HITTING THE MARK
Targeted Agent Shows Promise in Biliary Cancer

The experimental agent selumetinib showed promising results in people with advanced biliary cancer in a multi-institutional study led by researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James).

Findings from this 28-patient phase II study indicate that selumetinib, also known as AZD6244 (ARRY-142886), inhibits the MEK protein, which cancer cells need to proliferate and survive.

The tumor shrank to an undetectable level in one patient, and two patients showed partial tumor shrinkage. In 17 patients, the tumor stopped growing for up to 16 weeks in most cases. On average, patients experienced no cancer progression for a promising 3.7 months, even though nearly 40 percent had prior therapy (such tumors tend to resist further treatment).

"Biliary cancer has no good standard of care," says principal investigator Tanios Bekaii-Saab, MD, medical director of gastrointestinal oncology at the OSUCCC – James. He notes that most patients present at later stages of the disease, which has a universally poor outcome. "Our study provides a strong rationale for developing this agent further in larger trials, which we hope will enable us to establish a new standard of care."

Bekaii-Saab says patients who lacked a target protein called pERK did not seem to respond to the drug. "This suggests that we may be able to identify which patients are most likely to benefit from this agent," he adds.

Published in the Journal of Clinical Oncology.

AUSPICIOUS AGENT
Novel Drug Highly Active in CLL Patients

An interim analysis of a phase II clinical trial indicates that an experimental agent for chronic lymphocytic leukemia (CLL) is highly active and well tolerated both in previously treated patients and in those who have relapsed and are resistant to other therapy.

The agent, PCI-32765, is the first drug designed to target Bruton’s tyrosine kinase, a molecule essential for CLL-cell survival and proliferation.

Study leader John C. Byrd, MD, director of the Division of Hematology at Ohio State, presented the findings at the 2011 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

The trial involves 78 patients with previously untreated or relapsed and refractory CLL or small lymphocytic leukemia. This analysis involved the first 21 cases in the untreated-patient group and the first 27 individuals in the relapsed/ refractory-patient group. One patient in each group had a complete remission, while 13 patients in the previously untreated group and 12 patients in the relapsed group had partial remissions.

"These are early findings, so patients with partial remissions could improve to complete remissions with further observation," Byrd says.

Amy Johnson, PhD, co-led pre-clinical CLL work on PCI- 32765 at Ohio State, along with Byrd. Those findings, published in the journal Blood, showed that the agent targets B lymphocytes and spares T lymphocytes. If the agent behaves the same way in humans, "It could dramatically improve outcomes for CLL patients," Byrd says.

TINY DETECTION
microRNA Findings May Lead to Blood Test for Lung Cancer

OSUCCC – James researchers have identified characteristic patterns of microRNA molecules (miRNA) in the blood of lung cancer patients that might reveal the presence and aggressiveness of the disease, and perhaps who is at risk of developing it.

These patterns may be detectable up to two years before the tumor is found by computed tomography (CT) scans. The findings could lead to a blood test for lung cancer, according to principal investigator Carlo Croce, MD, director of the Human Cancer Genetics Program at Ohio State.

Croce and his collaborators identified the molecular patterns in tissue and blood samples collected from patients participating in a clinical trial examining the use of spiral CT scans to screen for lung cancer. The trial involved 1,035 individuals aged 50 years or older who had smoked at least a pack of cigarettes a day for 20 years or more.

"It might be possible to use these patterns of abnormal microRNAs in the plasma to detect lung cancer in people with the disease," Croce says. "The abnormal microRNAs were also present in blood serum well before the tumors were detected by a sensitive method such as spiral CT scan, suggesting the possibility of identifying high-risk patients on the basis of miRNA profiling."

Published in the journal Proceedings of the National Academy of Sciences.

TRIPLE TREATMENT
Low-Dose Sorafenib May Improve Therapy for Head and Neck Cancer

Adding low doses of the targeted agent sorafenib to the chemotherapy and radiation now often used to treat head and neck cancer might significantly improve patient care and quality of life, a preclinical study at the OSUCCC – James suggests.

The findings indicate that adding sorafenib would maintain treatment efficacy while permitting lower doses of chemotherapy and radiation, thus decreasing harsh side effects. The triple combination was well-tolerated in an animal model.

About 49,200 new cases of head and neck cancer are expected in the United States this year, and 11,500 people are expected to die from it. Treatment is often unsuccessful because the tumors become resistant to both chemotherapy and radiation therapy.

"This preclinical study suggests that using low-dose sorafenib plus chemotherapy and radiation could have significantly milder side effects while maintaining effectiveness," says principal investigator Pawan Kumar, PhD. "Our findings provide a scientific rationale to evaluate this combination strategy through a clinical trial."

"Our results suggest a potentially novel strategy in which sorafenib combined with low doses of chemotherapy, radiation therapy or both is as effective in treating head and neck cancer as much higher doses used in existing treatment," says study co-author Theodoros Teknos, MD, who directs the Division of Head and Neck Surgery at Ohio State.

Published in the journal Molecular Cancer Therapeutics.

PROGNOSTIC PROGRESS
Gene Change Signifies Better Response to Treatment

Arnab chakravarti, MD, Chair and professor of Radiation Oncology, co-director of the Brain Tumor Program, member of the Experimental Therapeutics Program and the Max Morehouse Chair in Cancer Researchn.

New research proves that a change in the MGMT gene can identify which patients with glioblastoma will respond better to treatment. Testing for this gene can distinguish patients with a more- or less-aggressive form of this disease – the most common and deadliest type of primary brain cancer – and help guide therapy.

Examining the MGMT gene in tumors removed from 833 patients with glioblastoma, the researchers found that when the gene promoter is altered by a chemical change called methylation, patients respond better to treatment.

"We show that MGMT methylation represents a new genetic test that can predict clinical outcomes in glioblastoma patients treated with radiation combined with the chemotherapeutic drug temozolomide," says co-author Arnab Chakravarti, MD, chair of Radiation Oncology and co-director of the Brain Tumor Program at the OSUCCC – James.

"Glioblastomas are a collection of different molecular and genetic entities that behave uniquely and require personalized treatment," adds Chakravarti, who is the translational-research study chair for the study.

The findings were presented in June at the 2011 American Society of Clinical Oncology (ASCO) meeting.

To refer a patient, please call The James Line New Patient Referral Center toll free: 1-800-293-5066.

PRECLINICAL FINDINGS
Component of Chinese Herbal Remedy Might Block Brain Tumor's Spread

E. Antonio Chiocca, MD, PhD professor and chair of Neurological Surgery, Dardinger Family Endowed Chair in Oncological Neurosurgery and co-leader of the OSUCCC – James Viral Oncology Program

The active ingredient in a traditional Chinese herbal remedy might help treat deadly brain tumors, according to a study by OSUCCC – James researchers.

The laboratory and animal study suggests that a substance called indirubin blocks both the migration of glioblastoma cells, preventing their spread to other areas of the brain, and the migration of endothelial cells, inhibiting the formation of tumor blood vessels.

"We have pretty good methods to stop glioblastoma from growing in the human brain, but these therapies fail because tumor cells migrate from the original site and grow elsewhere in the brain," says co-principal investigator E. Antonio Chiocca, MD, PhD, professor and chair of neurological surgery and co-leader of the OSUCCC – James Viral Oncology Program.

"Our findings suggest that indirubins offer a novel therapeutic strategy for these tumors that simultaneously targets tumor invasion and angiogenesis," he says.

Indirubin is derived from the indigo plant. It is the active ingredient in the Chinese herbal remedy called Dang Gui Long Hui Wan, which is used to treat chronic myeloid leukemia. However, little is known about the form or dose used, or its effectiveness, side effects or drug interactions.

"Although indirubin looks promising in animal models, it has not yet been tested in humans, and it is not approved by the U.S. Food and Drug Administration," Chiocca cautions.

For other work on glioblastoma cell motility by Chiocca, see Researchers Discover Brain Tumor's "Grow-or-Go” Switch.

Published in the journal Cancer Research.

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