Breakthrough-The Frontiers of Cancer Research 


Study Identifies Key Molecules in Multiple Myeloma

Research led by scientists at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) links three molecules to a tumor-suppressor gene that is often turned off in multiple myeloma.

The silenced molecules—miR-192, miR-194 and miR-215—are microRNAs, a class of molecules discovered about a decade ago that are master regulators of many cell processes. This study suggests that reactivating these three molecules triggers expression of the P53 tumor-suppressor gene, which in turn slows the growth and leads to the death of myeloma cells, possibly presenting a new strategy for treating this disease.

"Our findings provide a rationale for the further exploration of these microRNAs as a treatment for multiple myeloma, which has few therapeutic options," says principal investigator CARLO CROCE, MD, professor and chair of Molecular Virology, Immunology and Medical Genetics, and director of the Human Cancer Genetics Program.

CARLO CROCE, MD, professor and chair of Molecular Virology, Immunology and Medical Genetics

Multiple myeloma begins as a benign condition called monoclonal gammopathy of undetermined significance (MGUS). Individuals with MGUS can live many years without treatment, but for unknown reasons this condition can evolve into myeloma. Studies have shown a relationship between P53 and a gene called MDM2. They have also shown that myeloma cells often have unmutated P53 genes but very little P53 protein. P53 protein levels are restored, however, when MDM2 expression is blocked.

Croce says the OSUCCC – James study, which examined the role of microRNA in regulating the P53 pathway in myeloma cells, provides the basis for developing a microRNA-based therapy for this disease.
Published in the journal Cell.

Normal Genetics May Influence Cancer Growth

A person's genetic background—the array of inherited genetic variations—may contribute to DNA changes that occur in tumor cells as cancer develops, an OSUCCC – James study suggests.

Comparing multiple independent tumors from people with squamous cell carcinoma (SCC) for DNA losses and gains in tumor cells, scientists found that the pattern of changes is quite similar in tumors from the same person but quite different in tumors from different individuals. The findings could help identify individuals at greater risk for developing cancer.

AMANDA TOLAND, PhD, Molecular Biology and Cancer Genetics Program

"Our data strongly support the idea that an individual's normal genetic constitution can strongly influence genetic changes that occur when he or she develops cancer," says study leader AMANDA TOLAND, PhD, of the Molecular Biology and Cancer Genetics Program at the OSUCCC – James. "They may also provide another strategy for identifying genetic variations within healthy individuals that increase their odds of developing cancer."

Toland and collaborators analyzed 222 SCC tumors from 135 organ transplant recipients, who as a group are 65 to 250 times more likely to develop SCC than people in the general population. The researchers examined three or more separate tumors from 25 of these individuals.

When they compared the genetic profiles of tumors from the same individual with those from other individuals for DNA copy number changes, they found that the changes in SCCs from the same patient were statistically similar but were significantly different when compared with other patients. They also found that, in some cases, a particular kind of genetic change is preferentially selected in tumors from the same individual.

"Overall," Toland says, "our findings provide strong evidence that an individual's genetic background plays a key role in driving the changes that occur in tumors during cancer development."
Published in the journal Public Library of Science Genetics.

Uncovering Prognostic Clues in Head and Neck Cancer

Tumor cells in the circulating blood of patients with squamous cell carcinoma (SCC) of the head and neck may predict disease recurrence and reduced survival. An increased number of circulating tumor cells (CTCs) also correlates with a worse outcome.

Those are the early findings from an ongoing prospective study of the prognostic importance of CTCs by researchers at the OSUCCC – James.

"These findings suggest the presence of CTCs in the blood is correlated with reduced disease-free survival," says co-first author KRIS JATANA, MD, assistant professor of Otolaryngology – Head and Neck Surgery at Ohio State and Nationwide Children's Hospital. "If these results are supported with continued prospective follow-up, CTCs could be used prognostically to help further individualize therapy."

Currently, no prognostic blood test exists for this malignancy.

To identify CTCs, the researchers first removed normal cells so that only abnormal (cancer) cells remained, a method called negative depletion. They eliminated all of the normal red blood cells by rupturing them, then removed normal white blood cells by labeling them with magnetic nanoparticles and using a magnetic field to pull them out of each sample. After that, they stained and manually counted the abnormal cells.

The study involves 48 patients who underwent surgical inter-vention for SCC of the head and neck. To date, no instances of cancer recurrence or disease-related mortality have occurred in patients with no CTCs, but the study has found a correlation between an increasing number of CTCs and a worse prognosis.
Published in the journal Archives of Otolaryngology, Head and Neck Surgery.

Virus May Battle Brain Tumors Better With Bacterial Enzymes

OSUCCC – James researchers have shown that oncolytic viruses, which are engineered to destroy cancer cells, might be more effective against brain malignancies if equipped with an enzyme that helps them penetrate the tumor.

The enzyme, called chondroitinase, helps the virus work its way through thickets of protein molecules that fill spaces between cells. When tested in animals transplanted with a human glioblastoma, the most common and deadly form of brain cancer, the enzyme-armed virus improved survival by 52 percent compared with controls, and in some cases it eliminated the tumor.

"Our results show for the first time that an oncolytic virus with this enzyme can spread more effectively through the tumor, under-scoring the potential for using chondroitinases to enhance the capacity of oncolytic viruses to destroy cancer cells," says study leader Balveen Kaur, PhD, of the OSUCCC – James Viral Oncology Program.

Derived from the intestinal bacterium Proteus vulgaris, the enzyme removes sugar chains that branch from proteoglycans that fill the narrow spaces between cells. Cutting away these branches helps the virus spread through the tumor.

In this study, Kaur and collaborators injected human glioblastoma cells under the skin of eight mice. They treated the resulting tumors with the enzyme-armed virus. These mice survived an average of 28 days, with two animals remaining tumor-free after 80 days. Control animals, treated with a virus that lacked the enzyme, survived an average of 16 days.

In another experiment, mice with human glioblastomas transplanted into the brain survived 32 days versus 21 days for control animals, an improvement of 52 percent. Again, two animals lived more than 80 days and showed no trace of the tumor afterward.
Published in the journal Clinical Cancer Research.

Loss of Gene Promotes Brain Tumor Development

Research at the OSUCCC – James shows that loss of the NFKBIA gene promotes glioblastoma multiforme, the most common and deadly form of brain cancer. The study, published in the New England Journal of Medicine, also suggests therapies that stabilize this gene may improve survival for certain patients.

Survival of 49 glioblastoma patients in Study Set 7. Estimated median survival for patients with tumors that had high expression of NFKBIA was about 131 weeks, compared with 75 weeks for patients with low NFKBIA expression.

"We show that NFKBIA status may be an independent predictor of survival in certain patients with glioblastoma," says senior co-author ARNAB CHAKRAVARTI, MD, professor and chair of Radiation Oncology and co-director of the Brain Tumor Program. "We also show that this gene plays a key role in glioblastoma behavior and could be useful for predicting treatment outcomes."

An estimated 18,500 new cases of glioblastoma occur annually among Americans and result in 12,760 deaths.

First author MARKUS BREDEL, who holds a joint appointment with Ohio State and at University of Freiburg Medical center, notes that most cases of glioblastoma are driven by overexpression of the EGFR gene, "but our study indicates that loss of the NFKBIA gene is an equally potent driver of glioblastoma development. We found that glioblastomas generally show either abnormally high levels of EGFR or loss of NFKBIA, but not both."

In addition, Chakravarti was principal investigator for an OSUCCC – James study suggesting that certain patients with spinal cord tumors have better long-term survival than others following radiation therapy. This study also indicates that photon-based radiotherapy results in better survival than proton-beam therapy for these tumors.

The researchers say this is the first study to report long-term outcomes of spinal-cord tumor patients treated by modern radiotherapy techniques.

"Our findings need to be verified in a larger number of patients, but they suggest that individuals younger than 54, those with ependymomas and those treated with photon-based versus proton-beam therapy have better overall survival," Chakravarti says. "Perhaps most surprising is that the subset treated by protons appears to do worse, even though these patients have more favorable pretreatment demographics."
Published in the International Journal of Radiation Oncology, Biology, Physics.

MARKUS BREDEL, MD, PhD, adjunct associate professor of Radiation Oncology

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

Molecular Rationale for Combining Agents Against Breast Cancer

A study by researchers at the OSUCCC – James presents a rationale for treating breast cancer using two targeted agents: one that inhibits an overactive, cancer-causing pathway in cancer cells, and one that reactivates silenced tumor-suppressor genes. Both types of agents are being evaluated individually in clinical trials.

In vivo findings demonstrate that two targeted agents are better than one. Huang and his colleagues injected breast cancer cells into mice, followed by either a histone deacetylase inhibitor (DAC), a PI3K inhibitor (LY294002) or both. The combination (red line) inhibited tumor growth better than either agent alone.

"This laboratory and animal study found that abnormal activation of the PI3K/AKT signaling pathway leads to the silencing of a number of tumor-suppressor genes that regulate cell proliferation, survival and motility, and angiogenesis. The study also showed that tumor growth is slowed by combining an agent that inhibits PI3K with a drug that reverses the epigenetic changes that cause gene silencing."

"The link we have uncovered between PI3K/AKT signaling and epigenetic silencing offers a new therapeutic strategy for breast cancer that combines a PI3K/AKT inhibitor and agents that target epigenetic changes," says study leader TIM H-M HUANG, PhD, of the OSUCCC – James Molecular Biology and Cancer Genetics Program.

The activation of one or more oncogenes and the silencing of tumor-suppressor genes are usually considered separate events that together lead to cancer. But this and earlier studies led by Huang show that the two events are sometimes linked.

Huang and colleagues are planning a clinical trial that will investigate the use of combined targeted drugs in metastatic breast cancer.
Published in the journal Cancer Research.

TIM H-M HUANG, PhD, Molecular Biology and Cancer Genetics Program 

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