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PUT TO THE TEST

Second Ohio State cancer drug enters clinical trial

For the second time within 2½ years, an experimental drug created by cancer researchers at the OSUCCC – James is being tested in a clinical trial.

Last summer, adult patients began receiving oral doses of AR-42, which is in a new class of drugs called histone deacetylase (HDAC) inhibitors, or compounds designed to reactivate genes that normally guard against cancer but are turned off by the cancer process.

AR-42 is designed to treat relapsed or treatment-resistant multiple myeloma, chronic lymphocytic leukemia or lymphoma. JOHN C. BYRD, MD, initiated the drug's development with CHING-SHIH CHEN, PhD, a cancer researcher and professor of Medicinal Chemistry in the College of Pharmacy.

The phase I/IIa clinical trial is assessing the safety and initial evidence of anticancer activity of the drug. Byrd says Ohio State is the only site worldwide accepting patients to this trial.
"Early tests in cancer cell models showed that AR-42 is 10,000-fold more potent than the starting/parent agent," says Chen.

In 2003, Byrd asked Chen to try to improve the potency of a short-chain fatty acid known to have a weak inhibitory effect against cancer growth. Chen worked with cancer center and pharmacy colleagues to develop the drug, originally called OSU-HDAC42, a broad spectrum histone and non-histone deacetylation inhibitor (pan-DAC).

The agent has been licensed to the biopharmaceutical company Arno Therapeutics, Inc., for clinical development.

"It is exciting to see this very potent broad-class I/II HDAC inhibitor enter the clinic for treatment of blood cancers, and we look forward to meaningful results," Byrd says, noting that CRAIG HOFMEISTER, MD, is principal investigator on the clinical trial.

In August 2009, the OSUCCC – James began enrolling patients in a clinical trial for AR-12, another anticancer agent designed by Chen's lab that also is being developed by Arno Therapeutics. AR-12 inhibits solid-tumor growth by triggering cancer cells to self-destruct.

Byrd is professor of Internal Medicine and the D. Warren Brown Designated Professorship in Leukemia Research. Chen holds the Lucius A. Wing Chair of Cancer Research & Therapy, and is professor of Medicinal Chemistry, of Internal Medicine, and of Urology.


E. Antonio Chiocca, MD, professor and chair of Neurological Surgery, Dardinger Family Endowed Chair in Oncological Neurosurgery.

SLEEPERS AWAKE
Conscious sedation for brain surgery may shorten hospital stay

The recovery time and cost of brain-tumor surgery might be reduced if surgery is performed while patients are awake during part of the procedure, a study at the OSUCCC – James suggests.

The study examined the outcomes of 39 patients treated for glioma. Doctors wanted to learn whether patients who received conscious sedation had outcomes different from those who underwent general anesthesia.

"Our data suggest that patients who received conscious sedation had shorter hospital stays, and that this reduced the cost of treatment," says study leader E. ANTONIO CHIOCCA, MD, PhD, professor and chair of Neurological Surgery. "This finding must be validated with a randomized prospective clinical trial, but if it holds true, it would mean that changing our way of delivering anesthesia may allow these patients to leave sooner and save resources."

Neurosurgeons usually reserve conscious sedation for patients with tumors near the brain's speech and sensorimotor centers, Chiocca says. The method was conceived in the 1950s to avoid or minimize damage to these centers. Since then, several studies have indicated that conscious sedation can result in more complications than general anesthesia, while other studies appear to show the opposite.

To investigate this question, Chiocca and colleagues studied the outcomes of 20 cases that used conscious sedation during surgery for gliomas and compared them with 19 cases that used general anesthesia.

The researchers evaluated patients for the number of days they remained in the hospital and for the cost of four items related to the surgery: the operating room, anesthesia, neurosurgical intensive care and the hospital room. Each patient was also evaluated for neurological complications.

No significant differences were found in the percentage of complications. As for the costs, the expense associated with the operating room and anesthesia were the same in both groups, and both groups spent similar time in intensive care. However, patients receiving conscious sedation had shorter hospital stays after leaving intensive care than patients receiving general anesthesia—3.5 vs. 4.6 days.

And the shorter hospital stays led to an average 36-percent decrease in post-intensive-care direct cost for cases receiving conscious sedation.

Published in the journal Cancer Prevention Research.


SUPER SUBSTANCE
Dietary supplement may block cancer cells

Researchers at the OSUCCC – James have discovered how a substance produced when eating broccoli and brussels sprouts can block the proliferation of cancer cells.

Compelling evidence indicates that the substance, indole-3-carbinol (I3C), may have anticancer effects and other health benefits. The findings show how I3C affects cancer cells and normal cells.

The laboratory and animal study discovered a connection between I3C and a molecule called Cdc25A, which is essential for cell division and proliferation. Research showed that I3C causes the destruction of that molecule and thereby blocks the growth of breast cancer cells.

"Cdc25A is present at abnormally high levels in about half of breast cancer cases, and it is associated with a poor prognosis," says study leader XIANGHONG ZOU, PhD, assistant professor of Pathology, who notes that the molecule also occurs at abnormally high levels in cancers of the breast, prostate, liver, esophagus, endometrium and colon, as well as in non-Hodgkin's lymphoma and other diseases such as Alzheimer's.

"For this reason, a number of anti-Cdc25A agents have been identified, but they have not been successful for cancer prevention or treatment due to concerns about their safety or efficacy," says Zou. "I3C can have striking effects on cancer cells. A better understanding of this mechanism may lead to the use of this dietary supplement as an effective and safe treatment strategy for cancer and other diseases associated with overexpression of Cdc25A."

For this study, Zou and colleagues exposed three breast cancer cell lines to I3C and observed that the substance caused the destruction of Cdc25A. They also pinpointed a location on that molecule that made it susceptible to I3C, showing that if that location is altered because of a gene mutation, I3C no longer causes the molecule's destruction.
Published in Cancer Prevention Research.

DOSING BY THE NUMBERS
Model may simplify high-dose radiosurgery planning

There is no straightforward way to determine the optimal dose level and treatment schedules for high-dose radiation therapies such as stereotactic therapy, used to treat brain and lung cancer, or high-dose brachytherapy for treating prostate and other cancers.

However, radiation oncologists at the OSUCCC – James may have solved this problem by developing a mathematical model that encompasses all dose levels.

Typically, radiation therapy for cancer is given in daily low doses spread over many weeks. Oncologists often calculate the schedules for these fractionated, low-dose courses using a mathematical linear-quadratic (LQ) model that is also used to evaluate radiation response, interpret clinical data and guide clinical trials.

"Unfortunately, the LQ Model doesn't work well for high-dose radiation therapy," says co-author NINA MAYR, MD, professor of Radiation Oncology. "Our study resolves this problem by modifying the current method to develop a Generalized LQ (gLQ) Model that covers all dose levels and schedules."

First author, Jian Wang, PhD, who passed away unexpectedly in June 2010, was largely responsible for developing the gLQ Model.

If verified clinically, Mayr says, the gLQ Model could guide the planning of dose levels and schedules needed for the newer radiosurgery and stereotactic radiation therapy and for high-dose brachytherapy procedures that are increasingly used for cancer patients.

Mayr says the new model could allow oncologists to design radiation dose schedules more efficiently, help researchers conduct clinical trials for specific cancers more quickly, and make high-dose therapies available to cancer patients much sooner.

"Our Generalized LQ Model determines appropriate radiation levels across the entire wide spectrum of doses, from low to high, and from many to very few treat-ments, which is a new approach," Mayr says.

Published in the journal Science Translational Medicine.



Tim H.-M. Huang, PhD, professor of Molecular Virology, Immunology and Medical Genetics at the OSUCCC – James

IN THE LOOP
Program helps breast cancer patients long after recurrence.

Cancer researchers at the OSUCCC – James have discovered a type of gene regulation and DNA behavior in breast cancer cells that may offer insight about environmental exposure to estrogen-like compounds.

The study provides the first evidence that cells can regulate many genes at once by looping their DNA, contributing to cancer when this process goes awry. This regulation, discovered in breast cancer cells as a response to estrogen, resulted in the silencing of 14 genes at once.

TIM H.-M. HUANG, PhD, professor of Molecular Virology, Immunology and Medical Genetics, and Pei-Yin Hsu, a visiting scholar in Huang's lab, located the DNA looping event in a breast cancer cell line gene cluster at chromosome region 16p11.2. They validated the finding using normal human breast epithelial cells and two animal models.

They also used the normal-cell model to determine if long-term exposure to nine estrogen-like chemicals can initiate gene silencing through this mechanism. These chemicals included diethylstilbestrol, two thalates and bisphenol A (BPA).

The suppressive effects varied in normal cells, but when investigators exposed rats to BPA for 21 days, they found concurrent suppression of 10 genes comparable to those located at 16p11.2. Huang says this suggests that continuous exposure to estrogen-like compounds might lead to permanent silencing of genes in this conserved cluster.

In healthy breast epithelial cells, 14 gene regulatory sites joined to form a temporary transcription site, Huang says. "But in breast cancer cells, there is no coordinated transcription site pairing, the DNA loops become tangled and the entire gene complex shuts down in a dead knot."

In some cases, he adds, this multi-gene regulatory mechanism can increase gene expression and oncogenic activity, further contributing to cancer.

"We offer a new concept in this paper for the collective regulation of gene transcription," says first author Hsu, who identified the loop structures and their significance. "We found that in normal breast cells, DNA looping is more flexible and brings different promoters together temporarily. But in cancer, this complex just locks up and causes long-term suppression."

For a demonstration of DNA looping, visit http://www.youtube.com/watch?v=4y0e6oumqdo

Published in the journal Genome Research.




Amy Johnson, PhD, assistant professor of Hematology and Medicinal Oncology


MOLECULAR MAYHEM
Targeted agent shows promise for chronic lymphoid leukemia

Researchers at the OSUCCC – James have identified an experimental agent that targets chronic lymphocytic leukemia (CLL) and perhaps other proliferative disorders of lymphocytes.

A study of cells from patient tumors shows that the small-molecule inhibitor CAL-101 promotes apoptosis in CLL cells and disrupts several external survival pathways needed for CLL cell viability and proliferation. The agent blocks the PI3K-delta molecule, an isomer of the P13K (phosphatidylinositol-3 kinase) pathway, which is activated mainly in hematopoietic cells.

"Our findings provide a rationale for developing CAL-101 as the first in a new class of targeted therapies for CLL," says principal investigator AMY JOHNSON, PhD, assistant professor of Hematology and Medicinal Chemistry. "A PI3K inhibitor hasn't been developed yet because this pathway is required for many essential cellular functions, but the identification of PI3K-delta, which is hematopoietic-selective, unlocks a potential therapy for B-cell malignancies."

CLL is the most common adult leukemia in the United States. Patients with the asymptomatic phase can live for many years even without treatment. Once the disease reaches the symptomatic phase, treatment is required, usually chemotherapy that often induces remission. But current therapies are not curative; nearly all patients relapse.

The PI3K pathway is essential for survival of cells generally. This made it an unsuitable target for small molecule inhibitors until recently when research showed that PI3K-delta expression occurs mainly in hematopoietic cell types.

Preclinical studies suggest that blocking this molecule may kill B cells with little toxicity to other hematopoietic cells.

The OSUCCC – James study found that: CLL cells show high PI3K pathway activity and PI3K-delta expression; CAL-101 preferentially kills CLL cells compared with normal B-cells; CAL-101 inhibits PI3K-delta and promotes apoptosis in primary CLL cells while disrupting multiple external survival pathways; CAL-101 cell killing is caspase-dependent and not diminished by stromal cells; and CAL-101 does not kill normal T cells or natural killer (NK) cells or reduce antibody-dependent cellular cytotoxicity, but it does lower production of inflammatory and antiapoptotic cytokines by activated T cells.

A phase I clinical trial of CAL-101 is under way in select relapsed or refractory hematologic malignancies at Ohio State and other centers.

Published in the journal Blood.

 

 
6-Jan-11
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