Zosia Chustecka

November 20, 2009

November 20, 2009 — Pancreatic cancer remains one of the deadliest of all cancers. By the time it is diagnosed, it is usually inoperable, and only about 5% of patients respond to chemotherapy. One of the reasons is that pancreatic tumors surround themselves with a protective wall of fibrous tissue, known as the stroma, which makes it "extraordinarily difficult" for drugs to get through, said Craig Thompson, MD, director of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. "This has been an intractable problem, and one that is unique in the cancer field," he added.

Dr. Thompson was speaking at a press conference during the AACR-NCI-EORTC 2009 International Conference on Molecular Targets and Cancer Therapeutics, during which several new approaches to the treatment of pancreatic cancer were highlighted.

"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," Dr. Thompson noted.

One approach highlighted at the press conference showed that an already marketed product, nab-paclitaxel (Abraxane), was effective at weakening the stroma surrounding the pancreatic tumor and enhanced penetration of the standard chemotherapy, gemcitabine (Gemzar).

What we are seeing here is a real paradigm shift.

"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, just the smart combination of what is already available," said Anirban Maitra, MD, associate professor of pathology and oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr. Maitra and colleagues presented data from mouse studies showing an almost doubling of the response rate. Histology examination showed that nab-paclitaxel depleted the stroma around pancreatic cancer mouse xenografts, allowing more gemcitabine to reach the cancer. Intratumoral concentrations were 3.7 times higher than those seen when gemcitabine was used alone.

This combination is turning it into a Swiss cheese full of holes.

"If you imagine the stroma as a hard American cheese, then this combination is turning it into a Swiss cheese full of holes," Dr. Maitra told journalists.

This combination of nab-paclitaxel plus gemcitabine has shown promise in an early clinical trial involving 67 patients conducted by researchers at TGen in Phoenix, Arizona. Preliminary results reported earlier this year showed that patients treated with the combination had a median survival of 10.3 months, compared with the 5.7 months that has been seen historically with gemcitabine alone (presented at the 2009 annual meeting of the American Society of Clinical Oncology: Abstract 4525).

"This near doubling of survival is remarkable," Dr. Maitra said, pointing out that adding the targeted therapy erlotinib to gemcitabine extends survival by only about 3 weeks.

A phase 3 trial of the combination of nab-paclitaxel and gemcitabine in pancreatic cancer is now in progress, and this might become a standard of care, Dr. Maitra reported.

Nab-paclitaxel is already marketed for use in breast cancer in specific circumstances, and was recently granted orphan drug status in the United States for the treatment of pancreatic cancer and stage 2b to 4 melanoma.

Intracellular Delivery With Nanotechnology

Another approach also improves drug delivery, but in a different manner. Researchers at Massachusetts General Hospital described how they used nanotechnology to deliver the antiangiogenesis agent bevacizumab (Avastin), together with a photodynamic therapy, directly into pancreatic tumor cells. In a series of mouse studies, the delivery of this combination of drugs showed at least a 2-fold reduction in metastasis to the liver, lungs, and lymph nodes, compared with bevacizumab alone.

Bevacizumab targets endothelial growth-factor receptors (EGFR), but when it is administered as an injectable, it can reach only the receptors outside the cells. "This is the first time that we have shown that it can effectively be delivered and work inside the cell as well," explained Tayyaba Hasan, PhD, professor of dermatology at Harvard University and Massachusetts General Hospital in Boston.

Such intracellular delivery could "drastically reduce the serious side effects associated with the drug" and could improve its efficacy, she said. "This could have a major clinical impact on diseases that are currently being treated with bevacizumab," she added.

The same approach — using nanotechnology to deliver therapies intracellularly — is being used for a different combination of products. Prakash Rai, PhD, a research fellow working with Dr. Hasan, described using a combination of 2 experimental products — C225, which targets EGFR, and PHA-665725, which targets the MET pathway — plus a photodynamic therapy. So far, this group has shown a reduction in tumor burden. Mouse studies are continuing to determine if there is any effect on metastasis or long-term survival.

MicroRNA to Suppress Tumor Growth

The final approach highlighted at the press conference was the use of microRNA, proteins that regulate gene expression, to suppress tumor growth. This approach has already demonstrated some benefit in liver cancer.

Liang Xu, PhD, MD, assistant professor of radiation oncology at the University of Michigan in Ann Arbor, presented in vitro data that showed that the microRNA product miR-34 acts as a tumor suppressor and, in particular, reduced the number of tumor-initiating cells, known as cancer stem cells. Further studies with miR-34 delivered by nanotechnology are now underway.

One important implication of this microRNA approach is that it might be applicable to many different cancers, Dr. Thompson noted. Various cancers have now been shown to have a population of cancer stem cells that are highly resistant to chemotherapy, he explained.

The researchers have disclosed no relevant financial relationships.

AACR-NCI-EORTC 2009 International Conference on Molecular Targets and Cancer Therapeutics: Abstracts A2, A127, A53, presented November 16, 2009; Abstract C246, presented November 18, 2009.


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