Ohio State Research Plays Large Role in FDA Approval of CLL Drug

On Feb. 12, 2014, the U.S. Food and Drug Administration expanded the approved use of the drug ibrutinib (Imbruvica®) to treat certain patients with chronic lymphocytic leukemia (CLL). Ibrutinib is the first drug designed to target a protein that is essential for CLL-cell survival and proliferation. Much of the clinical and basic-science research that led to FDA approval was performed by scientists at the OSUCCC – James, particularly by John C. Byrd, MD, and colleagues Amy Johnson, PhD, Jason Dubovsky, PhD, Jeffrey Jones, MD, MPH, Joseph Flynn, DO, MPH, Jennifer Woyach, MD, Kami Maddocks, MD, and Kristie Blum, MD.

Byrd and colleagues continued publishing work regarding ibrutinib throughout 2014, including a pair of studies that appeared in the New England Journal of Medicine. In June, Byrd, Johnson and Woyach published a study describing two genetic mechanisms of ibrutinib resistance in CLL. In July, Byrd was first author for a multi-institutional study of ibrutinib versus ofatumumab in previously treated CLL. The American Society of Clinical Oncology (ASCO) selected the latter study for inclusion in Clinical Cancer Advances 2015, ASCO’s annual review of progress against cancer and emerging trends in the field.

Study Identifies Likely Driver of Colorectal Cancer Development, Progression

New targets are needed in order to develop drugs that will more effectively treat colorectal cancer (CRC). A study by researchers at the OSUCCC – James and the University of Glasgow in the United Kingdom identified a molecule called microRNA-135b that is a likely driver of CRC. The researchers demonstrated that miR-135b is present at abnormally high levels in both mouse and human CRC tumors. They say the overexpression can be induced by mutations in well-known oncogenes or tumor-suppressor genes that frequently occur in CRC. Their findings suggest that this molecule could be an important therapeutic target and a biomarker of CRC progression. The study, led by Carlo Croce, MD, was published in the journal Cancer Cell.

New Biomarker Found for Older Patients with Acute Leukemia

Older patients with acute myeloid leukemia (AML) have worse outcomes than younger patients. In about half of these cases, the safest and most effective treatment is difficult to determine. But researchers at the OSUCCC – James described a new biomarker, based on patterns of molecules called long noncoding RNAs (lncRNAs), that might help doctors choose the least toxic, most effective treatment for older patients. LncRNAs are RNA molecules more than 200 nucleotide units long that are involved in regulating genes. The study, led by principal investigator Clara D. Bloomfield, MD, and first author Ramiro Garzon, MD, was published online in the journal Proceedings of the National Academy of Sciences.

Studies Show Potential for Targeted Therapy in Lung Cancer Patients

OSUCCC – James researchers led by David Carbone, MD, PhD, conducted studies that could improve therapy for patients with lung cancer. A study published in the Journal of Clinical Investigation examined the gene changes in a patient on a clinical trial who responded especially well to an experimental targeted drug called sorafenib. This “super responder” remained progression-free and asymptomatic for five years while taking the drug. The study suggests that scientists can discover gene mutations that drive cancer development and progression by analyzing genes in cancer cells from patients who fare far better or worse than others in a particular study. Read more A second study, published in the journal Cancer Research, focused on the targeted drug erlotinib. This drug is effective in treating advanced-stage lung cancer patients whose tumors have a particular gene mutation, but it is of little or no help to patients with early-stage tumors and the same gene mutation. The study discovered why this might be so, and it suggested that the problem may be solved by combining erlotinib with a second drug.

Gene Within a Gene Contributes to AML Aggressiveness

A small gene that is embedded in a larger, well-known gene is the true leukemia-promoting force usually attributed to the larger host gene, OSUCCC – James researchers learned in a study published in the journal Science Signaling. The study examined the degree to which the larger host gene, BAALC, and the smaller embedded gene, microRNA-3151, contribute to acute myeloid leukemia (AML). It also identified a drug that might inhibit the smaller gene’s activity. The study was led by Albert de la Chapelle, MD, PhD, Clara D. Bloomfield, MD, and Ann-Kathrin Eisfeld, MD.

Survival Molecule Helps Cancer Cells Hide From Immune System

A molecule that helps cancer cells evade naturally programmed self-destruction, an internal source of death, might also help malignant cells hide from the immune system, an external source of death. An OSUCCC – James study led by Denis Guttridge, PhD, showed that a molecule called nuclear factor kappa B (NF-kB) helps cancer cells by suppressing the immune system’s ability to detect and destroy them. Published in the journal Cell Reports, the findings suggest that immune therapy for cancer might be more effective if combined with drugs that inhibit NF-kB. They also provide details about how interactions between cancer cells and non-cancer cells assist tumor growth.

Low Dose of Targeted Drug Might Improve Cancer-Killing Virus Therapy

Viruses designed to kill cancer cells are being used in clinical trials to treat brain cancer and other malignancies. A study led by Balveen Kaur, PhD, at the OSUCCC – James suggested that combining a targeted agent called bortezomib with a particular cancer-killing virus might significantly improve the virus’s ability to kill cancer cells. The research, published in the journal Clinical Cancer Research, paves the way for a cancer treatment strategy that combines low doses of bortezomib with a cancer-killing virus to maximize the effectiveness of the virus with little added toxicity for patients.

Form of Immune Therapy Might Be Effective for Multiple Myeloma

New treatments are urgently needed for patients with multiple myeloma (MM), a cancer of the blood that is still incurable. An OSUCCC – James study led by principal investigator Jianhua Yu, PhD, and co-principal investigator Craig Hofmeister, MD, provided evidence that genetically altered immune cells might effectively treat MM. The researchers modified a type of human immune cell called T lymphocytes, or T cells, to target a molecule called CS1, which is found on more than 95 percent of myeloma cells, and to kill the cells. Their findings, published in the journal Clinical Cancer Research, presented a novel strategy for treating MM, and they hope to bring it to patients in a phase I clinical trial soon.

How Cancer Cells Thrive in Oxygen-Starved Tumors

A study at the OSUCCC – James identified the molecular pathway that enables cancer cells to grow in areas of a tumor where oxygen levels are low, a condition called hypoxia. The study, led by Nicholas Denko, MD, PhD, focused on how cancer cells use the amino acid glutamine. Under normal oxygen levels, healthy cells use glutamine largely to produce energy, with a small amount diverted to make fatty acids and lipids. But when oxygen levels drop in areas of a growing tumor, the hypoxic conditions activate a gene called H1F1, initiating a pathway that shifts the use of glutamine away from energy production and to the synthesis of lipids needed for cell proliferation. The findings were published in the journal Cell Metabolism.

Possible Target Identified for Future Brain Cancer Drugs

A molecule in cells that shuts down the expression of genes might be a promising target for new drugs designed to treat glioblastoma multiforme (GBM), the most frequent and lethal form of brain cancer, according to an OSUCCC – James study. Published in the journal Cancer Research, the study found that high levels of the enzyme PRMT5 are associated with aggressive growth of GBM. Researchers led by Robert Baiocchi, MD, PhD, and Balveen Kaur, PhD, showed that inhibiting PRMT5 can significantly improve survival in a laboratory model of GBM by thwarting the growth, proliferation and migration of GBM cells and by increasing the number of GBM cells that die by apoptosis (natural cell death). The findings suggest that PRMT5 is a possible prognostic factor and therapeutic target for GBM.

Potential Link Found Between Breast Cancer and Salivary Gland Cancer

The risk of developing cancer in a salivary gland may be higher in people with mutations in either of two genes associated with breast and ovarian cancer, according to a study conducted at the OSUCCC – James and published in the journal JAMA Otolaryngology – Head and Neck Surgery. Salivary gland cancer is rare, but this retrospective study suggested that it occurs 17 times more often in people with inherited mutations in BRCA1 and BRCA2 genes. BCRA1 or BCRA2 mutations confer a higher risk of breast and ovarian cancer in women and a higher risk of breast cancer in men. The researchers, led by Theodoros Teknos, MD, and Rebecca Nagy, MS, believe a BRCA-positive patient with a lump in a salivary gland should have it evaluated.

Experience Counts With Radiation Therapy for Head and Neck Cancer

When it comes to specialized cancer surgery, it’s generally true that the more experienced the surgeon, the better the outcome. The same might hold true for radiation therapy used to treat head and neck cancer, according to a study led by Ohio State researchers Evan Wuthrick, MD, and Maura Gillison, MD, PhD. Published in the Journal of Clinical Oncology with an accompanying editorial, the study compared survival and other outcomes in 470 patients treated with radiation therapy at treatment centers through a clinical trial held from 2002 to 2005. Patients treated at centers with high accrual to Radiation Therapy Oncology Group (RTOG) trials, a surrogate for treatment experience, had better survival than low-accruing centers. The trial was sponsored by the National Cancer Institute and organized by the RTOG.

Number of Cancer Stem Cells May Not Predict Outcome in HPV-Related Oral Cancers

Research at the OSUCCC – James suggests that the quality of cancer stem cells, rather than their quantity, may lead to better survival in certain patients with oral cancer. The researchers investigated cancer stem cell numbers in oral cancers associated with human papillomavirus (HPV) and in oral cancers not associated with the virus. Quintin Pan, PhD, was principal investigator for the study, which was published in the journal Cancer. “We show that high levels of cancer stem cells are not necessarily associated with a worse prognosis in head and neck cancer, a finding that could have far-reaching implications for patient care,” Pan says. 

Yoga Can Lower Fatigue, Inflammation in Breast Cancer Survivors

A study at the OSUCCC – James showed that practicing yoga for as little as three months can reduce fatigue and lower inflammation in breast cancer survivors. At the six-month point of the study—three months after the formal yoga practice had ended—results showed that, on average, fatigue was 57 percent lower in women who had practiced yoga compared to the non-yoga group, and their inflammation was reduced by up to 20 percent. Many studies have suggested that yoga has benefits, but study lead author Janice KiecoltGlaser, PhD, says this is the largest known randomized controlled clinical trial that includes biological measures. The study appeared in the Journal of Clinical Oncology.

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