Oral Cancer - Confronting the Enemy

The Human Toll

Rick Bender is sometimes called "the man without a face," a description he feels suitably describes his appearance. After 14 years of using spit (or smokeless) tobacco, he was diagnosed with oral cancer and underwent surgery that resulted in the loss of part of his tongue, half his jaw, and partial use of his right arm. Rick Bender is evidence of the damage oral cancer can do to a face, a person, a life.

Oral or pharyngeal cancer will be diagnosed in an estimated 34,000 Americans this year, and will cause more than 8,000 deaths. The disease kills one person every hour -- more people than cervical cancer, Hodgkin's disease, or malignant melanoma. When the definition of oral cancer is expanded to include laryngeal cancer, which shares risk factors with oral cancer, the number of cases in the United States, per year, climbs to 41,000 and the number of deaths to 12,500. Oral cancer is the sixth most common cancer worldwide and the third most common in developing nations.

Some might say the old adage, "the cure is worse than the disease," applies to existing treatments for oral and pharyngeal cancers. Victims of oral cancer not only deal with the debilitating side-effects of radiation and chemotherapy but with the very visible evidence of surgery. Surgery to treat oral cancer is often extensive and disfiguring and may involve removing parts of the face, tongue, cheek, or lip -- causing changes in appearance that can be especially difficult to live with in a society that values physical beauty. Chemotherapy and radiation to the head and neck cause their own problems: jaw pain, mouth sores, and salivary glands that cease to function, resulting in difficulty chewing, swallowing, and talking. Recovering the ability to speak clearly and adjusting to new oral prostheses are additional challenges.

As with any cancer, the threat of death is an overriding fear. Most disturbing about oral and pharyngeal cancer is the survival rate. In the United States it is approximately 50 percent, a statistic that has not changed appreciably over the past 20 years. Oral cancer is unusual in that it carries a high risk of second primary tumors. Patients who survive a first cancer of the oral cavity have up to a 20-fold increased risk of developing a second primary oral cancer. The heightened risk can last 5-10 years, sometimes longer. Until researchers learn more about this phenomenon, second primary tumors will remain a specter faced by all oral cancer patients.

Additionally, oral cancer, like many diseases, continues to take a disproportionate toll on minorities. Incidence peaks in African Americans 10 years earlier than in the general population, in whom the disease is usually diagnosed between ages 65-74. The difference in survival rates between whites and African Americans is staggering -- 55 percent of whites survive five or more years, while only 34 percent of African Americans live that long. African American males suffer the highest incidence and lowest survival rates of any group. Oral cancer is the fourth most common cancer among African American men in the United States.

What We Know...About How Cancer Develops

We've known for a long time that cancer cells, unlike normal cells, multiply uncontrollably, ignoring the usual signals to stop. We also know that cancer cells can metastasize -- migrate from their original site and set up shop in another part of the body, where they continue to multiply unchecked.

But over the past two decades cancer research has uncovered much more. We now know that all neoplastic transformations (cancers) result from mutations, or changes, in genes that control cell growth and behavior. These genes normally restrict cell proliferation and direct the cell to repair DNA damage, or failing that, to self-destruct, a process called apoptosis, or cell 'suicide.' The mutated genes free the cell from these controls, allowing it to divide continuously and to pass on the mutation(s) to its progeny.

What causes these mutations? Many factors come together to cause each type of cancer. Genetic mistakes can be inherited or they can be acquired as a result of exposure to chemicals, radiation, or viruses. Random mistakes also occur each day in the course of duplicating the three billion units in our DNA during cell division. No one mutation is enough to make a cell cancerous. Multiple genetic changes, in specific classes of genes, are needed to transform a normal cell into a neoplastic cell that grows out of control. A small percentage of people inherit a susceptibility for certain types of cancer, putting all their body's cells one step closer to the disease.

What We Know...About Oral Cancer

Scientists now understand that oral cancers, which are included in the category of head and neck cancers, result from a multistep process of accumulated genetic mutations caused by many factors. Tobacco and alcohol use, diet, viruses, and a possible genetic susceptibility may all work together in various combinations to cause these cancers.

Using tobacco -- including cigarettes, pipes, cigars, and spit tobacco-is a well-established risk factor for oral cancer, as it is for some other cancers. Tobacco in any form contains carcinogens and nicotine, an addictive chemical that can keep the user hooked. A popular betel quid-spit tobacco mixture, used throughout India, has been implicated in the high rate of oral cancer in that part of the world.

Excessive alcohol consumption can also increase a person's chance of developing oral cancer. One theory suggests that alcohol generates metabolites, or byproducts of metabolism, that are carcinogenic to humans; the major metabolite of ethanol is acetaldehyde, a recognized animal carcinogen. Alcohol also might "grease the wheels" for tobacco by acting as a solvent and making it easier for carcinogenic agents to penetrate the oral tissues.

Rick Bender-
In his own words

Rick Bender appeared in a videotape titled"Dangerous Game," produced by the National Institute of Dental and Craniofacial Research, the National Cancer Institute, and the Centers for Disease Control and Prevention. In addition to Rick, the videotape featured major league baseball players and trainers who talked about the dangers of using spit tobacco, also called smokeless tobacco. The video was distributed to major and minor league baseball teams, and was made available to high schools as part of a package that includes pamphlets for students and a teachers' guide.

"The ulcer grew to about the size of a dime shortly after the first of the year there in '89. I then pretty much resolved to myself that, 'hey, Rick you've got cancer.' They had to take a third of my tongue -- they took all the lymph glands out of the side of my neck to biopsy them to make sure the cancer hadn't progressed into my lymph system, which, luckily, knock on wood, it hadn't. They ended up having to cut my jaw just to get to my tongue.

Using both tobacco and alcohol produces a much greater risk for oral cancer than using either substance alone. It is estimated that approximately 75 percent of all oral and pharyngeal cancers in the United States are caused by smoking and drinking, with most of these cases caused by tobacco and alcohol working synergistically.

Viruses, too, are thought to be involved in the development of these cancers. The human papillomavirus (HPV), particularly the HPV-16 and HPV-18 strains, and the herpes viruses are now considered possible contributors to some cases of oral cancer. DNA from HPV and certain herpes viruses, including Epstein-Barr, cytomegalovirus, and herpes simplex, has been detected in oral cancer biopsies. Genes encoded within these viruses are implicated in the initiation of the multiple steps required for a normal cell to become malignant. Interestingly, scientists have recently linked a new virus with AIDS-related Kaposi's sarcoma (KS), a cancer that has a preference for the head and neck. Oral lesions are present in about half of KS cases and the hard palate and gingiva are the most commonly affected areas. The newly identified virus, called human herpesvirus 8, has been found in all forms of KS, suggesting it might be involved in the sarcoma's development. A direct causal role, however, has not yet been established.

Research also suggests that a diet lacking fruits and vegetables could contribute to oral cancer, an idea postulated about other cancers as well. These foods contain antioxidants that trap harmful molecules, a process that can help prevent cancer-causing genetic mutations. The consumption of Cantonese salted fish from early childhood on has been associated with oral cancer in some Asian countries.

It [chewing tobacco] was an addiction. Today, I don't consider it a nasty habit as much as it is a dangerous habit -- a very dangerous habit. When I first started chewing, it was billed as a safe alternative to smoking. That's so far from the truth it's not even funny. It's just real far from the truth.

If somebody's chewing now -- quit. Quit now before it's too late. Don't wait till something like happened to me happens to them or a sore comes along--whether it's cancerous or not -- to quit. Quit now. Quit now before it's too late."

--Rick Bender works with state health departments, associations, and the spit tobacco consortium NSTEP (National Spit Tobacco Education Program) to educate youngsters about the dangers of using spit tobacco. He travels the country talking to schoolchildren about his experiences with spit tobacco use and his battle with oral cancer.

NIDCR and NCI continue their efforts to warn adults and children that spit tobacco is not a safe alternative to cigarettes.

Virtually all oral cancers are squamous cell carcinomas, cancers of the epithelial cells that line many parts of the body, including the mouth. These cancers can develop in any part of the oral cavity or oropharynx. The most common sites are the tongue, the lips, and the floor of the mouth. Cancers of the hard palate are uncommon in the United States. Research has shown that changes in oral epithelial cells often are manifested as lesions called leukoplakia, a white patch, or erthyroplakia, a red patch, which can be early signs of oral cancer.

Research is revealing what goes on beneath the cell surface -- at the genetic level -- to set the cancer process in motion. Scientists now realize that multiple mutations in specific classes of genes contribute to head and neck cancer. The two classes most fully characterized to date are proto-oncogenes and tumor suppressor genes. Proto-oncogenes code for proteins that stimulate cell division; altered forms, called oncogenes, can cause stimulatory proteins to be overactive, with the result that the cell divides more rapidly than usual. Scientists have so far identified the oncogenes (EGFR)/c-erb 1, ras family, c-myc, int-2, hst-1, PRAD-1 (CCND1 or cyclin D1), and bcl-1 as possible participants in head and neck cancers.

Tumor suppressor genes code for proteins that inhibit cell division. When these genes mutate, the corresponding protein may no longer be produced correctly and cell division may occur when it should not. Inactivated tumor suppressor genes that are suspected in head and neck cancer include Rb, p16 (MTS1 or CDKN2), and p53, whose failure is already implicated in approximately 60 percent of all human cancers. p53 has been of great interest to cancer researchers since it was discovered that the molecule could stop tumors from forming when it is functioning properly. Located on the short arm of chromosome 17, p53 works by recognizing damage to a cell's DNA and stopping the process of cell growth and division until the damage is repaired. If that fails, p53 can launch the cell's 'suicide' software, causing the cell to undergo apoptosis.

As more and more genetic events are implicated in head and neck cancers, scientists are now converging on the next question: in what order do those events occur to cause tumor development? One team has already proposed part of the answer by developing a preliminary genetic progression model for head and neck cancers.

The National Institute of Dental and Craniofacial Research: Asking the Questions, Seeking the Answers

Knowing the order and manner of genetic events involved in head and neck cancers has obvious appeal. Health professionals and patients can now look forward to confronting cancer on the molecular level -- where it originates -- instead of waiting to deal with its aftermath. It may one day be possible to detect the disease at its earliest stage using biomarkers found in blood and saliva; develop better tests for tracking the progression of cancer; and design therapies based on fixing or replacing mutated genes.

Through its grants program -- including the Oral Cancer Research Centers co-funded with the National Cancer Institute -- and in projects conducted on the NIH campus, NIDCR is seizing the opportunity to explore the range of topics related to oral and pharyngeal cancer. This article describes only a few of NIDCR's ongoing efforts and a handful of findings by NIDCR researchers and others in this burgeoning field.

Viruses, Variations, and Environment-Studies on Oral Cancer Etiology

For many years the human papillomavirus (HPV) has been suspected as a possible culprit in the etiology of oral cancer. Two types of the virus, HPV-16 and HPV-18, are found in oral cancer tissues more frequently than in normal tissues. Scientists are still not sure, though, how HPV might contribute to the development of oral cancer.

Recently, a team of NIDCR-funded investigators at the State University of New York Health Sciences Center in Syracuse discovered mutations in the long control region (LCR) of HPV-16 and HPV-18 taken from oral cancer cell lines. This region of the virus plays an important role in regulating the expression of two viral genes called E6 and E7. Earlier research implicated overexpression of these two genes in the development of cervical cancer, and the oral cancer researchers suspect the same phenomenon might be at play producing oral neoplasms. They speculate that the LCR mutations disturb the normal balance between up- and down-regulation of E6 and E7, leading to their overexpression and thus to oral cancer. Future research by these scientists and others will focus on trying to locate concrete molecular evidence of E6 and E7 overexpression in oral cancer cells. Taken together, these studies will eventually help confirm, or rule against, HPV's involvement in oral cancer development.

Animal and cell line studies have led two other groups of NIDCR grantees to make discoveries about genetic variations that might play a part in oral cancer development. At the Harvard School of Dental Medicine one group has identified, isolated, and partially characterized an oral tumor suppressor gene. Discovered in the hamster oral cancer model, the gene is dubbed 'doc-1' for 'deleted in oral cancer.' The mutation of this gene in malignant hamster oral keratinocytes leads to a reduction of its expression and protein production, while re-expression of the gene results in the reversion of malignant phenotypes to normal.

Importantly, the scientists now have data to support the existence of a human version of doc-1. They also have evidence that the gene seems to work by regulating cell cycle progression, as do other tumor suppressor genes such as Rb and p53. Studies are currently under way to determine whether doc-1 is a tissue-specific tumor suppressor or whether it might be involved in the development of other cancers as well.

A team of NIDCR-supported scientists at the University of Pittsburgh has shown that genetic variations occurring in head and neck cancers have been extended to include the FHIT gene, which was not previously associated with these malignancies. The finding that 22 of 26 squamous cell carcinoma lines showed aberrations in this gene strongly indicates that its function may be important in the development and progression of these neoplasias. Studies on the FHIT gene are continuing, and the scientists hope their findings will add to the knowledge of underlying genetic variations related to oral cancer.

A country halfway around the world and a U.S. island territory are the sites of two NIDCR studies correlating environmental and biological factors with oral cancer. In Taiwan, researchers are studying families with multiple members affected by nasopharyngeal cancer (NPC). The study capitalizes on recent investigations of NPC in Taiwan that found strong evidence of a genetic susceptibility to the disease and identified dietary factors that might contribute to its development. The current project is providing scientists with an ideal opportunity to investigate the association of NPC with environmental factors such as diet and to identify and characterize susceptibility genes for the disease. The molecular genetic work resulting from this study will almost certainly have implications for research into other subtypes of oral and pharyngeal cancer.

Closer to home, a case-control study of oral cancer is continuing in Puerto Rico, chosen as a study site because of its high oral cancer mortality rate for males. One of the study's strengths is that it is population-based, with cases derived from the island's central cancer registry. Biological specimens and information on diet and the use of tobacco and alcohol have already been collected from the 800-plus participants, and data analysis has begun. The idea is to discover how behavioral factors and genetic variations influence the development of oral cancer.

Diagnosing the Disease

Currently, diagnosing oral cancer relies on studying the histopathology of tissues through biopsy. X-ray technologies, like computed tomography, and other imaging techniques such as magnetic resonance imaging are sometimes used to detect the location and extent of the primary tumor. These techniques can help determine the stage of the tumor based on its size and whether it has spread. But cancer that can be evaluated by these imaging technologies has already taken root. Now, scientists are looking for ways to find cancer before it becomes clinically evident. To this end, many investigators are searching for markers at the molecular level that could warn of impending cancer.

In one such search for biomarkers, scientists at the University of Texas M.D. Anderson Cancer Center, an NIDCR Oral Cancer Research Center, are looking for alterations in short sequences of DNA called "microsatellites" on p53 and five other genes that might signal oral cancer. By examining cell samples from archived tissue of normal and dysplastic epithelium and invasive lesions, they plan to determine the most consistent biomarkers for each stage of oral cancer. In another phase of the study, the researchers will use tissue from recently diagnosed oral cancer patients to correlate genetic biomarkers with disease stage, tissue changes, tumor aggressiveness, and key epidemiological factors over several years.

One molecule already suspected as a predictor of head and neck cancers is telomerase. This enzyme helps a cell to reproduce chromosomal ends and circumvent the mechanism that counts and limits the total number of times the cell can reproduce. When cells become immortal they appear to bypass this safeguard and are able to replicate without limit. Telomerase is absent from most healthy cells, but present in almost all tumor cells. Scientists at Johns Hopkins University in Baltimore have recently found evidence of telomerase activity in oral rinses collected from head and neck cancer patients. Further research is necessary to discover whether telomerase is a marker consistently associated with head and neck squamous carcinoma. If so, telomerase activity may one day be used to detect the presence of cancer cells in the oral cavity and upper aerodigestive tract.

Until reliable biomolecular markers are identified, clinicians must rely on visual examination of oral tissues to detect precancerous lesions. Research by NIDCR, however, has indicated that less than 15 percent of American adults report they have ever had the head and neck examination that could reveal early signs of cancer. In an effort to improve this situation, NIDCR is focusing on encouraging dentists and other health care practitioners to perform this simple, potentially lifesaving, screening examination.

NIDCR's National Oral Health Information Clearinghouse (NOHIC) distributes a poster titled, "Detecting Oral Cancer: A Guide for Health Care Professionals," which offers a step-by-step pictorial guide on how to conduct the exam. Additionally, NOHIC has developed a companion slide show based on the poster. The slide show is distributed with a script and copies of the poster, patient education pamphlet titled, "What You Need to Know About Oral Cancer," and 'tips card' that lists signs and symptoms of the disease. NOHIC sends these materials to dentists, physicians, nurse practitioners, and other health care providers around the country.

Degrading and Invading-Studying Metastasis

Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream or lymph system. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissue. By degrading these proteins, cancer cells are able to breach the ECM and escape. When oral cancers metastasize, they commonly travel through the lymph system to the lymph nodes in the neck.

In studying oral cancer metastasis, scientists at the NIDCR-NCI Oral Cancer Research Center at the University of Alabama at Birmingham are focusing on matrix metalloproteinases (MMPs), a group of enzymes implicated in the metastatic process. Currently, they are looking at the MMP collagenase, an enzyme that can degrade collagen -- one of the ECM proteins. In healthy tissue, collagenase is activated only at appropriate times, and reacts with collagen to aid in wound healing, in fighting infection, and in the normal turnover of cells. In cancer, however, collagenase becomes active at the wrong time and enables cells to escape from the parent tumor.

Early data from the collagenase studies suggest that many oral tumor cells can produce the active form of the enzyme. In one of their experiments, the scientists used purified collagen in a tissue culture dish as an extracellular matrix model and then placed human oral tumor cells on top of the collagen. Upon removing the tumor cells, the scientists found a hole eaten through the collagen layer -- evidence, they say, that activated collagenase was present underneath the tumor cells. The researchers ultimately hope to prevent collagenase activation in tumor cells and pre-empt the metastatic process.

At the University of California, San Francisco, another NIDCR-NCI Oral Cancer Research Center, researchers are studying a viscous molecule called hyaluronic acid (HA), a building block of the "glue" that anchors cells to one another. The molecule is present on the surface of cancer cells as well, and allows them to become motile and to create space into which they can move, two requirements for metastasis. Saliva's HA-rich environment gives cancer cells further opportunity to fulfill these two requirements, and may be the reason oral cancers can be so aggressive, the scientists say. In some cancers, high levels of HA and its receptor, CD44 (in certain forms), have been correlated with advanced metastatic behavior. In these latest NIDCR studies, the scientists will evaluate whether HA and CD44 are predictors of oral cancer metastasis by documenting their levels in cell culture and in human biopsy specimens. The scientists say these potential biomarkers may be of enormous value in identifying patients at increased risk for developing malignancy, and also in predicting which lesions might be particularly aggressive. Additional studies are aimed at trying to determine whether hyaluronidase, an enzyme that breaks down HA, can inhibit oral cancer metastasis.

One compound that has already shown anti-metastatic activity is a non-antimicrobial tetracycline analogue called CMT-3. Current research on this molecule evolved from earlier NIDCR studies on periodontal disease that found tetracyclines could inhibit collagenase activity independently of their antibiotic property. In recent laboratory tests, NIDCR-funded researchers at the State University of New York at Stony Brook found that CMT-3 inhibits cancer cells from degrading and crossing synthetic basement membrane. The analogue also showed promise in a rat model of prostate cancer in which it reduced tumor size in some animals, caused tumor remission in others, and inhibited metastasis to the lung. Additional safety and efficacy studies, now under way, are necessary steps in moving toward the planned clinical testing of this compound. Further anti-metastasis studies could lead to application of CMT-3 in treating many cancers, including oral cancer.

Curbing a Killer

Traditionally, surgery and radiation were the only treatments thought to be effective against oral cancer, with chemotherapy used as a palliative measure. Within the last decade scientists have found that certain drugs do indeed work against oral cancer. Researchers are now using radiation and chemotherapy in tandem, giving cancer a 'one-two' punch in an effort to knock it out. One of the newest drugs in the oral cancer treatment armamentarium is paclitaxel (Taxol, Bristol-Myers Squibb Co.), which has shown some success in treating other cancers. Currently, clinical researchers are studying paclitaxel as a treatment for oral cancer, using the drug by itself and in combination with other chemotherapeutic agents and radiation therapy.

Long before drugs are used in the clinic, they undergo extensive testing for safety and efficacy. Countless compounds initially thought to have some activity against cancer ultimately fail. But a few, like paclitaxel, do not. So researchers continue to screen thousands of compounds searching for those that show evidence of antitumor activity. Recently, NIDCR and the National Cancer Institute have become partners in the effort to identify natural or synthetic agents that demonstrate activity against squamous cell carcinoma. NIDCR is now testing the ability of certain agents -- already shown to have antitumor activity by an NCI cell line assay -- to diminish growth of squamous cell carcinoma lines in vitro and in vivo . The scientists hope to confirm the efficacy of these compounds and move them a step closer to clinical testing.

Other research is focused on inventing new systems to test potentially therapeutic compounds. NIDCR-funded investigators at the M.D. Anderson Cancer Center are developing a unique tissue slice organ culture (TSOC) that consists of normal, premalignant, and malignant human oral tissue slices kept alive in the laboratory. The advantage of the TSOC is that it preserves tissue organization, cell interaction, and cell function more so than do cultured cell lines. Because the model essentially mimics in vivo conditions, it is ideal for testing numerous agents in various amounts and combinations. Oral cancer research has been hindered by the methods usually employed to investigate growth and differentiation of normal and premalignant oral cells. Culturing normal oral cells is complicated, and no successful method for culturing genuine premalignant oral cells exists. The scientists hope to establish the TSOC system as the standard for examining normal, premalignant, and malignant oral tissues.

Using the TSOC the scientists are looking at the ability of vitamin A analogues (retinoids) and sodium butyrate, a four-carbon fatty acid, alone or in combination, to reverse aberrations in cell growth and differentiation. Scientists already know that one retinoid, called isotretinoin, can reverse premalignant oral lesions; however, the analogue has side effects that preclude its prolonged use. One of the research goals is to identify other retinoids with similar or better efficacy than isotretinoin, and analyze them to determine whether they may have fewer side effects. If so, these compounds could be candidates for clinical testing. The scientists also hope to investigate whether butyrate might be effective in preventing or treating oral malignancies.

Complementing the vast array of laboratory experiments are clinical studies aimed at testing new cancer treatments or helping to improve the quality of life for patients living with the disease. At the University of Chicago and Northwestern University, another NIDCR-NCI Oral Cancer Research Center, scientists in one clinical study are looking at the chemotherapeutic effects of 5-fluorouracil (5-FU) in combination with radiation therapy. One problem with using this drug has been that the enzyme dihydropyrimidine dehydrogenase (DPD) can degrade 5-FU and lower its level in the body below a therapeutic range. To circumvent this problem, the scientists are testing 5-FU in combination with a chemical that blocks DPD action, which might keep the cancer-fighting drug at its therapeutic level. Scientists will correlate the activity of 5-FU with enzyme activity and with patient response and survival. By conducting studies aimed at elucidating the idiosyncrasies of this powerful drug, the researchers hope to learn how to use it most effectively against oral cancer.

In patients with advanced cancer, one of the primary goals is to reduce the symptoms of large tumors and preserve organ function, thus maintaining or improving quality of life. This is the focus of another study at the University of Chicago-Northwestern University. Clinicians are analyzing the effects of high-dose radiotherapy combined with chemotherapies on tongue strength and swallowing function in patients with advanced cancer. Using the latest imaging techniques, scientists are able to observe even minute changes in organ function.

Biotherapies

Suppose there were a mutant cold virus that killed only cancer cells? Or a genetic 'cocktail' whose ingredients could provoke tumor-specific immune activity? Or what if there were a technique that allowed clinicians to replace a damaged p53 gene with a normal version? In fact, these are all therapies under study by head and neck cancer researchers right now. They are examples of a new approach to cancer treatment known as 'biotherapy.' Biotherapies are biological, based on the molecules and genes involved in the cancer process. A decided advantage of these therapies is that unlike chemically based chemotherapy or physically based radiotherapy -- which can harm healthy cells as well as tumor cells -- biotherapies can target tumor cells but leave other cells relatively unscathed. How successful will these therapies turn out to be? Ongoing research, like that described below, will eventually be able to give us the answer.

One biotherapy being studied at ONYX Pharmaceuticals has shown success in the clinical setting. The technique consists of a mutant adenovirus that selectively infects and kills only cells that are deficient in p53, such as tumor cells. (Lacking the E1B protein that shuts down p53, the mutant adenovirus can't reproduce in cells with normal p53; but it can replicate in and thus kill cells that do not have functioning p53. See diagram) ONYX has tested this adenovirus in a small number of patients with head and neck cancer who had not responded to surgery, radiation, and in some cases chemotherapy. The adenovirus treatment produced significant destruction of tumors in some patients and lesser improvement in several others. Scientists do not yet know if the tumor cells are dying because of direct viral assault or from attack by the immune system on virus-infected cells.

A different kind of biotherapy uses a type of molecule called a ribozyme, which is able to bind to and destroy RNA. NIDCR oral cancer researchers at SUNY in Syracuse have developed ribozymes that destroy the RNA of tumor-associated human papillomavirus and have devised a method for introducing them into cancer cells in vitro to inhibit tumor cell growth. Of major importance was their finding that the tumor suppressor protein, p53, usually absent in HPV-containing tumor cells, could be detected in the cells into which ribozymes had been introduced. These results imply that the ribozyme inhibited the HPV gene product(s) involved in the breakdown of p53. These studies provide a strong basis for current investigations designed to determine if ribozymes can inhibit tumor formation in an animal model by the administration of HPV-positive tumor cells.

To Be or Not To Be...Cell Suicide As Cancer Therapy?

Apoptosis, or cell 'suicide,' is a backup system that prevents runaway division by alerting a cell to DNA damage and initiating self-destruction. Although apoptosis is bad for the cell, it is ultimately good for the body, which this way rids itself of damaged genetic material. Learning more about apoptosis is key to fully understanding cancer, and ultimately to developing strategies based on harnessing this process as a cancer therapy.

At the University of Chicago, NIDCR- and NCI-funded scientists are studying whether alterations in the susceptibility of tumor cells to undergo apoptosis contribute to the development, progression, or recurrence of oral and pharyngeal cancer. Their current studies focus on the bcl-2 gene family. Within the family are genes that code for proteins that suppress cell death, such as bcl-2 and bcl-xl, while others promote apoptosis. So far, the scientists have correlated overexpression of bcl-xl in human oral cancer tissue with a poor prognosis, and overexpression of bcl-2 with a more hopeful outcome. These findings are consistent with their earlier work on breast cancer. Those studies showed that bcl-xl overexpression was associated with a higher tumor grade and increased number of positive lymph nodes, and tumors expressing bcl-2 were of a lower grade and a smaller size.

For their latest studies on bcl-xl, the scientists created a transgenic mouse model that overexpresses the protein in the mouth, throat, and skin. When the animals' skin was exposed to known carcinogens, approximately 70 percent of them developed invasive skin cancer, whereas only 18 percent of the control group developed the disease. The scientists are now beginning studies of the oral mucosa using a similar transgenic model. Can a cell be tricked into dying? Ultimately, the scientists hope to be able to answer this question as they learn more about the apoptotic process and the so-called 'cell survival genes' that code for proteins like bcl-xl.

A three-gene 'cocktail' is the focus of a unique gene therapy strategy set to be tested soon by NIDCR grantees at Johns Hopkins University. The herpes simplex virus thymidine kinase (HSV-tk) "suicide" gene and genes for two cytokines -- interleukin-2 (IL-2) and granulocyte macrophage colony stimulating factor (GM-CSF) -- will be delivered via an adenovirus into a mouse model of oral cancer. The scientists speculate the therapies will act synergistically. Here is why: The HSV-tk therapy causes oral cancer cells to commit 'suicide' in the presence of certain anti-herpetic drugs such as ganciclovir. As that occurs, the tumor cells release cellular debris and antigens recognized by immune cells. The HSV-tk/ganciclovir therapy, then, not only works to reduce tumor size, but also sets the stage for tumor-specific immune activity by IL-2 and GM-CSF. In turn, the two cytokines stimulate specific immune cells that are able to recognize and help destroy tumor cells.

Further along in the research pipeline is an apoptosis-based therapy using the p53 gene. Clinical investigators at the M.D. Anderson Cancer Center and Introgen Pharmaceuticals, Inc., recently completed a study on the safety of p53 gene therapy in a small number of patients with head and neck cancer. The study was a dose-escalation trial in which the investigators used an adenovirus to deliver normal p53 gene into the patients' tumors. All the patients had advanced, recurrent cancers of the head and neck and had failed conventional treatment. The researchers found that the gene therapy was not only free of serious side effects, it actually resulted in tumor regression in some patients. With its safety now documented, scientists can move the p53 treatment to the next stage of clinical testing.

Where Do We Go From Here?

Clearly, our exploration into the fundamental mechanisms of cancer must continue -- for every step in the cancer development process is a potential target for new therapies. Basic research has already paid off in many ways, showing us that specific classes of genes are involved in cancer development, that environmental factors can trigger genetic mutations, and that cancer cells spin out of control and proliferate unchecked. Within the next few years NIDCR studies on cell signaling, cell cycle regulation, tumor angiogenesis, and a myriad of other topics might further elucidate how cancer develops and spreads, information that is paramount to learning how to stop the disease.

We must also continue to educate -- spreading the word that many cases of oral cancer can be avoided by changing certain behaviors. Quitting tobacco use, stopping excessive drinking, and eating a diet rich in fresh fruits and vegetables are all things people can do now to reduce their risk of developing the disease. Clinicians, too, can help save lives by performing the simple head and neck examination, and by talking to patients about cancer's early warning signs.

Oral cancer is a disease whose survival rate has not improved appreciably in decades, a disease that has a high rate of second primary tumors, and a disease that leaves its mark on survivors in the form of facial disfigurement. Through basic, translational, clinical, and community-based research, and through public and professional education, NIDCR is continuing its fight against oral cancer, working to ensure that no one need ever suffer from this devastating disease.