Frontiers

Breakthrough Summer 2013 

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CLINICAL IMPLICATIONS
New Agent May Control Breast Cancer Growth and Spread

CARLO CROCE, MD,
professor and chair, Molecular Virology, Immunology and Medical Genetics; director, Human Cancer Genetics and the John W. Wolfe Chair in Human Cancer Genetics

A study led by researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) suggests an experimental drug can slow breast-cancer aggressiveness, reverse resistance to the drug fulvestrant and maybe improve efficacy of other breast-cancer drugs.

Findings from the laboratory and animal study might offer a new strategy for treating breast cancer. The drug, called AS1411, belongs to a class of agents called G-rich aptamers. It works by blocking the cell’s production of microRNA, molecules that help cells control the amount and kinds of proteins they make. Abnormal levels of certain microRNAs are a hallmark of many cancers.

    Specifically, the drug inhibits a protein called nucleolin that plays a critical role in the microRNA maturation process.

    “This study of the role of nucleolin in microRNA regulation has clear clinical implications,” says principal investigator Carlo Croce, MD, director of Human Cancer Genetics at Ohio State and a member of the Molecular Biology and Cancer Genetics Program (MBCG) at the OSUCCC – James.    

    “It supports a novel treatment for breast cancer that reduces cancer aggressiveness and restores drug sensitivity by inhibiting the processing of specific microRNAs that are highly expressed in cancers.”

    First author Flavia Pichiorri, PhD, assistant professor of Hematology and also a member of the MBCG Program, notes that nucleolin is a promising therapeutic target for microRNA modulation in cancer cells.

    “To our knowledge, this is the first large study to show a clear association between nucleolin and specific microRNAs that are causally involved in cancer,” Pichiorri says. “We also believe it’s the first study to show that targeting nucleolin with a G-rich aptamer can control breast-cancer metastasis in an animal model through microRNA regulation.”


Published in the Journal of Experimental Medicine




ENZYME INHIBITION
Study Shows How Vitamin E Can Help Prevent Cancer

CHIN-SHIH-CHEN, PhD,
professor of Medicinal Chemistry and Pharmacognosy, member of the Molecular Carcinogenesis and Chemoprevention
Program, and the Lucius A. Wing Chair of Cancer Research & Therapy


Researchers at the OSUCCC – James have identified an elusive anticancer property of vitamin E that has long been presumed to exist but difficult to find.

Many animal studies have suggested that vitamin E could prevent cancer, but human clinical trials following up on those findings have not shown the same benefit.

In this study, researchers showed in prostate cancer cells that one form of vitamin E inhibits the activation of an enzyme that is essential for cancer cell survival. Loss of the enzyme, Akt, led to tumor cell death. The vitamin had no negative effect on normal cells.

“This is the first demonstration of a unique mechanism of how vitamin E can have some benefit in terms of cancer prevention and treatment,” says lead author Ching-Shih Chen, PhD, professor of Medicinal Chemistry and Pharmacognosy at Ohio State, and an investigator in the Molecular Carcinogenesis and Chemoprevention Program at the OSUCCC – James.

But Chen cautions that taking a typical vitamin E supplement won’t offer this benefit for at least two reasons: The most affordable supplements are synthetic and based predominantly on a form of the vitamin that did not fight cancer as effectively in this study; and the human body can’t absorb the high doses that appear to be required to achieve the anticancer effect.

“Our goal,” Chen says, “is to develop a safe pill at the right dose that people could take every day for cancer prevention. It takes time to optimize the formulation and the dose.” He has filed an invention disclosure with the University, and Ohio State has filed a patent application for the agent.

Vitamin E occurs in numerous forms based on chemical structure; the most commonly known form belongs to a variety called tocopherols. Of the tocopherols tested in this study, the gamma form had the most anticancer potency.

Published in the Journal Science Signaling


SUBSET SIGNATURES
Triple-Negative Breast Cancer Subtypes Identified Using microRNA

CHARLES SHAPIRO, MD
director of Breast Medical Oncology at the OSUCCC – James and professor of Internal Medicine at Ohio State

A large-scale study of triple-negative breast cancer shows that small molecules called microRNAs can be used to define four subtypes of this aggressive malignancy.

The findings, by researchers at the OSUCCC – James who are working with collaborators in Italy, could lead to new screening methods, prognostic markers and perhaps targeted treatments for this aggressive and often-fatal form of breast cancer.

“Treating women with triple-negative breast cancer is challenging because this malignancy can be very different genetically from one patient to another,” says co-senior investigator Charles Shapiro, MD, director of Breast Medical Oncology at the OSUCCC – James and professor of Internal Medicine at Ohio State. “We believe these microRNA signatures define novel subsets of triple-negative breast cancer and offer new insights into the biology of the disease and better ways to treat these patients.”

The microRNAs that compose the signatures are involved in regulating cell growth, proliferation and survival, and also in cell movement and migration.

“These findings strongly suggest that microRNAs play an important role in triple-negative breast cancer and might be used to better identify the most effective treatment for a patient’s tumor,” says co-senior investigator and researcher Kay Huebner, PhD, professor of Molecular Virology, Immunology and Medical Genetics at Ohio State.

“Several of the deregulated microRNAs we found in the cancer samples are involved in chemoresistance or radioresistance. MicroRNA profiles can help us improve and personalize therapies for individual patients,” she says.

Triple-negative breast cancer accounts for about 15 percent of all breast cancers. It is characterized by cancer cells that lack estrogen and progesterone receptors, and by overexpression of the HER2 receptor. For this reason, these tumors do not respond to hormone therapies or HER2-targeted treatments.


Published in the Journal PLOS ONE

 

RE-EMPOWERING P53
Drug Restores Cell Suicide in HPV-Related Head and Neck Cancer

QUINTIN PAN, PhD,

associate professor of Otolaryngology at Ohio State and a member of the Experimental Therapeutics Program at the OSUCCC – James

Researchers have designed a drug to block a newly discovered mechanism by which the human papillomavirus (HPV) causes head and neck cancer. Though more study is needed, they believe the new agent might offer a safer treatment for these tumors when combined with a tapered dose of standard chemotherapy.
 
HPV-positive head and neck cancer has become three times more common since the 1970s, and it could reach epidemic levels in the future, say researchers at the OSUCCC – James who led the study.

“We believe these findings will help meet the real need for more effective and safer therapy for a growing number of HPV-positive head and neck cancer patients,” says principal investigator Quintin Pan, PhD, associate professor of Otolaryngology at Ohio State and a member of the Experimental Therapeutics Program at the OSUCCC – James.

The research, which mainly used head and neck cancer cells, shows that a protein produced by the virus blocks a protein made by the host cell. The cell protein, called p300, regulates a gene called p53 that both controls cell division and protects the body against cancer by causing cells to die before they become malignant.

By blocking the cell protein, HPV forces the host cell to live instead of die and to proliferate and form tumors. The prospective new drug, called CH1iB, prevents the viral protein from binding with the cell protein. This restores the function of the p53 tumor-suppressor gene and triggers the death of the cancer cells.

“Our study revealed a new mechanism for p53 inactivation in HPV-positive head and neck cancer, and this allowed us to develop an agent that disrupts that interaction and reactivates p53 in this disease,” Pan says. “Our preclinical studies show CH1iB can reactivate p53 and eliminate HPV-positive head and neck cancer cells.”


Published in the journal Oncogene.



MOLECULAR MIGHT
Small Molecules in Blood May Gauge Radiation Effects After
Exposure

ARNAB CHAKRAVARTI, MD,
professor and chair of the Department of Radiation Oncology, co-director of the Brain Tumor Program, and The Max Morehouse Chair in Cancer Research

OSUCCC – James researchers have identified molecules in the bloodstream that might accurately gauge the likelihood of radiation illness after exposure to ionizing radiation.

 The animal study shows that X-rays or gamma rays alter the levels of certain molecules called microRNA in the blood in a predictable way. If verified in humans, the findings could lead to new methods for rapidly identifying people at risk for acute radiation syndrome after occupational exposures or accidents such as the Fukushima Daiichi nuclear reactor incident.

    The microRNA markers might also help doctors plan radiation therapy for individual patients by taking into account how different people respond to radiation treatment, the researchers say.

    “Our study reports the identification of a panel of microRNA markers in mice whose serum levels provide an estimate of radiation response and of the dose received after an exposure has occurred,” says senior author Arnab Chakravarti, MD, professor and chair of the Department of Radiation Oncology at Ohio State, where he also is co-director of the Brain Tumor Program.

    “Accurate dose evaluation is critical for making medical decisions and the timely administration of therapy to prevent or reduce acute and late effects,” Chakravarti says.

    The findings might also one day allow doctors to evaluate radiation toxicity during the course of therapy based on an individual’s biology. “This would particularly benefit leukemia and lymphoma patients who receive total body irradiation in preparation for stem-cell transplantation,” Chakravarti says.

    First author Naduparambil Jacob, PhD, a research assistant professor of Radiation Oncology, says the study could be an important step in the development of biological dosimetry, or biodosimetry, a technology for identifying people at risk for acute radiation illnesses that develop within weeks of radiation exposure, and for cancers and degenerative diseases that can occur months or years later.

Published in the journal PLOS ONE.


HEMATOLOGIC MALIGNANCIES MARKER UNMASKED
Study Identifies Possible Acute Leukemia Marker and Treatment Target

GUIDO MARCUCCI, MD,
leukemia specialist, associate director for translational research at the OSUCCC – James, and The Charles Austin Doan Chair of Medicine

A study led by researchers at the OSUCCC – James has identified microRNA-155 as an independent prognostic marker and treatment target in patients with acute myeloid leukemia (AML) that has normal-looking chromosomes (i.e., cytogenetically normal AML, or CN-AML).

The study found that, when microRNA-155 (miR-155) is present at abnormally high levels in CN-AML cells, patients are less likely to have a complete remission, and they experience a shorter disease-free period and shorter overall survival. The effect is independent of other known prognostic gene mutations present in the cells.

The findings suggest that miR-155 plays a pivotal role in CN-AML development and could be a target for emerging drugs designed to inhibit microRNAs, says first author Guido Marcucci, MD, a leukemia specialist and associate director for translational research at the OSUCCC – James.

“MiR-155 would be relatively easy to measure at diagnosis,” Marcucci says. “We believe it will prove to be a good marker for stratifying patients according to recurrence risk and a good target for emerging compounds designed to inhibit microRNAs.”

 “Overall, our findings indicate that miR-155 expression is a strong and independent prognostic marker in CN-AML, and they provide clinical validation of data from preclinical models that support a crucial role of miR-155 in leukemia,” says principal investigator Clara D. Bloomfield, MD, a Distinguished University Professor who serves as cancer scholar and senior adviser to the OSUCCC – James.

The researchers also note that, because a molecule called NF-kB is believed to regulate miR-155, treatments that inhibit that molecule might also help patients with high miR-155 levels.

Cells use microRNA molecules to help regulate the kinds and amount of proteins they make. Abnormal levels of certain microRNAs are likely to play a key role in cancer development. Abnormally high expression of miR-155 is associated with lymphoma, aggressive chronic leukemias and certain solid tumors, and microRNA levels have been associated with patient survival.

Published in the  Journal of Clinical Oncology with an accompanying editorial and an “Understanding the Pathway” article

 






 
30-Jul-13
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