After first determining that in vitro cancer cells incubated with 2-DG and exposed to low concentrations of ABT-263/737 died, the researchers conducted animal studies. They found that when 2-DG was injected into animals, it predominantly accumulated in cancer cells that were subsequently killed by an injection of ABT-263/737. The two-step approach successfully induced apoptosis in leukemia, hepatocarcinoma, lung, breast and cervical cancers. Yamaguchi said it caused cell death at many stages of cancer development, including a difficult-to-treat, chemo-resistant, highly metastasized form of prostate cancer.
"Since the combination of 2-DG and ABT-263/737 induces rapid apoptosis through the intrinsic pathway, meaning through mitochondria, it leaves little room for interference by a cancer cell's highly active mutagenic programs," Perkins said.
The combined treatment, however, does not work on all cancers. "There are certain cancers that are resistant or in which this would cause lymphopenia and thrombopenia," said Yamaguchi. Lymphopenia and thrombopenia are a loss of white blood cells or platelets, respectively. The scientists are developing "workarounds" to counteract these adverse effects, possibly by using stored hematopoietic stem cells for transplant after treatment.
"We are now trying to initiate a clinical trial for the combination," said Yamaguchi. "Since both 2-DG and ABT-263 (Navitoclax) are already in Phase II clinical trials (for other treatments), we know something about the safety of these agents. Once we take precautionary measures, the 2-DG-ABT combination therapy may prove an effective alternative to some existing cancer therapies. We may have found a simple, partial solution to a very complex disease."
|Contact: Scott LaFee|
University of California - San Diego