Plant Compound May Block Tobacco-Induced Lung Cancer

Deguelin, a natural plant product, may interfere with the development of tobacco-induced lung cancer by interfering with the cellular processes that turn normal cells cancerous.

Previous studies have found that deguelin inhibits the proliferation of premalignant and malignant human bronchial epithelial cells by inhibiting the activation of a cellular pathway called P13K/Akt, which helps cancerous cells survive. Ho-Young Lee, Ph.D., of the University of Texas M. D. Anderson Cancer Center in Houston, and colleagues treated mice with deguelin to determine whether deguelin could block tobacco-induced lung tumorigenesis, which occurs through Akt activation.

They found that deguelin decreased Akt activation and the number of tobacco-induced lung tumors in the treated mice compared with untreated mice with no detectable toxicity. The authors conclude that deguelin should be considered for testing as a chemopreventive agent for early stages of lung carcinogenesis.

In an editorial, Stephen S. Hecht, Ph.D., of the University of Minnesota Cancer Center in Minneapolis, points out the difficulties in designing mouse models of tobacco-induced lung carcinogenesis that can then be applied to current and former smokers. That said, he writes, “the work reported by Lee et al., as well as that being carried out in other laboratories, holds some promise for new approaches to lung cancer chemoprevention.”

The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at jncicancerspectrum.oxfordjournals.org.

Kate Travis
kate.travis@oxfordjournals.org
Journal of the National Cancer Institute
jncicancerspectrum.oupjournals.org

Biomira’s Phase 2 Lung Cancer Vaccine Trial Shows No Safety Concerns

Biomira Inc announced the interim results of a phase 2 non-small cell lung cancer (NSCLC) single-arm, multi-centre, open label study of BLP25 Liposome Vaccine (L-BLP25) showing that the new formulation of the vaccine is not different from the previous formulation from a safety perspective. The reformulated vaccine incorporated manufacturing changes intended to secure the future commercial supply of the vaccine.

Though not a head-to-head comparison, the phase 2 trial compared the new formulation of L-BLP25 to the formulation used in the phase 2b trial, which was completed in 2004. A comparison of baseline and post-four vaccination laboratory tests for each trial, and between trials was conducted. For the majority of patients in both trials, the laboratory results were within the normal range for both time points. Also examined, for the same time frame, were adverse events, and injection site reactions. Although the two trials have slightly different patient populations and different sample sizes, based on the information reviewed, there is no clinical rationale to indicate that the two vaccine formulations are different from a safety perspective. The new formulation incorporated manufacturing changes intended to secure the future commercial supply of the vaccine.

In October, Biomira and Merck KGaA of Darmstadt, Germany announced that follow-up of patients enrolled in the phase 2b trial had determined a median survival for the vaccinated subset of Stage IIIB locoregional patients of 30.6 months compared to 13.3 months observed for the same stage patients who did not receive the vaccine, a difference of 17.3 months.

Tests to resolve a contract manufacturing stability issue are ongoing, with results expected in the first quarter of 2006.

The Companies

Biomira is a biotechnology company specializing in the development of innovative therapeutic approaches to cancer management. Biomira’s commitment to the treatment of cancer currently focuses on the development of synthetic vaccines and novel strategies for cancer immunotherapy. We are The Cancer Vaccine People™.

Merck is a global pharmaceutical and chemical company with sales of EUR 5.9 billion in 2004, a history that began in 1668, and a future shaped by 28,600 employees in 54 countries. Its success is characterized by innovations from entrepreneurial employees. Merck’s operating activities come under the umbrella of Merck KGaA, in which the Merck family holds a 73 per cent interest and free shareholders own the remaining 27 percent. The former U.S. subsidiary, Merck & Co., has been completely independent of the Merck Group since 1917. Merck KGaA has built a strategic oncology portfolio by developing and in-licensing product candidates in four areas — monoclonal antibodies, therapeutic vaccines, immunocytokines and angiogenesis inhibitors.

EMD Pharmaceuticals Inc., the U.S. affiliate of Merck KGaA, is a fully integrated pharmaceutical company with an initial emphasis on launching new products in oncology. Located in Durham, N.C., EMD focuses on meeting patient and physician needs with pioneering pharmaceutical products and services.

BIOMIRA INC.
2011 – 94 St. Edmonton
AB
Canada T6N 1H1
Tel: (780) 450-3761
Fax: (780) 463-0871
http://www.biomira.com

Hycamtin(R) receives positive opinion in Europe for treatment of patients with relapsed small cell lung cancer

GlaxoSmithKline (GSK) announced that HYCAMTIN(R) (topotecan powder for concentration for solution for infusion) received positive opinion from the European Committee for Human Medicinal Products (CHMP) for the treatment of patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate. HYCAMTIN is the first drug to receive a positive opinion from the CHMP for the treatment of relapsed SCLC. The CHMP’s positive opinion will now be proposed for final marketing approval by the European Commission. The product previously received approval in Europefor the treatment of metastatic ovarian cancer after failure of first-line or subsequent therapy.

“HYCAMTIN offers clinicians an important therapeutic option for patients with relapsed SCLC,” said Mikael von Euler, Vice President Europe Oncology Medical Development Centre, GSK. “HYCAMTIN is an excellent example of GSK’s commitment to pursuing new therapeutic options for the compounds in its oncology portfolio.”

The positive European opinion was principally based on three key Phase III studies. The first Study (protocol 090) compared the safety and efficacy of HYCAMTIN to the triple combination cyclophosphomide, doxorubicin and vincristine (CAV) in patients with sensitive SCLC. Median overall survival was comparable between the two arms of the study (25.0 versus 24.7 weeks, p = 0.80).

The second Study (protocol 396) compared the safety and efficacy of an oral formulation of topotecan versus IV HYCAMTIN in patients with sensitive SCLC. Median overall survival was comparable between the two arms (33.0 versus 35.0 weeks, Hazard Ratio = 0.98) and both treatments were generally well-tolerated.

The third Study (protocol 478) was conducted to prove the survival benefit of second-line chemotherapy for relapsed SCLC patients. The study was conducted using oral HYCAMTIN plus best supportive care and compared safety and efficacy to best supportive care (BSC) alone. Median overall survival for HYCAMTIN(R) plus BSC was 25.9 weeks compared to 13.9 weeks for patients who received BSC alone (p = 0.01).

“These studies demonstrate that single-agent HYCAMTIN is active in relapsed SCLC.” said Mikael von Euler. “Furthermore, the HYCAMTIN versus best supportive care study (protocol 478) has proven for the first time that treatment of relapsed SCLC in appropriate patients can offer symptom as well as survival benefit.”

About Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related death in the world. Small cell lung cancer accounts for 15 to 18 percent of all cases and is among the most aggressive of all pulmonary tumors.

An estimated 40,000 patients within the EU die of SCLC every year. The natural course of untreated SCLC results in a median survival time of 8 to 16 weeks.

About HYCAMTIN(R)

HYCAMTIN(topotecan HCl for Injection) is a chemotherapeutic agent that belongs to a class of drugs known as topoisomerase I (topo-I) inhibitors. Topo-I is an enzyme essential for the replication of DNA, and therefore cell division, in both normal and cancer cells. Interaction between topo-I and HYCAMTIN results in damage to the cell’s genetic material and the death of dividing cancer cells.

HYCAMTIN is registered in the European Union (EU), and 59 other countries around the world for the treatment of relapsed ovarian cancer following platinum-based therapy. In addition HYCAMTIN is registered for the treatment of sensitive relapsed small cell lung cancer (SCLC) in 39 countries worldwide. More than 230,000 patients have been treated with HYCAMTIN since its launch in 1996. More information on HYCAMTINcan be found at http://www.emea.eu.int.

Important Safety Information

HYCAMTINcan suppress the body’s ability to produce blood cells, in particular the white blood cells which fight infection. This condition is known as neutropenia. The clotting elements (platelets) can also be decreased, a condition known as thrombocytopenia. HYCAMTIN is contraindicated in patients who have a history of hypersensitivity reactions to topotecan or any of its ingredients. HYCAMTIN should not be used in patients who are pregnant or breast-feeding, or in those with severe bone marrow depression.

About GlaxoSmithKline

GlaxoSmithKline (NYSE: GSK) is one of the world’s leading research-based pharmaceutical and healthcare companies. GlaxoSmithKline is committed to improving the quality of human life by enabling cancer patients to do more, feel better and live longer. For more information, visit http://www.gsk.com.

References:

1. O’Brien MER, Ciuleanu T, Tsekov H, et. al. An open-label, multicenter, randomized, phase III comparator study of supportive care alone or in combination with oral topotecan in patients with relapsed resistant small-cell lung cancer. In press.

2. Maghfoor I. Lung cancer. www.emedicine.com. Accessed 10/6/05.

3. National Cancer Institute. www.cancer.gov. Accessed 11/8/05

4. Jemal A, Murray T, Samuels A, et al. Cancer statistics. CA Cancer J Clin 2003 ; 53 : 5-26.

5. Janssen-Heijnen ML, Coebergh JW. The changing epidemiology of lung cancer in Europe. Lung Cancer 2003; 41: 245-58.

6. von Pawell J. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-67

http://www.gsk.com

Minimally Invasive Surgery May Increase Options For Octogenarians With Some Lung Cancers

While some patients, including the elderly, may not be good candidates for the physical demands of open chest surgery, a new study suggests that even those between the ages of 80 and 94 may benefit from video-assisted thoracoscopic surgery (VATS) for early stage, localized, non-small cell lung cancer.

Sandy Van
sandy@prpacific.com
Cedars-Sinai Medical Center
www.csmc.edu

Race And Gender Affect Lung Cancer Clinical Trial Participation

A new study finds significant disparities by race and gender in the enrollment of patients into lung cancer clinical trials. Published in the January 15, 2006 issue of CANCER (interscience.wiley.com/cancer-newsroom), a peer-reviewed journal of the American Cancer Society, the study indicates that women and African-Americans were least likely to enroll in treatment trials for lung cancer, and identifies a need to improve educational and outreach efforts to make clinical trials available to a wider range of patients.

While clinical trials are important because they test the efficacy of the next generation of potentially life-saving treatments, only five percent of cancer patients participate in clinical trials. Reports have demonstrated that systemic factors in the healthcare system, such as cost, patient education, and physician biases may explain the low accrual rates. But gender and racial inequalities also are apparent, forcing lawmakers in 1993 to direct the healthcare system to encourage women and minority participation. Not only does lack of participation by minorities and women shut them out of the next generation of potentially life-saving treatment, but it also makes it all the more difficult for clinicians to translate treatment benefits and risks found in a clinical trial to these under-represented patient populations.

To evaluate the enrollment rate and the factors predicting enrollment, Wei Du, Ph.D., and colleagues from Wayne State University reviewed data from 427 lung cancer patients (175 African-Americans and 252 from other races) who were eligible for clinical trials between 1994 and 1998 at one center, the Karmanos Cancer Institute in Detroit.

Of this group, 21 percent (91 patients) participated in a lung cancer treatment clinical trial. The researchers found that patients who did not participate were more likely to be African American (45 percent versus 25 percent of enrollees), female (43 percent versus 32 percent of enrollees), and over the age of 70 (24 percent versus 10 percent of enrollees). The researchers say their results should be viewed with caution given that the study looked at enrollment at a single medical center, and did not study other factors that may play a role in clinical trial participation. Those include a lack of trust in the medical establishment, lack of knowledge about clinical trials, and the effect of religious belief or spirituality on the willingness to participate.

Still, they conclude: “New recruitment strategies targeting specific patient subgroups might be helpful in ensuring equal representation of women and minority groups in cancer clinical trials.”

Article: “Predictors of Enrollment in Lung Cancer Clinical Trials,” Wei Du, Shirish M. Gadgeel, Michael S. Simon, CANCER; Published Online: December 12, 2005 (DOI: 10.1002/cncr.21638); Print Issue Date: January 15, 2006.

John Wiley & Sons, Inc.
http://www.interscience.wiley.com

Lung Cancer Surgery – Study Suggests Racial Disparities Stem From Doctor-Patient Interaction

Even when they have equal access to specialized care, blacks with potentially curable lung cancer are about half as likely as whites to undergo surgery that could save their lives, according to a study by Dana-Farber Cancer Institute researchers.

Designed to identify the causes of racial discrepancies in lung cancer treatment in the United States, the research ruled out unequal access to medical care as the sole explanation. It did show that blacks were somewhat less likely to be offered lung cancer surgery, and were slightly more likely to refuse it than were whites. Overall, the study found that blacks who had equal access to care were 45 percent less likely than whites to have lung cancer surgery.

These findings point to a subtle and complex “communications problem” underlying the inequality, said Christopher Lathan, MD, of Dana-Farber and lead author of the report that is published online by the Journal of Clinical Oncology and is scheduled to run in the journal’s Jan. 20 print issue. “Something’s not happening. There was no specific reason that could be found, but there needs to be more attention paid to the doctor-patient interaction.”

The generally poorer health of blacks and other racial minorities is often blamed on social and financial obstacles to obtaining medical care. The new study, however, documents that the lower rate of surgery for black lung cancer patients “is not just about access to care or not being physically able to undergo treatment,” said Craig Earle, MD, of Dana-Farber and the paper’s senior author. “There still seems to be a racial disparity.”

According to the American Cancer Society, lung cancer is the leading cause of cancer deaths among blacks Americans, and blacks have the highest lung cancer mortality rate in the United States. It is estimated that 15,500 blacks will die from lung cancer in the United States in 2005 (accounting for nearly a quarter of all cancer deaths), and that more than 19,000 will be diagnosed with the disease, which is approximately 14 percent of all new cancer cases among blacks.

Yet, blacks have been previously found less likely to get surgical treatment. Someone who is diagnosed before the cancer has spread very far – Stage I or II – has up to a 50 percent chance of being alive at five years if surgery is performed. Untreated, the disease is almost always fatal.

The researchers, who also included Bridget Neville, MPH, of Dana-Farber, analyzed cancer registry records and insurance claims of 21,219 Medicare-eligible patients diagnosed with non-metastatic lung cancer between 1991 and 2001. With Medicare, inequalities due to insurance coverage were eliminated. Of these patients, 14,224 had undergone invasive procedures to “stage” the disease by its extent, which is a guide to treatment decisions.

The procedures included bronchoscopy, the insertion of a viewing tube into the lungs, and mediastinoscopy and thoracoscopy, where surgeons make incisions in the chest wall under general anesthesia, through which viewing scopes are placed. Blacks were 25 percent less likely than whites to have staging examinations.

But even after being referred for and undergoing staging, only 36 percent of blacks – but 50 percent of whites – were among the 6,972 who went on to receive surgical treatment. The difference in surgery rates was 45 percent.

“We thought that if all the patients had been staged – which suggests that they had access to the appropriate specialists and implies some level of trust in the medical system – that they would have the same rate of surgery,” said Lathan. “We were quite surprised to find this was not the case.”

The study did not address cultural factors, but Lathan said blacks might be mistrustful of the medical system and less aware of the potential benefits of the invasive surgery. Lathan, who is black and treats lung cancer patients, added that physicians may be less inclined to try and persuade reluctant black patients to strongly consider the surgery, particularly if a patient lacks good social support during recovery.

While urging further study, Lathan advised all patients to “make sure they’re getting all the resources they need, even if it means challenging their physicians a little bit.” For physicians, he added, “it’s really important that we spend as much time thinking about how we communicate with our patients as we do about how to treat them.”

The study was funded by Dana-Farber and by a National Institutes of Health training grant.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
http://www.dfci.harvard.edu

Study Finds Racial Disparities In Treatment For Lung Cancer

Black patients with treatable lung cancer are less likely to undergo comprehensive diagnostic procedures and surgery as white patients with the same severity of the disease, regardless of whether they have similar access to specialized medical care, according to a study scheduled to appear on Jan. 20 in the Journal of Clinical Oncology, the New York Times reports. For the study — led by Christopher Lathan, an instructor of medicine at Harvard Medical School — researchers examined 21,219 patients older than age 65 with treatable non-small-cell lung cancer. Researchers used data from 11 tumor registries established in a previous nationwide study. According to the new study, about 14,000 participants underwent invasive procedures to determine the form and severity of their cancer, and black participants were 75% as likely as white participants to undergo such procedures. In addition, among participants who underwent such procedures, black participants were more than half as likely as white participants to undergo surgery, the study finds. The results of the study remained consistent when researchers controlled for age, severity of cancer and other diseases. Health coverage and the ability to pay were not factors in the study because Medicare covered costs for all participants.

Reaction
Lathan said of the racial disparities identified in the study, “In our society, it is always hard to rule out racism.” However, he added, “Most doctors want the right thing for folks. The way a physician communicates and what he expects weigh heavily. And we haven’t looked at that. It’s a complex situation. It’s not just conscious or unconscious racism.” According to Lathan, “The major point is that African-American patients are still getting surgery less often than white patients. There is something happening here that is more than access to care.” Researchers also attributed the racial disparities identified in the study to lack of access to care, low-quality primary care and mistrust of the health care system among black participants. John Stewart, an assistant professor of surgery at Wake Forest University who was not involved in the study, said, “An underlying implication of this work is that the well-documented disparity in survival from lung cancer in African-American patients can be directly attributable to inadequacies in diagnosis, staging and therapy” (Bakalar, New York Times, 1/3).

The study is available online. Note: You must have Adobe Acrobat Reader to view the study.

“Reprinted with permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Vitamin A Analog Is A Potential Lung Cancer Preventative With Few Side Effects

The ideal substance to prevent cancer would block tumor growth without causing unpleasant or dangerous side effects. Researchers at Washington University School of Medicine in St. Louis now report that a compound related to vitamin A shows promise in preventing or slowing tumor growth in mice prone to lung cancer. The compound, called bexarotene, doesn’t cause the severe skin irritations that have limited the use of other vitamin A derivatives in cancer therapies.

“In the cancer prevention field, you look for drugs that can be given to healthy patients who have a higher risk of developing cancer,” says Ming You, M.D., Ph.D., director of the Chemoprevention Program at the Siteman Cancer Center. “These patients wouldn’t want to take a medication that makes them feel sick when they don’t have cancer. So the drugs should be very well-tolerated and not cause harmful side effects.”

In other studies, bexarotene showed some promise in cancer treatment. It extended survival in patients with non-small cell lung cancer, the most common type of lung cancer and one that has a five-year survival rate of less than 5 percent when diagnosed at the advanced stage.

In the current study, due to appear in an upcoming issue of Oncogene, Yian Wang, M.D., Ph.D., associate professor of surgery, You, professor of surgery, and colleagues demonstrate that lung-cancer-susceptible mice receiving non-toxic doses of bexarotene ended up with fewer and smaller benign and malignant tumors than mice that were not treated with bexarotene. The researchers saw a reduction of almost 50 percent in terms of total tumor burden in mice who were given bexarotene for 12 weeks after the animals had already developed benign tumors following injection of a lung carcinogen. Bexarotene also inhibited the progression of benign to malignant tumors by about 50 percent. The mice were engineered to have the genetic alterations seen in human lung cancers, so they readily develop lung cancer when given known lung carcinogens.

“Seeing this magnitude of response in such a strongly susceptible mouse suggests bexarotene is a potentially viable lung cancer prevention candidate,” You says.

Vitamin A analogs called retinoids have been studied for several years as potential chemotherapeutic agents because they help regulate cell division, growth, differentiation and proliferation. A new class of these vitamin A relatives has been created that includes bexarotene. These substances are called the rexinoids, so named because they are attracted to a molecule on cell surfaces called RXR.

Rexinoids tend to be much less toxic than retinoids, and among them bexarotene has so far shown the most promise as a chemopreventive medicine. However, although it causes far fewer side effects, bexarotene does have the effect of increasing blood lipid levels in many patients. Patients taking bexarotene often need to take a drug to lower their cholesterol and triglyceride levels.

A new rexinoid called UAB30, just becoming available for laboratory studies, seems to have the potential to reduce even the high-lipid side effect.

“We will be testing this new compound, too, and if it turns out to be effective, these rexinoids will most likely become candidates for clinical trials in patients with precancerous nodules or bronchial dysplasia,” You says. “If the trials show reduction of cancers, I think these drugs may well become routinely used for lung cancer prevention.” Prevention is considered vital to decreasing the impact of lung cancer, which accounts for 32 percent of cancer deaths in men and 25 percent of cancer deaths in women. The majority of lung cancer patients are not diagnosed until their cancer has reached an advanced stage, and current treatment regimens do not substantially improve the outcome for most of these patients.

“Advanced or metastatic cancer is sort of a genius at adapting,” You says. “By that point, the cancer cells that have survived have overcome so many obstacles and gained so many abilities that they are difficult to kill. They have a very unstable genome that can change quickly to resist the treatments we use. It’s best if you attack cancer in its infancy or at the precancerous stage. The earlier the better.”

Wang Y, Zhang Z, Yao R, Jia D, Wang D, Lubet RA, You M. Prevention of lung cancer progression by bexarotene in mouse models. Oncogene 2006.

Funding from the National Institutes of Health supported this research.

Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center is the only NCI-designated Comprehensive Cancer Center within a 200-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine.

Gwen Ericson
ericsong@wustl.edu
Washington University School of Medicine
http://medinfo.wustl.edu

Scientists Find Unusual Lung-cancer Tumor-suppressor Gene

Researchers have identified a new and unusual tumor suppressor gene that may be important in cancers of the lung and head and neck. The study shows that restoring the inactivated gene can slow the growth of tumor cells.

The gene, known as TCF21, is silenced in tumor cells through a chemical change known as DNA methylation, a process that is potentially reversible.

The findings might therefore lead to new strategies for the treatment and early detection of lung cancer, a disease that killed an estimated 163,510 Americans in 2005. The study could also lead to a better understanding of the molecular changes that occur in tumor cells during lung-cancer progression.

Tumor-suppressor genes are genes that normally prevent cells from growing out of control. The loss or silencing of one or more tumor-suppressor genes is believed to be an important part of cancer development.

The study, by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, was published online in the Jan. 13 early edition of the Proceedings of the National Academy of Sciences.

The newly discovered gene is unusual because it can alter normal epithelial cells, causing them to change to a more primitive state. Epithelial cells form the skin and line the body’s passageways and hollow organs. They are also the source of the most common forms of cancer.

The more primitive cell type, known as a mesenchymal cell, is more commonly found in embryos and is capable of migrating to other tissues. This suggests that the silencing of the TCF21 gene might help a tumor to spread to other areas of the body, a process known as metastasis.

The gene is also often silenced or lost in a variety of other cancers, including breast and ovarian cancer, melanoma and lymphoma.

“The fact that this gene is silenced in many cancer types strongly suggests that it plays an important role in cancer development,” says principal investigator Christoph Plass, a professor of molecular virology, immunology and medical genetics and a researcher in the OSU Human Cancer Genetics Program.

In addition, says first author Laura T. Smith, a postdoctoral fellow in Plass’ laboratory, “because this gene is silenced by DNA methylation, it might be possible to reactivate it using drugs that reverse the methylation process. This could provide a new strategy for treating these cancers.”

The gene is found on chromosome 6 in a region known as 6q23-24, an area that contains hundreds of genes. Other researchers have searched this region looking for mutations that might lead them to a silenced tumor-suppressor gene, but, Plass says, “that strategy has been unsuccessful.”

DNA methylation, which is a chemical change and not a mutation, is another way that genes are silenced. For this study, Plass and his colleagues systematically scanned the same chromosome region using a technology known as restriction landmark genome scanning, which identifies methylated genes.

The researchers examined the region in about 50 tumor samples from patients with head and neck squamous-cell carcinomas and with non-small-cell lung cancer, which is responsible for about 85 percent of lung cancer cases. From this, they identified TCF21 as a gene often silenced by methylation compared with normal airway cells.

“A picture is emerging that certain genes tend to be silenced mainly by DNA methylation, while others tend to be silenced by genetic mutations,” Plass says. “This gene seems to be silenced by DNA methylation.”

Through a series of experiments, Plass and his colleagues showed that an active TCF21 gene can, in fact, be silenced by DNA methylation, and that drugs that reverse methylation can reactive it.

The researchers also used a lung-cancer cell line to show that if the active version of the TCF21 gene is placed in tumor cells, the active gene will slow the cells’ growth rate.

Lastly, the researchers showed that mice injected with lung-tumor cells that had an active TCF21 gene developed tumors that were two to three times smaller than tumors that developed from cancer cells with a silent TCF21 gene.

Plass and his colleagues are now studying the possible role of TCF21 in metastasis.

Funding from the National Cancer Institute and the National Institute of Dental and Craniofacial Research supported this research.

Darrell E. Ward
Darrell.Ward@osumc.edu
Ohio State University
http://researchnews.osu.edu

Palliative Radiation Actually A Cure For Some Lung Cancer Patients

About one in a hundred patients with apparently incurable non-small cell lung cancer (NSCLC) survive five or more years after being given relatively small doses of radiation therapy (RT) meant to ease symptoms, according to a new study. Published in the March 1, 2006 issue of CANCER, a peer-reviewed journal of the American Cancer Society, the study says a new subset of patients with NSCLC appears to have disease that is curable with minimal therapy, and may explain occasional cures attributed to unconventional therapies or faith healing.

NSCLC is by far the most common type of lung cancer. With an overall five year survival of only 40 percent, it is also one of the deadliest. If caught early, five year survival can reach 60 percent. Five year survival in farther advanced disease is approximately 15 percent.

Patients who are diagnosed with disease that is too advanced for curative treatment remain eligible for palliative therapies intended to provide symptom relief, including comparatively low doses of localized RT. Physicians have long made clinical observations that some patients receiving palliative RT long outlive their estimated survival and a few report even cures. Given that therapeutic doses of RT are much higher, it is not surprising that these reports require evidence-based confirmation.

Michael Mac Manus, M.D., a radiation oncologist at the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues clinically followed 2337 confirmed and apparently incurable NSCLC patients who had received palliative dose RT.

Approximately 1.1 percent of the 2337 survived five or more years, including 18 who achieved an apparent cure. Although five year survivors were more likely to have higher functional scores at diagnosis and less likely to have metastatic disease compared to patients who lived less than five years, there were no other conventional prognostic factors to predict survival with palliative-dosed RT.

“Our data,” conclude the researchers “show that close to 1 percent of patients with NSCLC have prolonged survival with doses of palliative RT that would not normally be considered sufficient for long term disease control.” Future studies should focus on identifying patient characteristics because “prospective identification of such patients could potentially profoundly influence treatment.”

Article: “Unexpected Long-Term Survival after Low-Dose Palliative Radiotherapy for Nonsmall Cell Lung Cancer,” Michael P. Mac Manus, Jane P. Matthews, Morikatsu Wada, Andrew Wirth, Valentina Worotniuk, CANCER; Published Online: January 23, 2006 (DOI: 10.1002/cncr.21704 ); Print Issue Date: March 1, 2006.

John Wiley & Sons, Inc.
http://www.interscience.wiley.com