Emerging Therapies in Pancreatic Cancer Show Promise
PHILADELPHIA – Pancreatic cancer remains one of the deadliest and hardest to treat cancers. After diagnosis, patients tend to live only six months and less than 5 percent survive to five years.
“In terms of a patient population, there is very little we can do for them once we find the cancer,” said Craig Thompson, M.D., director of the Abramson Cancer Center at the University of Pennsylvania.
The currently available treatment is gemcitabine, which is sold as Gemzar by Eli Lilly and Company, but the response rate with this treatment is typically only 5 percent. Researchers are working to develop new ways of treating pancreatic cancer and early scientific studies are showing promise.
As part of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Thompson moderated a press conference on emerging treatments in pancreatic cancer on Tuesday, Nov. 17, 2009, in Room 202 of the Hynes Convention Center in Boston, Mass., from 1:00 p.m. to 2:00 p.m. ET.
Researchers presented new data on nanotechnology methods of delivering therapies, angiogenesis, microRNA and the tumor microenvironment.
“Successful treatment of pancreatic cancer is going to require new and creative thinking from the scientific community, and the research being presented at this meeting is a good example of that,” said Thompson.
The following abstracts were presented at the press conference:
# A2. Targeting intracellular VEGF using nanotechnology for sub-cellular delivery of bevacizumab improves efficacy of combination therapy against pancreatic cancer
New nanotechnology-based delivery of a common anti-angiogenesis agent improved efficacy in models of pancreatic cancer, suggesting a possible therapy for this hard to treat disease.
Researchers at Massachusetts General Hospital used bevacizumab, sold under the brand name Avastin by Genentech, which is an anti-angiogenesis drug designed to starve cancerous tumors of the blood they need to grow. The Food and Drug Administration (FDA) has approved the agent for several cancers (including breast and colorectal cancers) and oncologists use it to treat other cancers as well.
Avastin works by removing vascular endothelial growth factor (VEGF), which is a protein that stimulates new blood vessel growth in tumors. However, as administered currently, it has had limited efficacy because it can only remove some of the VEGF on the outside of the tumor cell. VEGF can still thrive inside the cell where it is made and continues to be secreted outside, long after the injected Avastin has disappeared and thus contributes to tumor growth.
“In order for these agents to work you have to deliver them at the right place at the right time. While Avastin is able to partially mop up VEGF outside a tumor cell, this is the first time we have been able to show that it can effectively be delivered and work inside the cell as well,” said Tayyaba Hasan, Ph.D., professor of dermatology at Harvard Medical School and Massachusetts General Hospital.
Hasan and colleagues designed a nanotechnology-based delivery device to simultaneously deliver Avastin along with an FDA approved light-activated chemical within the tumor of mouse models of pancreatic cancer. In a previous small study, photodynamic therapy, a light activated therapy, enhanced the treatment outcome in pancreatic cancer. However, in clinical trials where standard chemotherapy for pancreatic cancer was combined with bevacizumab, there was no benefit to survival.
Their results showed that the nanotechnology successfully delivered Avastin to the interior of a pancreatic cancer cell and improved the acute treatment response in mice treated with the nanotechnology compared with those treated with Avastin alone. The combination with photodynamic therapy was associated with even greater improvements.
Absent the nanotechnology delivery, at the low doses of agents used, neither Avastin nor photodynamic therapy significantly improved the acute treatment effect of Avastin. The researchers also noted that Avastin delivered by nanotechnology caused at least a two-fold reduction in metastasis to the liver, lungs and lymph nodes.
“This finding represents a new paradigm for Avastin-based treatment that could be delivered with greater effectiveness and with less toxicity,” said Hasan.
# C246. Nab-paclitaxel targets tumor stroma and results, combined with gemcitabine, in high efficacy against pancreatic cancer models
Treatment with nab-paclitaxel appears to weaken the stroma, or protective wall, surrounding a pancreatic tumor and increase the potency of gemcitabine, the most commonly used agent for pancreatic cancer, when the two drugs are used in combination.
“What we are seeing here is a real paradigm shift, because it shows that effective treatment does not necessarily require a fancy new molecular therapy but just the smart combination of what is already available,” said Anirban Maitra, M.D., associate professor of pathology and oncology at the Johns Hopkins University School of Medicine.
Both gemcitabine, sold as Gemzar by Eli Lilly and Company, and nab-paclitaxel, sold as Abraxane by Abraxis Bioscience, are clinically available treatments. Researchers at TGen in Arizona and other clinical centers in the United States have already tested the combination in humans and reported preliminary results earlier this year demonstrating a median survival of 10.3 months, as compared to the previously reported 5.7 months survival seen with gemcitabine alone.
Maitra and colleagues sought to determine the mechanism behind that dramatic finding in 11 freshly generated pancreatic cancer mouse xenografts from Johns Hopkins laboratories.
Replicating the human trial, the researchers found the response rate of the combination in mice was almost double of what was seen with either agent alone.
A further evaluation by histology at the cellular level showed that nab-paclitaxel depleted the stroma surrounding pancreatic tumors and thus was able to facilitate delivery of gemcitabine more effectively. Those treated with the combination had a gemcitabine concentration in tumors that was 3.7-fold higher than what was seen with gemcitabine alone.
“What we have done is effectively make gemcitabine-resistant tumors into gemcitabine-sensitive tumors with the added punch of nab-paclitaxel, so we’re getting synergy of the two-drug combination and better delivery of gemcitabine where it needs to be,” said Maitra.
# A127. Combination therapy targeting EGFR/MET crosstalk using nanotechnology improves photodynamic therapy treatment of pancreatic cancer
Simultaneous inhibition of the epidermal growth factor receptor (EGFR) and MET signaling pathways significantly reduced pancreatic tumor burden and toxicity when inhibitors were delivered using nanotechnology, according to research conducted at Massachusetts General Hospital.
“These pathways are key to the growth of pancreatic tumors, and the fact that we were able to deliver these inhibitors in combination represents a significant step forward,” said Prakash Rai, Ph.D., a research fellow working in the Tayyaba Hasan, Ph.D., laboratory at Massachusetts General Hospital.
Cell growth pathway inhibition is a recognized therapy for cancer, and current treatment regimens typically deliver large molecules such as antibodies outside of a cell, whereas the smaller molecules that are readily delivered inside the cell are often associated with high toxicity. In this report, nanotechnology appears to overcome these problems; it was able to simultaneously deliver an antibody and a small molecule inside the cell while reducing the toxicity of the small molecule.
To target EGFR, researchers used C225, a receptor antibody that has shown no survival benefit in patients with pancreatic cancer. Because different cancer growth pathways have “cross talk” capabilities, combinations that simultaneously target these “cross-talking” pathways may have better outcomes. For the current study, Rai and colleagues simultaneously targeted the EGFR and the MET pathways by combining C225 with the small molecule inhibitor PHA-665752 in a nano-construct.
“Combination pathway inhibition is extremely important because if you just inhibit one pathway, the cancer cells are smart enough to grow using the other signaling pathway, so you have to attack both at once,” said Rai.
These two therapies were further enhanced by a light-activated treatment, photodynamic therapy, which by itself was reported to have improved median survival in pancreatic cancer patients in a small study. Nanotechnology-based delivery of the two agents successfully positioned the therapy on the inside of a tumor cell and reduced the local tumor burden.
The researchers are continuing their studies to determine if there is any effect on metastasis and long-term survival.
# A53. Tumor suppressor microRNA miR-34 inhibits human pancreatic and gastric cancer stem cells
Treatment with miR-34, a microRNA, significantly reduced pancreatic and gastric cancer stem cells, which suggests the molecule may be a potential therapeutic agent in these cancers.
Cancer stem cells are the tumor cells left over after chemotherapy that, in nearly all cases, lead to regrowth of the tumor. Typically, these cells are resistant to conventional treatments. Researchers are looking to microRNAs, which are proteins that regulate gene expression, as potentially therapeutic and they have already demonstrated some benefit in liver cancer.
“MiR-34 may be a new player in treatment for these very aggressive tumors because it acts as a tumor suppressor and can be delivered effectively,” said Liang Xu, Ph.D., M.D., assistant professor of radiation oncology at the University of Michigan.
Xu and colleagues examined the role of miR-34 in p53-mutant human pancreatic and gastric cancer cell lines. They found that restoration of miR-34 inhibited tumor cell growth, increased cell death and sensitized the cancer cells to chemotherapy and radiation.
Significantly, restoration of miR-34 reduced the number of tumor initiating cells, or cancer stem cells.
Xu is currently leading a research team that will investigate miR-34 as a potential therapeutic agent delivered by patented nanotechnology, which is funded by a grant from the National Institutes of Health.
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