Frontiers

Breakthrough – The frontiers of cancer research 


AMISH ADVANTAGE

Study Shows Clean Living May Lower Cancer Rates

When Ohio State researchers began studying a sect of Amish living in Ohio, they theorized they would find higher incidence rates of cancer, mainly because Amish religious beliefs and traditions limit contact with mainstream society, and intermarriage within their relatively small population could increase cancer-related gene mutations.

But they found just the opposite, says Judith Westman, MD, clinical director of the Division of Human Genetics in The Ohio State University College of Medicine. Westman says the Amish study suggests that clean living can lead to a healthier life.

Overall cancer rates in this population were 60 percent of the age-adjusted rate for Ohio and 56 percent of the national rate. The incidence of tobacco-related cancers among Amish adults was 37 percent of the rate for Ohio adults, and the incidence of non-tobacco-related cancer was 72 percent.

“The Amish are at an increased risk for a number of genetic disorders, but they probably have protection against many types of cancer both through their lifestyle and through genes that may reduce their susceptibility to cancer,” says Westman, who co-authored the study with Amy Ferketich, PhD, a researcher with the OSUCCC-James’ Cancer Control Program.

The study, which spanned 1996-2003 and is the first of its kind, looked at the incidence of 24 types of cancer among the Amish. Of those 24, the incidence of seven of them – cervical, laryngeal, lung, oral cavity/pharyngeal, melanoma, breast and prostate – was low enough compared with the Ohio rate to be statistically significant.

Westman and Ferketich say the low cancer incidence in the Ohio Amish may be partially explained by lifestyle factors such as limited tobacco and alcohol consumption, lack of sexual promiscuity, active or labor-intensive lifestyles, and proper dress for avoiding sunlight exposure when working outdoors.

Published January 2010 in Cancer Causes & Control.


PROSTATE PROGNOSTICATION

Blood-vessel viewing may predict tumor behavior

A prostate cancer diagnosis raises an important question for physicians and their patients: Will the tumor grow quickly, requiring continuous treatment, or slowly, allowing therapy and its risks to be safely delayed?

The answer may lie in the size and shape of blood vessels within the tumor, according to research led by The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC-James) in collaboration with the Harvard School of Public Health.

A study of 572 men with localized prostate cancer indicates that aggressive tumors tend to have blood vessels that are small, irregular and primitive in cross-section, while vessels in indolent tumors look more normal.

“It’s as if aggressive prostate cancers grow faster, and their blood vessels never fully mature,” says study leader Steven Clinton, MD, PhD, a prostate cancer specialist and researcher at the OSUCCC-James. “Prostate cancer is heterogeneous, and we need better tools to predict whether a patient has a form that is aggressive, fairly average or indolent so we can better define a course of treatment – surgery, chemotherapy, radiotherapy, hormonal therapy, or potentially new drugs that target blood vessels – that is specific for each person’s type of cancer.”

After an average follow-up of 10 years, 44 of the 572 men in this study had developed metastatic cancer or died of their cancer. Men whose tumors had smaller vessel diameters were six times more likely to have aggressive tumors and die of their disease, and those with the most irregularly shaped vessels were 17 times more likely to develop lethal prostate cancer.

The findings, which were independent of Gleason score and prostate specific antigen (PSA) level, apply to men with local disease, whose PSA is only modestly elevated, and who are younger and more likely to choose surgery. “If our findings are validated by larger studies, the measurement of tumor blood vessel architecture might help determine choice of therapy,” Clinton says.

Published Nov. 20, 2009, in the Journal of Clinical Oncology.


ROLE REVERSAL
Stem cell activators switch function, repress mature cells

In a developing animal, stem cells proliferate and differentiate to form organs. A new study shows how a crucial step in this process happens and how a reversal of that step contributes to cancer.

The study, led by researchers at the OSUCCC-James, shows for the first time that three proteins – E2f1, E2f2 and E2f3 – play a key role in the transition that stem cells make to their final differentiated state.

These proteins stimulate stem cells to proliferate, but once the cells begin to differentiate into their final type, the proteins switch function and stop them from dividing. The research also shows how these proteins can switch course yet again in cells that have mutations in the retinoblastoma (Rb) gene. Mutated Rb genes occur in many cancers, suggesting that E2f proteins might offer a safe therapeutic target in these tumors.

“We show that these E2fs are gene activators in stem cells but then switch to gene repressors when stem cells begin differentiating,” says study leader Gustavo Leone, PhD. “This is a very important step in differentiation. As organs form, there comes a time when their growth must stop because an organ needs only a certain number of cells. The switch by these proteins from activators to repressors is essential.”

Before, no one suspected that these regulatory proteins had any role in differentiated cells, Leone says. “It was thought they were important only in proliferating cells like stem cells. But that’s not true.”

Leone and colleagues show the function of the proteins in differentiation in mouse embryos, retinas, lenses and intestines. They also show how the three proteins could revert back to gene activators in cancer cells and promote tumor growth in cancers with Rb mutations.

Published Dec. 17, 2009, in back-to-back papers in Nature.


WHEN BAD IS BETTER
Mutated gene a good sign for older leukemia patients too

Almost half of people younger than 60 with acute myeloid leukemia (AML) may be cured, but that number plunges to 5-16 percent for people 60 and older.
A study at the OSUCCC-James indicates that some older AML patients whose cancer cells have NPM1 gene mutations respond better to therapy and survive longer.

Mutations in this gene signal a favorable prognosis in younger patients with AML; this new study indicates that the same is true for older patients, suggesting that they should be offered stronger therapy.

“These findings were completely unexpected,” says study leader Clara D. Bloomfield, MD, a Distinguished University Professor who serves as cancer scholar and senior adviser to the OSUCCC-James. “Even patients over 70 who have NPM1 mutations do better than those with the normal gene. This study supports the importance of understanding and thinking positively about what we can do for older people with leukemia.”

Bloomfield and colleagues examined the outcomes of 148 AML patients 60 and older with normal cytogenetics, a feature seen in more than half of adults with AML. All of the patients had been treated through one of two national clinical trials sponsored by the Cancer and Leukemia Group B (CALGB).

Overall, 83 patients (56 percent) had NPM1 mutations. Of those, 84 percent had a complete remission, compared with 48 percent of patients whose cancer cells had a normal NPM1 gene. Patients with the mutated gene also had a significantly higher three-year survival rate: 35 percent compared with 8 percent.

“The favorable response of patients with NPM1 mutations suggests these mutations may represent a marker that can be used to stratify older patients with cytogenetically normal AML to intensive chemotherapy, which is often avoided in older patients,” says co-author Guido Marcucci, MD.

Published Feb. 1, 2010, in the Journal of Clinical Oncology.


MATHEMATICAL MODEL
Curing cervical cancer cases may be in the numbers

Cervical cancer is curable when caught early, but in a third of cases the tumor either responds poorly to therapy or recurs later, when it is more difficult to cure.

Quicker identification of non-responding tumors may be possible using a new mathematical model developed by researchers at the OSUCCC-James. The model uses information from MRI scans taken before, during and after therapy to monitor changes in tumor size. That information is plugged into the model to predict much earlier whether a case is responding well to treatment. If not, the patient can sooner be offered a more aggressive or experimental therapy.

The study used MRI scans and outcome information from 80 cervical cancer patients receiving a standard curative course of radiation. “The model enables us to better interpret clinical data and predict treatment outcomes for individual patients,” says principal investigator and radiation physicist Jian Wang, PhD.

“The outcome predictions presented in this paper were based solely on changes in tumor volume as derived from MRI scans, which can be easily accessed,” Wang says. “The model is very robust and can provide a prediction accuracy of 90 percent for local tumor control and recurrence.”

A strength of the model, says first author Zhibin Huang, PhD, is its use of MRI data to estimate three factors that play key roles in tumor shrinkage and that vary among patients: the proportion of tumor cells that survive radiation exposure; the speed at which the body removes dead cells from the tumor; and the growth rate of surviving tumor cells.

The model is applicable to all cervical cancer patients, and the investigators are developing a model that can be applied to other cancer sites, Wang says.

Published Jan. 15, 2010, in Cancer Research.


TARGETING T CELLS
Multicenter study reduces transplant risk in AML patients

Patients with acute myeloid leukemia (AML) who were treated as part of a multicenter study by the Blood and Marrow Transplant Clinical Trials Network had excellent survival and a low risk of graft-vs.-host disease, the major complication of transplantation.

Steven Devine, MD, director of the Blood and Marrow Transplant Program at the OSUCCC-James, was co-chair and first author of the study.

During the three-year study at eight centers, 44 AML patients received allogeneic stem cell transplants from related donors whose immune system markers were identical to those of the patients. This type of transplant is the most effective means of preventing relapse in AML patients who are in complete remission but at high risk for relapse.

Graft-vs.-host disease occurs in 30-40 percent of patients who receive transplants from related donors, limiting the use of this otherwise curative procedure. The disease is most effectively prevented by removing the T cells that cause it from the donor graft via T-cell depletion. However, Devine says T-cell depletion is not often used because there is no FDA-approved method for it.

“We designed a clinical trial for adult AML patients that used a single processing method for depleting T cells that did not require post-transplant graft-vs.-host disease prophylaxis,” Devine says. Since the T cells were removed ahead of time, none of the patients had to be on drugs to prevent rejection or graft-vs.-host disease.

After six months, 81 percent of patients in the study had achieved disease-free survival, and 64 percent maintained disease-free survival at one year. The results are close to what is observed using other current transplant procedures, but with fewer complications related to graft-vs.-host disease. Devine says the study confirms the feasibility of using a uniform method of T-cell depletion.

Presented at the 51st Annual Meeting of the American Society of Hematology, December 2009.


PROTEIN PICKOFF
Targeted agent prolongs survival in chronic leukemia model

Current therapies for human chronic lymphocytic leukemia (CLL) often damage the immune system, leading to infections that are the primary cause of death for these patients.

But an experimental oral agent called 17-DMAG may help overcome this problem, according to a study by researchers at the OSUCCC-James.

The laboratory and animal find-ings indicate that this agent is highly selective for CLL cells and has minimal effect on normal immune cells, suggesting that it may leave a patient’s immune system healthy, the researchers say.

“This agent turns off multiple proteins that cancer cells need to survive, and we show that this activity occurs both in CLL cells from patients and in a CLL mouse model,” says study leader Amy Johnson, PhD.

“Our findings strongly support testing this agent in CLL patients in a phase I clinical trial.”

The research showed that the drug significantly prolonged survival in a CLL mouse model. Animals treated with the agent survived an average of 75 days, compared with 66 days for animals that didn’t receive it.

The agent works by inhibiting the action of protein HSP90, which is active mainly in CLL cells. This protein accompanies and protects other proteins as they are being made by CLL cells.

These other proteins include AKT, RAF and Zap-70, all of which are important for the survival and growth of the cancer cells. Blocking the protective protein leads to destruction of the other proteins.

In addition, the agent reactivates a gene called FOXD3. This same research group showed in previous work that FOXD3 is silenced early during human CLL development, a change that likely plays an important role in CLL progression.

Presented at the 51st Annual Meeting of the American Society of Hematology, December 2009.

 
13-May-10
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