v4n4 - Science Fiction in the 21st Century

New approaches take shape in cancer detection, treatment and response evaluation.

Breakthrough discoveries have changed how doctors think about cancer. Scientists are developing a way to manipulate gene expression to allow certain therapies to work. New methods that tell doctors if a drug is working show promise. And in the next decade, sub-microscopic machines may be sent into the body to diagnose and treat cancer at the earliest stage. Armed with these novel strategies, experts predict an inevitable paradigm shift.

Gene Knockdown Technology

RNA interference, or small interfering RNA (siRNA), silences genes by preventing the development of proteins, such as HER2 and vascular endothelial growth factor, that are overexpressed in cancer cells.

Cancer cell DNA contains mutant genes called oncogenes that promote uncontrolled cell growth. Inside all cells, DNA carries the cell’s genetic information inside the nucleus. Because DNA cannot pass through the nuclear membrane, messenger RNA (mRNA) takes pieces of information that code for a certain protein from the DNA. Outside the nucleus, the mRNA acts as a signal to turn on cellular production of the protein.

With intravenous siRNA therapy, it binds to the mRNA before it can signal protein production, and through a series of events, the mRNA is destroyed before the information is used to make the protein responsible for cancer growth. Targeting the mRNA itself is potentially a more efficient approach than blocking the activity of growth factor proteins.

Some siRNAs currently in preclinical research could be used in combination with chemotherapy to battle drug resistance. Sirna-027 targets the VEGF receptor, which is involved in promoting growth of new blood vessels. Another siRNA in development by Sirna Therapeutics targets the VEGF pathway in cancer. In preclinical trials, it reduced tumor growth by half by inhibiting the protein production of VEGF when compared with controls. Testing of siRNAs in cancer patients is expected to begin in early 2006.

Evaluating Tumor Response

Currently, physicians determine if therapy is successful by measuring the size of the tumor and if it has grown, stabilized or shrunk. Advances in imaging can help doctors determine if cancer therapies are working within weeks instead of months. Image-guided interventional clinical trials are evaluating the role of therapies directed by imaging techniques.

Annexin V is a protein that binds to dead or dying cells, including cancer cells. When annexin V is linked to a radioisotope marker, an imaging scan can show if cancer cell death is occurring. Researchers can use this information to decide if therapy should be continued or a new therapy tried.

Because annexin V is attracted to apoptosis (programmed cell death), scientists are researching whether annexin V can be tagged with a toxin that will be delivered directly to the cancer cell. The more apoptosis at the tumor site, the more annexin V will be attracted to cancer cells and the better the drug will work.

Positron emission tomography (PET), an imaging tool used to diagnose cancer, is now being tested to determine if cancer therapy is working much earlier than conventional imaging scans, such as computed tomography and magnetic resonance imaging. PET scans use a fluorescent marker, such as FDG (fluoro-deoxyglucose), to show tumor growth. Because cancer cells have a higher metabolic activity than healthy cells, deoxyglucose is gobbled up by cancer cells faster than normal cells. When deoxyglucose is marked with a radioisotope, cancer cells can be located. When predicting therapy response, doctors can compare PET scans taken before and after therapy to determine if metabolic activity of cancer cells has increased or decreased rather than waiting for the volume of the tumor to change.

Other fluorescent markers are being explored in addition to FDG. Fluoro-L-thymidine (FLT) can show tumor changes earlier than FDG-PET. One study found that a 10-minute FLT-PET scan taken two weeks after the first round of chemotherapy can help predict if a specific chemotherapy regimen will have long-term benefit in breast cancer patients. It has shown the best results when used to judge response in large and aggressive tumors.

Nanotechnology and Cancer

Imagine tiny machines that could enter the human body, diagnose cancer immediately upon its development, treat the cancer, monitor the progress of the treatment and detect any recurrence. It sounds like science fiction, but nano-technology applications for cancer may be a reality within the next decade. Nanotechnology in development for cancer applications include:

• Cantilevers are minuscule bars anchored at one end that have been designed to aid in cancer detection at an extremely early stage. The cantilevers are designed to bend when they bind to DNA sequences or proteins present in specific types of cancer, indicating to the physician that cancer is present.
• Nanopores, miniature holes that allow DNA strands to pass through one at a time, let researchers find errors in the DNA code that are associated with cancer.
• Nanotubes are carbon rods about half the diameter of a DNA molecule. These devices enable researchers to trace the shape of DNA. Computers then make a map based on the DNA shape that enables researchers to locate mutations that may develop into cancer.
• Quantum dots are nano-sized crystals used to create probes to detect DNA sequences associated with cancer.
• Nanoshells are made up of beads coated with gold in various thicknesses, which determines what wavelengths of light the beads will absorb. Heat generated when the nanoshells absorb light has killed tumor cells in laboratory cultures while leaving nearby cells unharmed. Some nanoshells absorb near-infrared light, which can easily penetrate 1 or 2 inches of human tissue.

Before these devices can be used in the clinic, scientists need to solve problems such as how to keep them in the body long enough to do their job without making them so large that they accumulate in the organs and become toxic. It is estimated that devices used for a single purpose, such as quantum dots for cancer detection and nanoshells for cancer treatment, may be available within five to 15 years. The multifunction machines are expected within 15 to 20 years.