Research

IBRUTINIB CONTINUES TO SHOW PROMISE AGAINST CLL AND MCL

Clinical studies published in the New England Journal of Medicine suggest
t​he drug ibrutinib shows strong potential as a safe, effective, targeted treatment for patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL), currently incurable cancers. The studies were co-led by researchers at the OSUCCC – James and MD Anderson Cancer Center. One involved a phase Ib/II clinical trial in which CLL patients showed an overall response rate of 71 percent. The other involved a phase II clinical trial in which patients with relapsed or refractory MCL showed an overall response rate of 68 percent. These studies have resulted in FDA approval of ibrutinib for the treatment of patients with relapsed MCL. The CLL study co-leader at Ohio State was John C. Byrd, MD. The MCL study co-leader at Ohio State was Kristie Blum, MD.

LOSS OF TINY MOLECULE MIGHT LEAD TO LIVER CANCER

A study led by the OSUCCC – James showed that the loss of an RNA molecule called miR-122 in liver cells might cause cancer, and that restoring the molecule may slow tumor growth and offer a way to treat the disease. The animal study, published in the Journal of Clinical Investigation, found that when miR-122 is missing, the liver develops tumors resembling hepatocellular carcinoma, the most common liver cancer. However, restoring miR-122 to nearly normal levels by delivering the miR-122 gene to liver cells dramatically reduced the size and number of tumors. “This suggests that miR-122 has a critical tumor-suppressor role in the liver and highlights the possible therapeutic value of miR-122 replacement for some patients,” says study leader Kalpana Ghoshal, PhD.

STUDY IDENTIFIES POSSIBLE ACUTE LEUKEMIA MARKER TREATMENT TARGET

A study led by OSUCCC – James researchers (senior author: Clara D. Bloomfield, MD) identified microRNA-155 as an independent prognostic marker and treatment target in patients with acute myeloid leukemia that has normal- looking chromosomes (called cytogenetically normal acute myeloid leukemia, or CN-AML). Published in the Journal of Clinical Oncology, the study found that when microRNA-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. First author Guido Marcucci, MD, says the findings suggest miR-155 plays a role in CN-AML development and could be a target for an emerging class of drugs designed to inhibit microRNAs.

STUDY REVEALS FIRST EFFECTIVE TREATMENT FOR CHEMO-INDUCED PERIPHERAL NEUROPATHY

OSUCCC – James researchers participated in what investigators believe is the first large phase III clinical trial to find an effective treatment for the pain of chemotherapy-induced peripheral neuropathy, a condition that stems from nerve damage. Some 20-40 percent of cancer patients who receive neurotoxic chemotherapy develop chemotherapy-induced peripheral neuropathy. Published in the Journal of the American Medical Association, this multicenter study – for which Charles Shapiro, MD, was senior author and Electra Paskett, PhD, MSPH, was a co-author – enrolled 231 patients who took either a drug called duloxetine or a placebo (inactive substance) for five weeks. The study concluded that, among patients with chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for five weeks resulted in a greater reduction of pain.​

CANCER WASTING DUE IN PART TO TUMOR FACTORS THAT BLOCK MUSCLE REPAIR

A study at the OSUCCC – James revealed that tumors release factors into the bloodstream that inhibit the repair of damaged muscle fibers, contributing to muscle loss during cancer wasting. The condition, known as cancer cachexia, accompanies certain types of cancer, causes life-threatening loss of body weight and lean muscle mass, and is responsible for up to one-in-four cancer deaths. There is no treatment for the condition, but this study, published in the Journal of Clinical Investigation, points to new strategies and drug targets for treating it. The researchers, led by principal investigator Denis Guttridge, PhD, looked at muscle stem cells that are associated with muscle fibers and are essential for repairing damaged fibers.

NANO DRUG CROSSES BLOOD-BRAIN BARRIER, TARGETS TUMOR CELLS

A nanotechnology drug in early development for treating aggressive brain tumors can cross the blood-brain tumor barrier, kill tumor cells and block the growth of tumor blood vessels, according to a laboratory and animal study led by researchers at the OSUCCC – James. Findings from the study, published in the journal Molecular Therapy, support further development of the drug, called SapC-DOPS. The blood-brain barrier is a tight assemblage of cells that protects the brain from blood toxins but also prevents drugs in the bloodstream from reaching brain tumors. Principal investigator Balveen Kaur, PhD, says SapC- DOPS shows activity in glioblastoma (brain cancer) and other solid tumors in preclinical studies.

STUDY SHOWS HOW STRESS GENE ENABLES CANCER TO SPREAD

OSUCCC – James researchers have linked a stress gene called ATF3 in immune cells to breast cancer metastasis (spread). Public-health studies have shown that stress is a cancer risk factor; the OSUCCC – James investigators say their study suggests that ATF3 may be the crucial link between stress and cancer. Their research suggests that cancer cells, by acting as stress signals, coax immune cells that have been recruited to a tumor to express ATF3, which then promotes the immune cells to act erratically and give cancer an escape route to other areas of the body. The study was published in the Journal of Clinical Investigation. Tsonwin Hai, PhD, was senior author.

TWO REPRESSOR GENES REGULATE CELL ENDOCYCLE

A group of proteins within the E2F gene family may play a crucial role in controlling mitosis, the most common form of cell division, but a study at the OSUCCC – James showed that two family members, E2F7 and E2F8, are vital for regulating a modified form of mitosis called the endocycle. The endocycle enables one cell to produce thousands of copies of its chromosomes with no cell division. This research, published in the journal Nature Cell Biology, showed that E2F7 and E2F8 control the endocycle in liver cells and certain cells of the placenta. Principal investigator Gustavo Leone, PhD, says the study identifies the first transcription factors to regulate the mammalian endocycle – a discovery that could have ramifications for human health and disease.

DELAYED TREATMENT FOR ADVANCED BREAST CANCER HAS PROFOUND EFFECT

A study by researchers at the OSUCCC – James showed that women who wait more than 60 days to begin treatment for advanced breast cancer face significantly higher risks of dying than women who start therapy shortly after diagnosis. Senior author Electra Paskett, PhD, MSPH, says that until this study, published in the Journal of Clinical Oncology, “We didn’t know the profound effect delaying treatment could have.” Researchers retrospectively examined 1,786 women enrolled in the North Carolina Medicaid system who were diagnosed with breast cancer from 2000-2002 and found no difference in survival rates for those who started treatment within 30 or 60 days. But a delay of more than 60 days among women with late-stage disease was associated with an 85 percent higher risk of breast cancer-related death compared with women treated sooner.

NEW AGENT MIGHT CONTROL BREAST CANCER GROWTH AND SPREAD

A study by OSUCCC – James researchers suggests that an unusual experimental drug can reduce breast-cancer aggressiveness, reverse resistance to the drug fulvestrant and improve the effectiveness of other breast cancer drugs. The researchers say their findings, published in the Journal of Experimental Medicine, suggest a new strategy for treating breast cancer. The drug, AS1411, blocks the cell’s production of microRNA molecules, some of which are associated with cancer. Specifically, the drug inhibits a protein called nucleolin that plays a critical role in microRNA maturation. Principal investigator Carlo Croce, MD, says this study supports a novel treatment for breast cancer that reduces cancer aggressiveness and restores drug sensitivity by inhibiting the processing of microRNAs that are highly expressed in cancers.

HPV CAN DAMAGE GENES AND CHROMOSOMES DIRECTLY, STUDY SHOWS

The virus that causes cervical, head and neck, anal and other cancers can directly damage chromosomes and genes where it inserts its DNA into human DNA, as shown in a new study led by OSUCCC – James researchers. Cancer-causing types of human papillomavirus (HPV) have long been known to produce two viral proteins – E6 and E7 – that are essential for cancer development. Here, scientists used whole genome sequencing of human cancer samples to show that fragments of the host genome were removed, rearranged or increased in number at HPV insertion sites. The researchers proposed a “looping” model by which abnormal viral replication may result in the extraordinary damage that occurs to host chromosomes near the sites of HPV integration. Maura Gillison, MD, PhD, and David Symer, MD, PhD, were co-senior authors on the study, published in the journal Genome Research.

PEOPLE WITH ALLERGIES MAY HAVE LOWER RISK OF BRAIN TUMORS

Research at the OSUCCC – James added to a growing body of evidence suggesting a link between allergies and reduced risk of brain cancers called glioma. Published in the Journal of the National Cancer Institute, the study suggests the reduced risk is stronger among women than men, although men with certain allergy profiles also have a lower tumor risk. The study strengthens scientists’ belief that having allergies or a related factor lowers the risk for this cancer. Lead author Judith Schwartzbaum, PhD, says scientists conducting this study analyzed stored blood samples taken from patients decades before they were diagnosed with glioma. Men and women whose blood samples contained allergy-related antibodies had an almost 50 percent lower risk of developing glioma 20 years later compared with people without signs of allergies.

microRNAs DEFINE CHEMORESISTANCE IN OVARIAN CANCER

Despite improvements in detection and therapies, only a small percentage of patients with advanced-stage ovarian cancer survive five years after initial diagnosis with this aggressive disease, which annually causes almost 125,000 deaths in the United States. The high mortality rate stems mainly from the body’s resistance to available therapies. But a study led by the OSUCCC – James, and published in the Proceedings of the National Academy of Sciences, analyzed tumor samples from 198 patients for human microRNAs (miRs). The study found that three microRNAs (miR-484, -642 and -217) can classify patient response to chemotherapy and that miR-484 is involved in controlling tumor angiogenesis (blood vessel formation), indicating an option in treating these patients. Carlo Croce, MD, was principal investigator.

SCREENING INITIATIVE HAS LIFE-SAVING POTENTIAL

The OSUCCC – James launched a statewide initiative to screen newly diagnosed colorectal cancer (CRC) patients and their biological relatives for Lynch syndrome (LS), a major cause of inherited colorectal, ovarian and uterine cancer. This effort, called the Ohio Colorectal Cancer Prevention Initiative (OCCPI), reveals others who may be at risk of developing these cancers so they can take precautionary measures. The initiative − supported by Pelotonia, the annual grassroots bicycle tour that raises millions of dollars for cancer research at the OSUCCC – James − is led by Heather Hampel, a certified genetic counselor who says some 3 percent of CRC cases result from LS, which is characterized by inherited mutations in certain genes. Each CRC patient found to have LS has, on average, an additional three relatives with LS. The OCCPI includes around 40 hospitals throughout Ohio that have implemented the LS screening program.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) 460 W. 10th Avenue, Columbus, OH 43210 Phone: 1-800-293-5066 | Email: jamesline@osumc.edu