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Break Through Winter 2013 

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HEDGEHOG HUNTING
A Possible Therapy for Tamoxifen-Resistant Breast Cancer

BHUVANESWARI RAMASWAMY, MD,
a medical oncologist specializing in breast cancer at the OSUCCC - James










SARMILA MAJUMDER, PHD,
a research assistant professor in Molecular and Cellular Biochemistry at Ohio State and member of the OSUCCC - James


Researchers at The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute (OSUCCC - James) have discovered how tamoxifen-resistant breast cancer cells grow and proliferate. The study suggests an experimental agent might offer a targeted therapy for tamoxifen-resistant breast cancer.

Like a second door that opens after the first door closes, a signaling pathway called hedgehog (Hhg) can promote the growth of breast-cancer cells after tamoxifen shuts down the pathway activated by the hormone estrogen. A second signaling pathway, called PI3K/AKT, is also involved.

Activation of the Hhg pathway renders tamoxifen treatment ineffective and enables the tumor to resume its growth and progression. As part of the study, the researchers analyzed more than 300 human tumors and found that those with an activated Hhg pathway had a worse prognosis.

Finally, the researchers showed that an experimental drug called vismodegib, which blocks the Hhg pathway, inhibits the growth of tamoxifen-resistant human breast tumors in an animal model. The drug is in clinical trials testing for other types of cancer.

Chemotherapy is currently used to treat hormone-resistant breast cancers, but it causes significant side effects. This study has identified targeted therapies that could be an alternative to chemotherapy for these resistant tumors.

"Our findings suggest we can target this pathway in patients with estrogen-receptor breast cancers who have failed tamoxifen therapy," says first author Bhuvaneswari Ramaswamy, MD, a medical oncologist specializing in breast cancer at the OSUCCC - James.

"We describe a link between the hedgehog signaling pathway, which promotes tamoxifen resistance, and the PI3K/AKT pathway," adds principal investigator Sarmila Majumder, PhD, a research assistant professor in Molecular and Cellular Biochemistry at Ohio State and member of the OSUCCC - James. "Targeting the hedgehog pathway alone or in combination with the PI3K/AKT pathway could be a novel therapeutic option for treating tamoxifen-resistant breast cancer."

Published in the Journal Cancer Research

Funding from NIH/National Cancer Institute grants CA137567 and CA133250, and a Pelotonia Idea Grant supported this research.


TRANSORAL TECHNIQUE
Robotic Surgery Through Mouth Safe for Removing Throat Tumors

ENVER OZER, MD,
a head and neck surgeon who specializes in robot-assisted techniques


Robotic surgery through the mouth is a safe and effective way to remove tumors of the throat and voice box, according to a study by head and neck cancer surgeons at the OSUCCC - James.

The researchers say this is the first report in the world literature to illustrate the safety and efficacy of transoral robotic surgery for supraglottic laryngectomy.

The preliminary study, which examined the outcomes of 13 head and neck cancer patients with tumors in the supraglottic region of the throat, found that robot-assisted surgery to remove these tumors through the mouth took about 25 minutes on average. The study also found that blood loss was minimal - a little more than three teaspoons, or 15.4 milliliters, on average, per patient. No surgical complications were encountered, and 11 of the 13 patients could accept an oral diet within 24 hours.

If, on the other hand, these tumors are removed via open surgery on the neck, the operation can take about four hours, require seven to 10 days of hospitalization and involve a tracheostomy tube and a stomach tube, the researchers say.

"The transoral robotic technique means shorter surgery, less time under anesthesia, a lower risk of complications and shorter hospital stays for these patients," says first author Enver Ozer, MD, clinical associate professor of Otolaryngology at Ohio State.

"It also means no external surgical incisions for the patient and better 3-D visualization of the tumor for the surgeon," says Ozer, a head and neck surgeon who specializes in robot-assisted techniques.

The cases examined in this study were part of a larger prospective study of 126 patients undergoing transoral robotic surgery between 2008 and 2011.

Published in the journal Head and Neck

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


INIMICAL INFLAMMATION
Study Shows How Chronic Inflammation Can Cause Cancer

ANJALI MISHRA, PhD,
a postdoctoral researcher
in Dr. Michael A. Caligiuri’s
laboratory


When present at high levels, a hormone-like substance produced by the body to promote inflammation can cause an aggressive form of leukemia, OSUCCC - James researchers have found.

Their study shows that high levels of interleukin-15 (IL-15) alone can cause large granular lymphocytic (LGL) leukemia, a rare and usually fatal disease, in an animal model. The researchers also developed a treatment for the leukemia that showed no discernible side effects in the animal model.

In addition, their findings show that IL-15 is overexpressed in patients with LGL leukemia and that it causes similar cellular changes, suggesting that the treatment should also benefit people with the malignancy.

"We know that inflammation can cause cancer, but we don't know the exact mechanism," says co-senior author Michael A. Caligiuri, MD, director of the OSUCCC and CEO of The James. "Here, we show one way it can happen, and we used that information to potentially cure the cancer."

The research was developed and carried out in collaboration with co-senior author Guido Marcucci, MD, associate director for translational research at the OSUCCC - James. "In this study, we show the joined role of genetic instability and microRNAs in leading directly to cancer," says Marcucci, who notes that this work is part of a long history of research at the OSUCCC - James that is revealing the role of microRNA in cancer and its potential as a therapeutic target.

"Once we understood how this inflammatory hormone causes this leukemia, we used that information to develop a treatment by interfering with the process," says first author Anjali Mishra, PhD, a postdoctoral researcher in Caligiuri's laboratory.

Caligiuri, Marcucci and Mishra were joined in this study by Robert Lee, PhD, professor of Pharmaceutics and Pharmaceutical Chemistry in Ohio State's College of Pharmacy, and a group of collaborators.

Published in the Journal Cancer Cell

NIH/National Cancer Institute grants
CA16058, CA95426, CA68458, CA09338,
CA140158, CA102031 and CA149623,
and National Science Foundation grant
EEC-0914790 supported this research.



AUSPICIOUS AGENT
Experimental Drug Ibrutinib Highly Active in CLL Patients

JOHN C. BYRD, MD,
director of the Division of Hematology; professor of Medicine, of Medicinal Chemistry and of Veterinary Biosciences; and the D. Warren Brown Designated Chair in Leukemia Research


Updated results from a phase Ib/II clinical trial indicate that a novel therapeutic agent for chronic lymphocytic leukemia (CLL) is highly active and well tolerated in patients who have relapsed and are resistant to other therapy.

The agent, ibrutinib (PCI-32765), is the first drug designed to target Bruton's tyrosine kinase (BTK), a protein essential for CLL-cell survival and proliferation. CLL is the most common form of leukemia, with about 15,000 new cases annually in the United States. About 4,400 Americans die of the disease each year.

Study co-leader John C. Byrd, MD, who directs the Division of Hematology at Ohio State and is a member of the OSUCCC - James, presented the findings in December 2012 at the 54th Annual Meeting of the American Society of Hematology (ASH) Annual Meeting in Atlanta, Ga.

The study found that response to therapy was high across cohorts, with 71 percent of previously untreated older patients experiencing a complete or partial response at either treatment dose (420mg and 840mg). The same response was observed in 67 percent of the relapsed patients and half of the high-risk patient cohort. After 22 months of follow-up, the disease had not progressed in 96 percent of previously untreated patients and 76 percent of relapsed and high-risk patients.

"These findings are exciting because they demonstrate ibrutinib's potential as a highly active, well-tolerated first-line therapy for CLL that produces a high rate of durable remissions - the remissions last months on end," Byrd says. "The drug is effective in part because patients are willing to stay on treatment since the side effects are very tolerable."

Only non-severe side effects such as diarrhea, fatigue, chest infection, rash, nausea, joint pain, and infrequent and transient low blood counts were observed. Investigators found no evidence of cumulative toxicity or long-term safety concerns with a median follow-up of 16 months for treated patients.

Visit the OSUCCC - James CLL Experimental Therapeutics Laboratory at cll.osu.edu.


LESS IS MORE
Reduced-Intensity Regimen Before BMT is Better for Older Leukemia Patients

STEVEN DEVINE, MD,
professor in the Division of Hematology at Ohio State
and director of the Blood and Marrow Transplant Program



A study led by researchers at the OSUCCC - James shows that preparing older acute myeloid leukemia (AML) patients for bone marrow transplants (BMT) with a reduced-intensity conditioning regimen is associated with higher rates of disease-free survival relative to the more typical treatments these patients usually receive.

The study was presented at the December 2012 American Society of Hematology (ASH) Annual Meeting in Atlanta, Ga.

Typically, the prognosis for older AML patients is poor. Even among patients who achieve complete remission through chemotherapy, survival rates are low due to high risk of relapse. While blood or bone marrow transplants can be a viable option for younger patients, conventional preparative regimens for the procedure are often too toxic for patients over age 60.

"With a reduced-intensity regimen leading up to a transplant, the disease-free survival rate in older patients reached 39 percent," says Steven Devine, MD, professor in the Division of Hematology at Ohio State and director of the Blood and Marrow Transplant Program. "These outcomes are better than those achieved using more conventional treatments and warrant additional comparison research focused on preventing relapse in this patient population."

The objective of the phase II, prospective, multicenter trial was to determine the feasibility and effectiveness of a uniform reduced-intensity conditioning regimen prior to a blood cell transplant in older AML patients in clinical remission. The primary endpoint was two-year disease-free survival. Researchers hypothesized that disease-free survival at two years would exceed 20 percent.

The study involved 123 AML patients in first clinical remission following chemotherapy, ages 60-74, who were transplanted at 21 centers across the country. Rates of both acute and chronic graft-vs.-host disease and treatment-related mortality were relatively low. No unexpected toxicities were associated with the transplants. Relapse was the most common cause of death.

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


AGE ANALYSIS
Older and Younger Chronic Leukemia Patients May Need Different Therapy

JENNIFER WOYACH, MD,
assistant professor in the Division
of Hematology at Ohio State


Doctors should use different therapies when treating older and younger patients with chronic lymphocytic leukemia (CLL), a new study at the OSUCCC - James suggests.

Age is usually not considered when determining treatment for people with CLL, but this study indicates that older people with the disease may not respond as well to the therapy used for most patients.

"Our analysis shows that optimal therapy for younger and older patients with chronic lymphocytic leukemia is likely to be different, at least when using current treatments," says first author Jennifer Woyach, MD, assistant professor in the Division of Hematology at Ohio State. "We hope this study will shape future research by highlighting the importance of enrolling older patients on clinical trials and of developing trials that specifically target older patients."

CLL most often occurs in people older than 65; the average age at diagnosis is 72. But most CLL clinical trial participants are in their early 60s.

"Our findings apply to both routine care of CLL patients 70 years and older and to future CLL trials," says principal investigator John C. Byrd, MD, who directS the Division of Hematology at Ohio State and is a member of the OSUCCC - James.

"The study suggests that chlorambucil is superior to fludarabine in older patients, and that CD20 antibody therapies such as rituximab are beneficial as front-line therapy for all CLL patients, regardless of age," Byrd says. "These data also show that future treatment trials for older adults with CLL should build on CD20 antibody therapies such as rituximab and ofatumumab, but not on fludarabine or alemtuzumab."

Byrd, Woyach and colleagues reviewed 663 CLL patients who were enrolled in four sequential CLL clinical trials evaluating front-line therapies. The researchers looked for differences in treatment outcomes between older and younger patients to identify the most effective therapy for older adults.

Published in the Journal of Clinical Oncology
NIH/National Cancer Institute grants CA31946, CA33601 and CA140158, and funds from the Leukemia and Lymphoma Society, the Harry Mangurian Foundation and the D. Warren Brown Family Foundation supported this research.
 
13-Feb-13
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