effort will involve two or three tumor types to be determined in the coming months. At the December news conference, the organizations said the full-scale project to develop a complete atlas of the cancer genome will only move forward if the pilot project is successful in unraveling cancer’s genetic blueprint.

No one has a crystal ball that can predict which avenues of current research will result in the most benefit for future patients. However, the better researchers understand the intricacies of cancer, the better they can treat it. Whether they are identifying the genetic mutations responsible for a specific tumor in a specific individual or determining which types of cells have the ability to spread, researchers are changing their approach to cancer treatment.