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Slipping Past Cancer's Barriers

Mauro Ferrari

Cancer’s Cunning Defenses

Like metastases, another key issue in cancer’s tenacity is the way that it “builds bunkers” to protect itself. There are many biological barriers in the body, and they can work in series, nesting within each other. All are subject to modifications in the process of cancer development. For example, as cancers grow, their internal hydrostatic pressure increases, opposing penetration into the tumor of drugs that circulate in the bloodstream. In addition, many cancers, including the high-mortality carcinoma of the pancreas, deploy a thin capsule of fibrous tissue around themselves, which is nearly impassable for medications. It is perhaps not surprising that most patients with an inoperable form of this pancreatic cancer survive less than six months from diagnosis.

Cancer also presents biological barriers at the individual cell level. Protective membranes can envelop the entire tumor cell, or its nucleus, or the vesicles that transport many drugs inside the cell. Even reaching the right cell with an exquisitely targeted drug is completely ineffective, therefore, unless the drug can get through those vesicles. Similarly, gene therapy requires that the nuclear membrane be breached.

As a cancer patient undergoes treatment, the challenges often get worse. The cells that repopulate cancers after chemotherapy generally are the hardiest survivors; they have an enhanced ability to expel substances toxic to them through particularly effective pumps in their membranes that push out ions and molecules. These cells stay dormant while the chemotherapeutic assault is raging, insulating themselves from injury, and then can reemerge after the storm and quickly regrow a new, often stronger cancer lesion. Having the right drugs is a good thing, but without delivery mechanisms that can overcome cancer’s formidable sequence of biological barriers, the drugs are limited, and will always be ineffective at eradicating metastatic disease.

The genetic diversity of cells in metastases ensures that cancer’s protective bunkers come in a large variety of forms as well. The chemical weapons that oncologists have to pierce and destroy one bunker many times will not harm most of the other barriers at all. Researchers have many drugs that work perfectly well against cancer cells in a cell culture dish, yet prove largely ineffective in clinical trials with patients.

New imaging tools can let us see how drugs penetrate into cancer lesions in living animal models of human cancer. When researchers, including myself and my colleagues, first did these experiments, we were initially surprised that drugs seemed to enter certain metastases, but not others, even in the same organ, although they came from the same primary tumor. But we have since found that this outcome is the almost universal norm.

These discoveries led me to a radical thought: It is not new drugs that we need, but profoundly new methods to make sure that the therapeutic agents (possibly even including some that had been discarded as failures) get into metastatic lesions and complete their job.

I do not believe that “curing cancer” will be possible unless we solve the problem of achieving effective mass transport against the diversity of biological barriers that cancer can build. So my colleagues and I have set out on this new approach, looking beyond better drugs and instead focusing on better ways to get them where they are needed.

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