Frontiers

BREAKTHROUGH Winter 2014 

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CLINICAL IMPLICATIONS
New Aent Shows Promise in CLL and MCL
















JOHN C. BYRD, MD,
professor and director of the Division of Hematology, and a CLL specialist at the OSUCCC – James














KRISTIE BLUM, MD,
associate professor in the Division of Hematology and head of the OSUCCC – James lymphoma program

The New England Journal of Medicine (NEJM) reported on exciting findings from two studies co-led by researchers at the OSUCCC – James and MD Anderson Cancer Center regarding the targeted experimental drug ibrutinib as an effective treatment for patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL).

The articles reported the outcome of two phase II clinical trials of ibrutinib, which is showing exceptional effectiveness against both malignancies.

The CLL study co-leader at Ohio State was John C. Byrd, MD, professor and director of the 

Division of Hematology, and a CLL specialist at the OSUCCC – James. The Ohio State co-leader of the MCL study, which involved 18 sites, was Kristie Blum, MD, associate professor in the Division of Hematology and head of the OSUCCC – James lymphoma program. NEJM first published the two studies together online with an accompanying editorial. The CLL study and the MCL study were then featured in the July 4 and Aug. 8 NEJM print editions, respectively. Read more online.


GENE ENABLER
Stress Gene Facilitates Breast Cancer Metastasis

TSONWIN HAI, PhD,
professor of Molecular and Cellular Biochemistry


In an unexpected finding, scientists have linked the activation of a stress gene in immune-system cells to breast cancer metastasis and patient outcome.

Senior author and OSUCCC – James researcher Tsonwin Hai, PhD, professor of Molecular and Cellular Biochemistry, says the study suggests that the gene, called ATF3, may be a crucial link between stress, cancer and a tumor cell’s ability to metastasize.

The results provide important insights into how tumor cells co-opt immune cells to enhance breast cancer metastasis, and they suggest that the stress gene could be a valuable drug target for inhibiting metastasis, Hai says. Additional research must confirm these results. Previous public health studies have shown that stress is a risk factor for cancer, and researchers already knew that ATF3 is activated, or expressed, when cells are stressed. Under typical circumstances, ATF3 activation can cause normal and benign cells to self-destruct if stressors such as irradiation or a lack of oxygen irrevocably damage the cells.

This research suggests that cancer cells coax immune cells present in the tumor to express ATF3. This then somehow causes the immune cells to act erratically, enabling tumor cells to escape to other areas of the body.

Hai and her colleagues first linked ATF3 expression in tumor-associated immune cells to worse outcomes among a sample of almost 300 breast-cancer patients. They followed that with animal studies and found that mice lacking ATF3 had fewer metastatic tumors to the lungs than did normal mice that expressed the gene.


Published in the Journal of Clinical Investigation.


ANTICANCER PEPTIDES
HER1 Receptor Targeted for Peptide Cancer Vaccine,Therapeutic Agents

PRAVIN KAUMAYA, PhD,
director of the Division of Vaccine Development and professor of Medicine, of Obstetrics and Gynecology, of Molecular and Cellular Biochemistry, and of Microbiology at Ohio State.

OSUCCC – James researchers led a study focused on the HER1/EGFR receptor as a target for peptide vaccine and therapeutic agents.
HER1 is a member of the epithelial growth factor (EGF) family of cell-surface receptors. The family, which includes the HER2 receptor, plays a central role in the development of a variety of human cancers. It is important for cancer-cell growth and metastasis and an indicator of poor patient survival.

The study, led by Pravin Kaumaya, PhD, director of the Division of Vaccine Development at the OSUCCC – James, identified two regions on the HER1 receptor as potential targets for cancer vaccine or therapeutic peptides. The two regions, defined as sequences 382–410 and 418–435, were the most specific and raised the strongest immune response in test animals.

“The findings could lead to novel peptide vaccines and mimetic inhibitors that target HER1 in tumors of the breast, lung, colon, and head and neck,” says Kaumaya, who is also professor of Medicine of Obstetrics and Gynecology, of Molecular and Cellular Biochemistry, and of Microbiology at Ohio State.

They might also overcome many of the significant shortcomings of antibody-based drugs such as cetuximab, he notes. These peptide agents, which are small proteins consisting of 10 to 50 amino acids, might be safer, more effective and less costly than the monoclonal-antibody-based drugs and small-molecule inhibitors now used to treat many malignancies, Kaumaya says.

“Peptide agents might enable the development of combination immunotherapies that avoid the mechanisms of resistance or secondary treatment failures sometimes experienced with antibody treatment,” Kaumaya says.

NIH/National Cancer Institute grant CA084356 supported this research.

Published in the Journal of Immunology.

 

MicroRNA TUMOR-SUPPRESSOR
A preclinical study led by OSUCCC – James researchers shows that microRNA-486 is a potent tumor-suppressor in lung cancer

PATRICK NANA-SINKAM, MD

associate professor of Medicine and a researcher with the OSUCCC – James Molecular Biology and Cancer Genetics Program

A study led by OSUCCC – James researchers found that microRNA-486 (miR-486) directly targets the insulin growth-factor pathway, which is important for cell survival and proliferation. Alterations in the pathway are believed to play an early role in tumor initiation and progression.

The molecule helps regulate proliferation and migration and the induction of programmed cell death, or apoptosis, in lung-cancer cells.

MicroRNAs are a class of short, non-coding RNAs that regulate the translation or degradation of messenger RNA and therefore the proteins that cells make. Certain microRNAs are frequently dysregulated in cancer.

The researchers further found that miR-486 is itself regulated by the tumor-suppressor gene p53, the most frequently altered gene in human cancers, and that activity of miR-486 is partially dependent upon functional p53. The study suggests that miR-486 might serve as a biomarker for lung cancer that is likely to respond to insulin-growth-factor inhibitors.

“MiR-486 appears to be a biomarker for lung cancer, but its mechanisms of action remain unclear,” says co-corresponding author Patrick Nana-Sinkam, MD, associate professor of Medicine and a researcher with the OSUCCC – James Molecular Biology and Cancer Genetics Program. “These findings show that miR-486 serves a tumor-suppressor function in lung cancer, and that miR-486 action is partially dependent on p53.”

The partial reliance of one tumor suppressor on another was a surprise, says principal investigator and co-corresponding author Carlo M. Croce, MD, director of human cancer genetics at Ohio State and the John W. Wolfe Chair in Human Cancer Genetics at the OSUCCC – James. “We don’t know yet what implications, if any, this might have for the development of targeted therapies.”

NIH/National Cancer Institute grant CA152758 supported this research.


Published in the Proceedings of the National Academy of Sciences.



SARCOMA SUPPRESSOR
Loss of MicroRNA Decoy Might Contribute to Development of Soft-Tissue Sarcoma

DENIS GUTTRIDGE, PhD,
professor of Molecular Virology, Immunology and Medical Genetics, and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program

OSUCCC – James researchers have discovered a novel mechanism responsible for the loss of a critical tumor-suppressor gene in rhabdomyosarcoma and other soft-tissue sarcomas. These rare cancers strike mainly children and often respond poorly to treatment; their cause is largely unknown. The discovery of the mechanism could lead to more effective therapies for these malignancies, says principal investigator Denis Guttridge, PhD, professor of Molecular Virology, Immunology and Medical Genetics, and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program.
    Guttridge and his colleagues found that the tumor-suppressor gene called A20 is silenced not by mutation but because a second molecule is lost, a small molecule called microRNA-29 (miR-29). They also found that miR-29 normally protects A20 from destruction. When miR-29 is absent, A20 is degraded. Loss of A20, in turn, leads to a dramatic rise in levels of a protein called NF-kB and to tumor progression.

    “NF-kB is a known tumor promoter, but we don’t know why it is upregulated in many cancers,” Guttridge says. The findings identify NF-kB as a therapeutic target in sarcoma, and A20 and miR-29 as potential biomarkers for sarcoma.
First author Mumtaz Yaseen Balkhi, PhD, notes that the findings move research closer to developing miR-29 therapy against NF-kB activation. “Other labs have tried to block NF-kB signaling using pharmacological inhibitors because of the perceived benefits for cancer treatment,” he says. “We provide an alternative route, showing that microRNA can do the same job by acting as a decoy.”

    “The loss of the A20 tumor-suppressor gene because the microRNA decoy is absent may represent another mechanism to explain why NF-kB is constitutively active in sarcoma cancers,” Guttridge says.

    Soft-tissue sarcomas make up about 15 percent of pediatric cancer cases. In 2013, about 11,400 cases of sarcoma were expected in the United States, and about 4,400 Americans were expected to die from the malignancy.

Published in the journal Science Signaling.


GLIOBLASTOMA
Nano Drug Crosses Blood-Brain Tumor Barrier, Targets Brain-Tumor Cells and Blood Vessels

BALVEEN KAUR, PhD,
professor and vice chair for Research of Neurological Surgery

An experimental drug in early development for aggressive brain tumors can cross the blood-brain tumor barrier, kill tumor cells and block the growth of tumor blood vessels, according to a study led by OSUCCC – James researchers.

The laboratory and animal study also shows how the agent, called SapC-DOPS, targets tumor cells and blood vessels. The findings support further development of the drug as a novel treatment for brain tumors.

SapC-DOPS (saposin-C dioleoylphosphatidylserine), is a nanovesicle drug that has shown activity in glioblastoma, pancreatic cancer and other solid tumors in preclinical studies. The nanovesicles fuse with tumor cells, causing them to self-destruct by apoptosis.

Glioblastoma multiforme is the most common and aggressive form of brain cancer, with a median survival of about 15 months. A major obstacle to improving treatment for the 3,470 cases of the disease that were expected in the United States last year is the blood-brain barrier, which protects the brain from toxins in the blood but also keeps drugs in the bloodstream from reaching brain tumors.

“Few drugs have the capacity to cross the tumor blood-brain barrier and specifically target tumor cells,” says principal investigator Balveen Kaur, PhD, professor and vice chair for Research of Neurological Surgery.
 
Kaur and her colleagues showed that SapC-DOPS does both and inhibits the growth of new tumor blood vessels, suggesting that the agent might one day be an important treatment for glioblastoma and other solid tumors, Kaur says. In addition, the agent sensitized hypoxic cells to killing by conventional treatment.

The findings, Kaur says, suggest that SapC-DOPS could have a synergistic effect when combined with chemotherapy or radiation therapy.

NIH/National Cancer Institute grants CA158372, CA136017, CA136017 and CA171733 supported this research.


Published in the Journal Molecular Therapy

 
16-Jan-14
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