Scientists at Johns Hopkins have discovered a potential strategy for cancer therapy by focusing on what’s missing in tumors.

Noticing the conspicuous absence of single-stranded genetic snippets called microRNAs in cancer cells, a team of researchers from Johns Hopkins and Nationwide Children’s Hospital delivered these tiny regulators of genes to mice with liver cancer and found that tumor cells rapidly died while healthy cells remained unaffected.

Publishing results of the study June 12 in cell.com/” target=”_blank” rel=”nofollow”>Cell, the researchers say they have provided one of the first demonstrations that microRNA replacement provides an effective therapy in an animal model of human disease.

“This work suggests that microRNA replacement may be a highly effective and nontoxic treatment strategy for some cancers or even other diseases,” says Josh Mendell, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine. “We set out to learn whether tumors in a mouse model of liver cancer had reduced levels of specific microRNAs and to determine the effects of restoring normal levels of these microRNAs to these cancer cells. We were very excited to see that the tumors were, in fact, very vulnerable to microRNA replacement.”

His team had considered the possibility that the replacement of a single small RNA might have little if any effect, especially in the setting of all the complex changes that drive the aberrant behavior of a cancer cell. But the tumor cells in the mouse were indeed sensitive to the restoration of the microRNA??”so much so that they died, rapidly.

“This concept of replacing microRNAs that are expressed in high levels in normal tissues but lost in diseases hasn’t been explored before,” Mendell says. “Our work raises the possibility of a more general therapeutic approach that is based on restoring microRNAs to diseased tissues.”

The Hopkins team was building on precedent-setting research (published January 2008 in Nature Genetics) showing that in a Petri dish, replacing microRNAs in lymphoma cells stopped the formation of tumors when the cells were injected into mice.

The new study involves animals that develop liver tumors closely resembling the human disease. Researchers chose to target the liver because, according to Mendell, it is a large organ whose function is detoxification and therefore, is a relatively accessible target for the delivery of small molecules, compared to other tissues.

Using a “special delivery” virus that can deliver genes to tissues without causing them any disease or harm, the researchers intravenously injected a fluorescent microRNA-containing virus into one group of mice with aggressive liver cancer, and injected a control virus containing no microRNA into another group. The viral delivery system was developed by Mendell’s father, Jerry Mendell, M.D., director of the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital in Columbus, and K. Reed Clark, Ph.D., associate professor and director of the Viral Vector Core Facility at Nationwide Children’s Hospital.

After three weeks, six of eight mice treated with the control virus experienced aggressive disease progression with the majority of their livers replaced by cancerous tissue. In contrast, eight of 10 of animals treated with the microRNA were dramatically protected, exhibiting only small tumors or a complete absence of tumors. Liver body weight ratios were significantly lower in the treated mice, further documenting cancer suppression.

“The livers of the mice that received the microRNA virus glowed fluorescent green, showing that the microRNA ended up where it was supposed to go, and the cancer was largely suppressed,” Mendell said.

Equally intriguing, he reported, “The tumor cells that received the microRNA were rapidly dying while the normal liver cells were completely spared. These findings, as well as the results of specific tests for liver damage, demonstrated that the microRNA selectively kills the cancer cells without causing any detectable toxic effects on the normal liver or other tissues.”

Mendell points out that the microRNA is normally present at high levels in non-diseased tissues, and especially in the liver. Mendell speculates that this is why healthy cells are very tolerant to therapeutic delivery of even higher levels of this microRNA. However, the sensitivity of tumor cells to this microRNA suggests that loss of this molecule is a critical step as normal cells become cancer cells.

“Since we were able to demonstrate such dramatic therapeutic benefit in this extremely aggressive model of human liver cancer, we are hopeful that similar strategies will be effective for patients with this disease,” says Mendell.

In addition to Joshua Mendell, authors of the paper are Jerry Mendell, K. Reed Clark, Janaiah Kota and Chrystal L. Montgomery, of The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio; and Raghu R. Chivukula, Kathryn A. O’Donnell, Erik A. Wentzel, Hun-Way Hwang, Tsung-Cheng Chang, Perumal Vivekanandan, and Michael Torbenson, all of Johns Hopkins University School of Medicine.

The research was supported by the National Institutes of Health, the Sol Goldman Center for Pancreatic Cancer Research and the Research Institute at Nationwide Children’s Hospital.

Source
Johns Hopkins Medicine

LITTLE FALLS, N.J., June 19 — Certain compounds in green tea may slow the progression of prostate cancer, researchers say.

Men with prostate cancer who consumed polyphenon E — a polyphenol found in green tea — had a significant reduction in biomarkers of cancer progression, James A. Cardelli, PhD, of Louisiana State University, and colleagues reported in the July issue of Cancer Prevention Research.

“These findings support a potential role for polyphenon E in the treatment or prevention of prostate cancer,” the researchers said.

Some studies have shown that green tea may be tied to a reduced incidence of prostate cancer, and its polyphenols have been regarded as a potential cancer therapy.

• Explain that men in a small phase II study who consumed a polyphenol found in green tea had a significant reduction in biomarkers of cancer progression, including VEGF and HGF.

But epidemiological data on green tea consumption are still inconclusive: some studies show possible benefits and others find no effects on risk ratios for cancer, the researchers said.

Last year said FDA announced that the evidence for green tea benefits was inconclusive, because people consume relatively small quantities.

So the researchers conducted an open-label, single-arm phase II clinical trial to determine the effects of short-term supplementation with active compounds in green tea on serum biomarkers in patients with prostate cancer.

The biomarkers included hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and prostate specific antigen (PSA).

They assessed 26 men, ages 41 to 68, who had been diagnosed with prostate cancer and were scheduled for radical prostatectomy.

The men consumed four capsules containing polyphenon E every day until the day before surgery. Four capsules are equivalent to about 12 cups of green tea, the researchers said.

They found a significant reduction in serum levels of the three biomarkers (P<0.03).

A total of 10 of 25 patients had more than a 25% decrease in HGF levels, and six of 25 had a greater than 25% decrease in their VEGF levels.

The researchers said that in vitro, EGCG (the main catechin in polyphenon E) rapidly blocked the production of HGF, and the block “seems to be at the level of transcription.”

EGCG also blocked the production of VEGF, which plays a critical role in the angiogenic process in cancer-associated fibroblasts, they said.

And age, race, and time on drug did not have a significant effect on the changes in serum biomarkers.

Some case studies have suggested that high doses of EGCG may have adverse effects on liver function.

But this study found that all markers of liver dysfunction decreased, five of them significantly: total protein, albumin, aspartate aminotransferase, alkaline phosphatase, and amylase.

“The doses that we used seem to be safe,” Dr. Cardelli said.

This raises a strictly practical question. The patients got results from taking concentrated active ingredients equal to 12 cups of tea daily.

“Does that translate to ‘If I drink 12 cups of green tea a day, will that work?’” Dr. Cardelli asked. “You can speculate, but I don’t know.”

Still, the researchers concluded that the data “support a potential role for polyphenon E in the treatment or prevention of prostate cancer.”

They said that the findings need to be “verified by larger, placebo-controlled clinical trials. The effects of different doses, long-term administration, and combination with other drugs remain to be seen.”

Polyphenon Pharma supplied the polyphenon E used in the trial. The researchers reported no conflicts of interest.

Primary source: Cancer Prevention Research

Source reference:
McLarty J, et al “Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro” Cancer Prev Res 2009; 2(7).

U.S. Representatives Rep. Artur Davis (D-AL), Steve Israel (D-NY) and Mary Jo Kilroy (D-OH) have introduced H.R. 2872, the Medicare Quality Cancer Care Demonstration Act of 2009. H.R. 2872 is a bill that will authorize Congress to direct the Centers for Medicare & Medicaid Services (CMS) to implement the Quality Cancer Care Demonstration (QCCD) project.

The Community Oncology Alliance (COA), a nonprofit group of medical practitioners who deliver cancer care across the country, has been working with the 111th Congress for the QCCD project, described as the “architecture of a solution” to today’s cancer care crisis. Health care reform is President Barack Obama’s top domestic issue, and when it comes to cancer care, it is overwhelmingly critical.

The QCCD is a multi-phased project that involves medical providers collecting data and implementing a patient-centric program that rewards quality cancer care while controlling costs. The objective of the QCCD is to combine two critical patient enhancing components: treatment planning and end of life care.

“As we address the health care crisis in this country, we can’t allow cancer care to fall by the wayside,” said Rep. Artur Davis (D-AL). “This bill would expand the availability and quality of care for millions of cancer patients and is a step in the right direction in closing the inequities in the payment system. This bill will help ensure an adequate level of both early treatment and end of life care for patients facing cancer.”

This national demonstration project would be implemented in phases by CMS. The QCCD would enable COA to assemble oncologists from practices across the country with advanced electronic medical records for cutting edge data to supplement Medicare claims presented to CMS. This structure would lead to a system that ensures quality cancer care while controlling costs.

The QCCD incorporates the fundamental elements in the healthcare reform debate - quality care delivery, evidence based medicine, care coordination, cost control and health information technology.

The increase in drug costs, combined with the decline in Medicare reimbursements and today’s financial crisis, has forced many cancer patients to abandon their treatment. This includes Americans with inadequate or no insurance, as well as seniors who cannot afford to pay the Medicare 20% co-insurance. Approximately 45% of cancer patients are covered by Medicare

“The Quality Cancer Care Demonstration project offers a means of moving forward immediately and the architecture for a solution to the current crisis in cancer care,” said Patrick Cobb, M.D., president of COA and managing partner of Hematology-Oncology Centers of the Northern Rockies in Billings, Montana. “All Americans deserve access to quality, affordable health care. And, before we can repair health care in general, we must fix this broken system.”

Quality Cancer Care Demonstration (QCCD) Project

Over eight months ago, COA convened a task force of community oncologists and medical policy experts to evaluate the crisis of community oncology and public and private payment systems. The months of evaluation, analysis and brainstorming resulted in the QCCD project, a two-phased Medicare demonstration that will allow Congress to direct the Centers for Medicare & Medicaid Services to implement the program. The project is designed to refine quality metrics and aligns incentives in the critical areas of cancer treatment planning and end-of-life care.

In two phases, the QCCD project first involves testing the metrics and reporting systems, and then involves the program implementation. The objective is to collect data to refine quality metrics and the reimbursement structure into a system that enhances quality cancer care while controlling costs.

COA has constructed a program that CMS can implement through the current coding and data collection systems. COA will augment the collected data from practices that have deployed advanced electronic medical record systems. Additionally, COA will propose the QCCD to private payers in an attempt to launch a national initiative designed to enhance the delivery of quality, affordable, and accessible cancer care to all Americans.

About Community Oncology Alliance (COA)

COA is a non-profit organization dedicated solely to community oncology. COA was founded by community oncology to advocate for patients and providers in the community oncology setting, where 84 percent of Americans with cancer are treated. In only six years of existence, COA has mobilized community oncology to become more politically active, and increased awareness on Capitol Hill about the community cancer care delivery system. Additionally, COA has brought together community oncology practices from across the country to share information in order to enhance the effectiveness and efficiency of the cancer care they provide to their patients. Currently, COA is working with the Congress in providing proactive solutions designed to protect the viability of the nation’s cancer care delivery system and patients’ access to quality, affordable cancer care.

The cancer death rate in the U.S. has declined due to earlier detection, the quality of treatment, and the accessibility of cancer care. However, according to the American Cancer Society, men still have an approximately one in two lifetime risk of developing cancer, with a risk of one in three for women

Source: Community Oncology Alliance