Study Urges Caution With Lenalidomide Dosage
By MITCH PHELPS, MD,
OSUCCC-James Experimental Therapeutics Program
A multiple myeloma study at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) unexpectedly showed that lenalidomide interacts with a protein in cells, affecting the drug’s dosage level.
Lenalidomide is an anti-inflammatory, and more than 390 clinical trials have been initiated to study its activity in cancer and other diseases.
This phase I clinical trial found that lenalidomide interacts with P-glycoprotein (Pgp), a molecule that pumps potentially toxic chemicals out of cells and aids in removing these chemicals from the body. Abnormally high levels of Pgp in cancer cells can be an important cause of drug resistance for many cancer patients.
The findings could lead to safer dosing of lenalidomide in a variety of diseases.
“This is the first report showing that lenalidomide interacts with Pgp, and our clinical data suggests this may be an important consideration for proper dosing of the drug,” says study leader Mitch Phelps, PhD, of Ohio State’s College of Pharmacy. “Some toxicities induced by lenalidomide can be severe and life-threatening.”
The clinical trial, which involved 21 patients with relapsed multiple myeloma, combined lenalidomide with temsirolimus, a drug that researchers knew from the start interacted with Pgp. During the study, lenalidomide levels in patients’ blood were often higher than expected, and some patients experienced such side effects as electrolyte imbalances and rashes that were also greater than expected.
To the investigators’ surprise, laboratory experiments showed that lenalidomide was removed from cells by Pgp, and the rate of removal was reduced when temsirolimus was included in the experiments. That suggested the two drugs interact via Pgp and potentially explained the altered lenalidomide levels in patients’ blood.
Phelps says pharmacokinetic interaction between the two agents, along with greater side effects than expected, led researchers to conclude that the interaction of the agents with Pgp may cause increased toxicity.
Published in the Journal of Clinical Oncology.
Immunogene Therapy Plus Standard Treatment Found Safe
By E. ANTONIO CHIOCCA, MD, PhD
professor and chair of Neurological Surgery and co-leader of the OSUCCC-James Viral Oncology Program
Researchers at Ohio State have learned through a clinical trial that a type of gene therapy is safe for treating a deadly brain cancer, even when combined with radiation therapy..
The phase I-B trial, conducted at the OSUCCC – James and at Methodist Hospital in Houston, involved a novel treatment that uses an adenovirus vector called AdV-tk. The vector is taken up by cancer cells, where it activates a drug that kills the cells. The vector is applied in the operating room after removal of tumors such as glioblastoma multiforme, the most common and dangerous form of brain cancer.
The findings suggest that this therapy might also stimulate an immune response against the tumor.
"This is the first time a gene therapy approach was combined with radiation in patients with a newly diagnosed glioblastoma," says first author E. Antonio Chiocca, MD, PhD, professor and chair of Neurological Surgery at Ohio State. "There had been a concern that combining these two treatments could be too toxic, but this was not the case. We don't know yet if this will improve survival, but these findings are encouraging."
Glioblastomas annually occur in about 18,500 Americans and kill nearly 13,000. Glioblastoma multiforme is the most common and lethal form of the malignancy, with an average survival of 15 months after diagnosis.
The tumors often recur because cancer cells typically migrate into adjacent brain tissue. This study, which involved 10 patients with glioblastoma multiforme and two with anaplastic astrocytoma, examined an immunogene therapy approach that is designed to kill these undetected cancer cells and prevent recurrence.
In addition to improved overall survival, the study revealed a significant rise in T lymphocytes in the tumors, suggesting that the gene therapy stimulated an immune response against the tumor, producing an "immunogene therapy" effect.
Published in the Journal of Clinical Oncology.
Starving Cancer Cells of Cholesterol Could Help Treat Glioblastomas
By DELIANG GUO, PhD
assistant professor of Radiation Oncology
Research suggests that blocking cancer cells' access to cholesterol may offer a new strategy for treating glioblastoma, the most common and deadly form of brain cancer, and perhaps other malignancies.
This treatment could be appropriate for tumors with a hyperactive PI3K signaling pathway, which accounts for up to 90 percent of glioblastoma cases.
Investigators at Ohio State and UCLA's Jonsson Comprehensive Cancer Center who led the study discovered that the hyperactive
signaling pathway is linked to cholesterol metabolism, and that inhibiting this pathway leads to the death of glioblastoma cells in an
"Our research shows that
the tumor cells depend on large
amounts of cholesterol for
growth and survival, and that
pharmacologically depriving tumor
cells of cholesterol may offer a
strategy for treating glioblastoma,"
says first author Deliang Guo, PhD,
of the Department of Radiation
Oncology at Ohio State.
"This study uncovers a mechanism that links a common oncogene with altered cell metabolism, and it potentially offers a strategy for blocking that mechanism and causing specific tumor-cell death without significant toxicity," says principal investigator Paul Mischel, MD, professor of Pathology at UCLA and adjunct professor of Radiation Oncology at Ohio State. "Our findings suggest that developing drugs to target this pathway may lead to more effective treatments for patients with this cancer."
Glioblastomas are difficult
to surgically remove because
malignant cells invade surrounding
brain tissue. Also, genetic
differences make some glioblastoma
cells in the tumor resistant to
chemo- and radiation therapy.
"Glioblastomas are among the most treatment-resistant of cancers, so new strategies are greatly needed," Guo says.
Published in the Journal of Clinical Oncology.
TWO FOR ONE
Novel Technique Reveals Both Gene Number & Protein Expression
ARNAB CHAKRAVARTI, MD
Max Morehouse Chair in Cancer Research, and a member of the OSUCCC-James Experimental Therapeutics Program
Researchers have discovered a
fluorescence microscopy technique
for simultaneously visualizing gene
number and protein expression in
The new technique, called the
fluorescent in situ gene protein
assay, combines traditional
fluorescent in situ hybridization
(FISH) with the in situ proximity ligation assay, which is capable
of resolving individual protein
The technique could permit a detailed analysis of the relationship between gene status and expression of the corresponding protein in cells and tissues. Study leaders say this may bring a clearer understanding of cancer and other complex diseases.
"To my knowledge, this is the first technique that allows us to concurrently address gene activity and corresponding protein expression in the same cells," says co-principal investigator Arnab Chakravarti, MD, chair of Radiation Oncology at Ohio State and co-director of the Brain Tumor Program at the OSUCCC – James. "The ability to resolve gene- and protein-expression changes across a tumor could help us understand what drives tumor behavior overall."
For this study, principal investigator Markus Bredel, MD, PhD, associate professor at the University of Alabama-Birmingham and adjunct associate professor of Radiation Oncology at the OSUCCC – James, along with Chakravarti and their collaborators, first assayed fixed human glioblastoma tumor cells, then paraffin-embedded human glioblastoma tissue. In both cases, they assayed for overexpression of a mutant form of the epidermal growth factor receptor gene, EGFRvIII, and for levels of its truncated protein in glioblastoma.
"This method has potential to perform a detailed analysis of the relationship between cancer gene status and corresponding protein expression in cells and tissues," Bredel says. "We demonstrate that the fluorescent in situ gene protein assay methodology is capable of resolving cancer gene and protein patterns simultaneously on a cell-by-cell basis, which is
particularly important in heterogeneous diseases such as cancer."
Published in the journal Neuro-Oncology
Lower Catalase Level Might Explain Higher Skin-Cancer Rate
(above) GREGORY LESINSKI, PhD
OSUCCC-James Innate Immunity Program
(right) TATIANA OBERYSZYN, PhD
OSUCCC-James Carcinogenesis and Chemoprevention Program
Men are three times more likely than women to develop a common form of skin cancer, and a study by researchers at the OSUCCC – James may help explain why. The investigators found that male mice had lower levels of an important skin antioxidant than female mice and higher levels of certain cancer-linked inflammatory cells.
The antioxidant, a protein called catalase, inhibits skin cancer by mopping up hydrogen peroxide and other DNA-damaging reactive-oxygen compounds that form during exposure to ultraviolet B light (UVB), a common source of sunburn and cancer-causing skin damage.
The findings suggest that women may have more natural antioxidant protection in the skin than men, perhaps raising men's risk of skin cancer, say study co-leaders Gregory Lesinski, PhD, a member of the OSUCCC – James Innate Immunity Program, and Tatiana Oberyszyn, PhD, of the OSUCCC – James
Molecular Carcinogenesis and Chemoprevention Program.
The UVB exposure also caused an inflammatory white-blood-cell population called myeloid-derived suppressor cells to migrate from the bone marrow into the exposed skin. Higher numbers of these cells moved into the skin of male mice than female mice.
"These cells might be a novel source of UVB-induced immune suppression," says first author Nicholas Sullivan, a research scientist in Oberyszyn's lab. The research suggests that these UVB-induced inflammatory cells contribute to the genesis of skin tumors and perhaps other tumors rather than simply facilitating cancer progression, as generally thought, Sullivan notes.
The researchers conducted the study using a strain of hairless mice that develops squamous cell carcinoma of the skin – the second most common skin cancer in humans – when exposed to UVB.
Published in the Journal of Investigative Dermatology.
HEREDITARY CANCER SYNDROME
Researchers Discover Hereditary Predisposition to Melanoma of the Eye
(left) FREDERICK H. DAVIDORF, MD
professor emeritus of Ophthalmology at Ohio State
(right) MOHAMED H. ABDEL-RAHMAN, MD, PhD
assistant professor of Ophthalmology at Ohio State
Ohio State University researchers have discovered a hereditary cancer syndrome that predisposes certain people to a melanoma of the eye, along with lung cancer, brain cancer and possibly other cancers.
An inherited mutation in a gene called BAP1 (BRCA1- associated protein-1) causes the hereditary syndrome, researchers say. The findings suggest that BAP1 mutations cause the disease in a small subset of patients with hereditary uveal melanoma and other cancers.
The uvea involves the iris, ciliary body and choroid layer of the eye. Uveal melanoma is the most common eye tumor in adults. It arises from pigmented cells called melanocytes that reside within the uvea, giving color to the eye.
"We are describing a new cancer genetic syndrome that could affect how patients are treated," says first author and cancer researcher Mohamed H. Abdel-Rahman, MD, PhD, assistant professor of Ophthalmology and of Medicine in the Division of Human Genetics at Ohio State.
"We are working with researchers at Nationwide Children's Hospital to develop a clinical test to screen for the BAP1 mutation," he says.
The research involved 53 unrelated uveal melanoma patients with high risk for hereditary cancer. Of these patients, three had germline variants in BAP1.
Study leader Frederick H. Davidorf, MD, professor emeritus of Ophthalmology at Ohio State, explained that BAP1 seems to play an important role in regulating cell growth and proliferation, and that loss of the gene helps lead to cancer.
"If our results are verified, it would be good to monitor these patients to detect these cancers early when they are most treatable," says Davidorf, who treats ocular oncology patients at Ohio State along with Colleen Cebulla, MD, PhD.
The findings are reported in the Journal of Medical Genetics.