Birmingham Researchers Work On Promising Cancer Drugs

Andres Forero, MD consults with a patient.
Currently, Birmingham area physicians and scientists are involved in research on several drugs that show promise for treating a variety of cancers.

Experimental Drug for Lymphoma

Patients with follicular lymphoma may have a new agent on their side. Clinical data showed that an experimental drug called AME-133v had a potent tumor-halting response in some patients suffering from this slow-growing, recurrent lymphoma.

“These first results suggest that AME-133v provides a mechanism of action that may be more potent and ultimately more effective than the treatments we have on hand,” said Andres Forero, MD, associate scientist at the UAB Comprehensive Cancer Center and consultant to Eli Lilly & Co., which funded the study.

Of the more than 56,000 cases of non-Hodgkin lymphoma diagnosed in 2005, 15 to 20 percent were follicular lymphomas, with 60 to 65 years the median age at diagnosis. Though follicular lymphoma can be treated with chemotherapy, the disease often returns after therapy is complete.

The Phase 1 clinical trial included 22 patients treated at UAB and six other sites around the nation.

In the UAB study, AME-133v was administered in combination with a standard chemotherapy agent sometime after the initial treatments had been given and after the re-emergence of the cancer.

Forero noted that the drug combination of AME-133v with chemotherapy was well tolerated by the body and caused minimal side effects. He explained that the experimental drug triggered signaling pathways within cells that slow or stop lymphoma cancer’s growth. Research has shown that a new class of anticancer agents like AME-133v, a class monoclonal antibody, can lengthen survival times.

Follicular lymphoma patients are currently being enrolled in a Phase 2 study.

Orphan Status for Pancreatic and Bile Duct Cancer Drug

“The major challenge in the treatment of pancreatic adenocarcinoma is the development of residual chemoresistant disease,” said Ewan Tytler, PhD, assistant professor in the UAB Department of Surgery, Gastrointestinal Section. Gemcitabine is currently the only FDA-approved drug for treating pancreatic cancer, but typically only 20 to 30 percent of patients respond to it.

However, Tytler is studying a new drug, triphendiol (NV-196), which could significantly raise the percentage of responders. Studies in animal models of pancreatic cancer showed that triphendiol combined with gemcitabine inhibited tumor growth more effectively than each drug alone. “In mice, we found that one cell type that was resistant to gemcitabine became sensitive if we administered triphendiol in combination with gemcitabine,” Tytler said. Combining the two drugs also resulted in greater cell death using only one-tenth the dosage of gemcitabine when used by itself.

Triphendiol shows potential for hitting the trifecta of cancer agents. The laboratory studies found that it arrested the cell cycle, induced cell death and had low toxicity to nonmalignant cells. “Having the combination of all three properties in one drug is unique,” said Tytler, who noted the drug’s potent way of killing cancer cells through the mitochondria. “This means that we’re killing the cell from the inside out. We’re not depending on signals from outside the cell to do it.”

Tytler and his colleagues — Xiaohong Wang, MD, and J. Anthony Thompson, PhD — assessed the potential of triphendiol using three pancreatic and two bile duct cell lines. The drug induced cell death and increased the effectiveness of chemotherapy in all cell lines used.

“Of course, there is still much work to be done before this could become a treatment protocol for cancer patients,” Tytler said. Triphendiol, developed by Marshall Edwards Inc., which funded the study, recently received orphan drug status from the FDA. The company has already tested the drug in Phase IA studies in human volunteers to assess tolerance and toxicity and demonstrated a good safety profile and successful pharmacokinetics. The next step is Phase 1B clinical trials to test different dose levels and assess preliminary efficacy in combination with gemcitabine in pancreatic cancer patients.

“A lot of people have lost their lives because of pancreatic cancer. It’s a very frustrating tumor to work with,” Tytler said. “I spent several years working with a combination of drugs that didn’t work. The fact that we’re seeing it working with a number of cell types in these pre-clinical studies is very encouraging.”

June 2008

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