miRNAs may generate new insights on cancer and possible future treatments

Scientists are methodically unlocking the biological processes that lead to cancer, and recent discoveries with microRNAs (miRNAs) are revolutionizing their understanding and leading to clinical trials of potentially effective treatments.

Nobel Laureate Phillip A. Sharp, Ph.D., institute professor at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge, will host a press conference on some of the recent research on miRNAs, which will be unveiled at the American Association for Cancer Research 101st Annual Meeting 2010.

"These abstracts are part of a revolution in cell biology that began in 2001 when the importance of miRNAs was recognized," said Sharp. "The science of miRNAs and related small RNAs will continue to generate new insights into cancer and possible future treatments."

The press conference will take place on Monday, April 19, at 8:30 a.m. ET in room 142 of the Walter E. Washington Convention Center, in Washington, D.C. Reporters who cannot attend in person can call in using the following information:

U.S. and Canada: (888) 282-7404
International: (706) 679-5207
Access Code: 59333848

Sharp said the study of miRNAs is a prime example of how high-level biology can play an important role in future patient care.

"There are currently highly watched clinical trials about the use of small RNAs in treating liver cancer. While we don't yet know if these trials will be successful or not, clearly the science is progressing to the point where clinical ideas are being tested," he said.

The following abstracts will be presented at the press conference:

4037. Higher expressions of miR-21, miR-106a, miR-181b and miR-203 are associated with poor prognosis in colorectal cancer patients

Researchers have identified a set of microRNAs (miRNAs) linked with a poor prognosis for colorectal cancers for black and white patients and a set that is associated with poor outcomes only for blacks.

Liselle Bovell, a graduate student working in the laboratory of Upender Manne, Ph.D., an associate professor in the department of pathology at the University of Alabama at Birmingham, said overexpressions of miR-21 and miR-106a are associated with an overall poor prognosis and that overexpressions of miR-181b and miR-203 are associated with poor outcomes in blacks.

"This knowledge gives us solid, prognostic information, so we can better manage patients with these cancers early after diagnosis or surgery," said Bovell.

MiRNAs are a family of small non-coding RNAs that regulate expression of various genes. Bovell said researchers have an increased interest in them because they are small, easy to handle and specific in their functions.

For the current study, Bovell examined a panel of the following microRNAs: miR-20a, miR-21, miR-106a, miR-181b and miR-203 in 104 blacks and 114 whites. All five of these miRNAs had higher levels in colorectal cancers compared with non-cancerous control tissue.

Increased levels of miR-181b and miR-203 were linked with shorter patient survival among blacks, but not whites. For both blacks and whites, increased expressions of miR-21 and miR-106a were linked with poor survival.

Increased expression of miR-20a was not linked with survival in either whites or blacks.

1946. Identification of miRNAs that contribute to melanoma brain metastasis

Results of an ongoing study expand the understanding of the mechanisms that control melanoma brain metastasis by showing several microRNAs (miRNAs) that are important mediators of metastasis.

These findings, which will be presented in full at the AACR 101st Annual Meeting 2010, may suggest potential new therapeutic targets.

"Specific components of the miRNA brain signature could have prognostic potential, and be able to identify at early stages of the disease melanoma patients at higher risk of developing brain metastasis," said Eva M. Hernando, Ph.D., assistant professor in the department of pathology and co-director of the M.D./Ph.D. program at NYU School of Medicine and member of the NYU Cancer Institute.

Patients with melanoma brain metastasis have a poor survival rate and are often excluded from clinical trials. There is currently no effective treatment for this devastating malignancy, according to Hernando.

Since little is known about the molecular mechanisms that govern this cancer's spread to the brain, Hernando and colleagues investigated the role for specific miRNAs in vitro and in vivo in the mediation and facilitation of melanoma brain metastasis in mice.

"Our study sheds light on previously unexplored mechanisms of miRNAs' role in the mediation of melanoma brain tropism," said Hernando.

While some miRNAs increased the metastatic potential of melanoma cells and the cells' ability to adhere to brain endothelial cells, other miRNAs contributed to the ability of the cells to invade the brain through the blood-brain barrier, according to Hernando. Alterations in another miRNA increased the ability of melanoma cells to reach the brain in mice.

"Over the past few years, more and more reports have shown significant and important roles for miRNAs in normal physiological processes and in several pathologies including cancer," said Hernando. "It was not surprising that miRNAs played a functional role in this process. However, we were pleasantly surprised to learn that our miRNA signature was validated in an independent cohort of samples."

5698. MicroRNA-31 acts as an oncomir in lung cancer by repressing specific tumor suppressors

MicroRNA-31 (miR-31) repressed specific tumor suppressors and, therefore, may be a novel pharmacologic target for lung cancer therapy and chemoprevention.

"We have uncovered a previously unrecognized oncogenic microRNA in mouse and human lung cancers, miR-31, which exerts its effects by repressing the expression of specific tumor suppressors," said Xi Liu, Ph.D., who was a graduate student in pharmacology and toxicology at Dartmouth Medical School at the time of the study. Liu is currently a postdoctoral fellow at the National Cancer Institute, National Institutes of Health.

MicroRNAs (miRNAs) encode small RNAs that regulate gene expression. These are useful to improve classification, diagnostic and prognostic information for cancer. Liu and colleagues conducted a study to identify miRNAs that are overexpressed in lung cancers compared with those of normal lung tissues, and to identify those that function as cancer-promoting miRNAs.

The researchers identified functionally important miR-31 target genes that included two tumor suppressors: large tumor suppressor 2 (LATS2) and PP2A regulatory subunit B alpha isoform (PPP2R2A). Expression of miR-31 was inversely related to LATS2 and PPP2R2A in both mouse and human lung cancers, according to Liu.

In a validation study, researchers detected 10 abundantly overexpressed miRNAs in a mouse model, then used human lung cancers to determine whether the same 10 were overexpressed. Findings showed three miRNAs were significantly overexpressed — miR-31, miR-136 and miR-376a.

"It was surprising that knock-down of only miR-31 repressed growth of mouse and human lung cancer cells and inhibited lung cancer formation in mice," Liu said.

Additionally, the tumor suppressors were repressed by miR-31 overexpression and substantially increased by miR-31 knock-down, which is a good predictor of loss of oncogenicity, according to Liu.

4033. MiR-21 upregulation in breast cancer cells leads to PTEN loss and Herceptin resistance

Scientists at the University of Texas M. D. Anderson Cancer Center have identified a microRNA (miRNA) that could potentially separate the patients who will respond to Herceptin from those who will not.

Herceptin was approved to treat HER2 positive breast cancer in 1998 and is considered by many to be a revolutionary therapy. However, only about 35 percent of patients who receive Herceptin as a single agent will respond to the therapy.

"If we know in advance who is going to respond to treatment, then this could possibly save patients from undergoing this treatment unnecessarily," said Sumaiyah K. Rehman, a third-year graduate student in the lab of Dihua Yu, M.D., Ph.D., Hubert L. and Olive Stringer distinguished chair in basic science, professor and deputy chair of the department of molecular and cellular oncology and director of the cancer biology program at the University of Texas M. D. Anderson Cancer Center.

Herceptin has been linked with heart problems in 2 percent to 7 percent of cases, and patients often have to weigh the risk of heart disorders against the risk of their continuing cancer.

In the current study, scientists found that breast cancer cells with increased miR-21 and reduced PTEN expression were significantly more resistant to Herceptin than control cells. PTEN loss had been previously linked to Herceptin resistance in another study published from the same group and confirmed by other research groups.

The scientists further tested this finding in patients and found that high levels of miR-21 were significantly correlated with poor response to Herceptin. Rehman said she would continue her study to better understand the mechanisms of miR-21-mediated resistance.

"MiRNAs have been reported to control up to 35 percent of our genome, so there are many discoveries remaining," said Rehman. "This is one drop of information in the bucket of knowledge that is hardly full in what we can learn."