Recent Advances

in Cancer Treatment

Progress in the conquest of cancer has occurred in many directions:

• early detection

• prevention

• genetics

• new therapies

• biologics

• drugs (see drugs for cancer)

• hormones (see hormones for cancer)

• gene therapy

• specialized technical advances

Recent Advances in Medical Oncology

Available in the Community

Monoclonal Antibodies

One exciting new advance is the development of monoclonal antibodies. Antibodies are made by all of us. They are part of the body's defense system. When you are invaded by germs or other potentially dangerous organisms, you produce antibodies in an attempt to kill the invaders. The substance your body is attacking is called an antigen. A monoclonal antibody has only one task. Its' task is to hunt down and kill a specific antigen.

It has been known for a number of years that tumor cells have some differences from normal cells. The problem has been to develop drugs which reliably distinguish between normal cells and cancerous cells. This has been extremely difficult and this inability to tell normal from tumor cells has resulted in the use of agents which cause considerable side effects.

Now several monoclonal antibodies have been developed which are in clinical use. The two that are available locally are Rituxan and Herceptin.

In order to better understand how these treatments work, please refer to the picture below.

Different receptors on cell surface, each has a specific function.

We want to get antibodies to attach to ones that give the cancer cell a growth advantage.

Each receptor plays a role in the survival and proliferation of the cell. For example, the receptor Her 2 Neu is found on 30 percent of all breast cancers. This receptor "looks for" growth factors. The cancer cell can then use these growth factors to thrive. Breast cancer cells with excess Her 2 Neu are biologically "meaner" than cells without Her 2 Neu.

Herceptin is an antibody that "fits over" the Her 2 Neu receptor found on the malignant breast cancer cell and renders it nonfunctional. This agent is currently being used to treat breast cancer patients. Herceptin causes no nausea, no hair loss, and no white blood count suppression. It can easily be given in the physician's office over two hours weekly.

Herceptin can be used alone or combined with other agents used in the battle against breast cancer.

Her 2 Neu cancer cell with many receptors on its surface.

This receptor has also been found in several other tumor types. Here in Anniston, we are currently part of a protocol study which is seeking to determine whether Herceptin might be active in the most common type of lung cancer.

Monoclonal antibody treatment has also been developed to treat lymphomas and leukemia.

Rituxan is an FDA approved moncloncal antibody that "looks for" the CD20 receptor. This receptor is often found on non-Hodgkins lymphoma cells and on chronic lymphocytic leukemia cells.

If the receptor is present, Rituxan will bind to it and initiate a chain of events leading to cell death. Rituxan has been a major boon to cancer patients because it is specific and thus it causes no toxicity to the cells of organs and tissues that do not have the receptor. Rituxan can be used alone or combined with standard chemotherapy drugs.

In the last several months, the FDA has released Mylotarg for the treatment of adults with acute myeloid leukemia (excluding acute promyleocytic leukemia). Mylotarg is a monoclonal antibody which "looks for" a receptor named CD 33. A poison has been attached to this monoclonal antibody. If CD 33 is present Mylotarg will bind to it, and the poison to which it is bound will kill the cell. Unfortunately, because of the poison attached to this monoclonal antibody, it is a much more toxic treatment than the two treatments discussed above.

Monoclonal antibodies coupled with a radioisotope are being developed and should be available in the next several months. These radiolabled monoclonal antibodies will be used in the fight against lymphonia.

Angiogensis

Angiogensis means the growth of new blood vessels. Most of you have read news releases about anti-angiogenesis drugs. One of these is available clinically and several are in patient trials.

When patients die from cancer they usually die from metastatic disease - that is disease that has spread through the bloodstream to other sites.

When cancer cells travel to a new site in the body, they can only divide a few times unless they get blood vessels to supply them with nutrients.

Metastsis is a complex process.

T= Tumor

C= Cancer Cells "wandering" in tissue around the main tumor mass

E= Endothelial cells (lining cells)

Lets picture the formation of new blood vessels as the steps required to build a road to connect a new hotel to a highway.

In building the new road, the 1st step would be to mobilize the bulldozers and clear out rocks, trees, stumps and all other obstructions. The next step would be to lay down asphalt to connect the highway to the hotel. Finally, the asphalt needs to set properly so that the road will be able to support the weight of the traffic.

In the 1st step of angiogenesis, a class of enzymes (metaloprotinases) act like miniature bulldozers that break down the basement membrane and the extracellular matrix surrounding existing blood vessels.

Several metaloprotinase inhibitors are in clinical trial.

Next, new blood vessel formation begins as cells divide to form a set of vascular tubes. This "laying down of the asphalt" is tightly regulated by a balance between factors that promote endothelial cell growth and factors that inhibit it. These new blood vessels are "host" and not "tumor". Metastatic tumors "call out" and get the patient to make the tumor its' blood supply.

Researchers have identified over a dozen naturally occurring compounds that promote blood vessel growth. Thus, unfortunately, there will not be one "magic bullet" to stop angiogensis. Even more of a problem: different patients with the same tumor type may have different angiogenesis factors; ie. Mr. Smith and Mr. Jones, both with prostate cancer, may express VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor) respectively. Thus each would require a different drug. VEGF is probably the best studied of these angiogensis factors.

Just as an aside, all patients with macular degeneration over express (have too much of) FGF. Therefore, this illness may soon have a new treatment which will be effective for many patients with this disease.

The various steps that help "set the asphalt" properly are not well understood.

Although these steps are complex, they provide several sites where interruption of one process could foil the entire "construction project".

Several anti-angiogenesis drugs are in clinical trial - likely 1 or more will be in wide spread use with in the next five years.

Thalidomide, which is available in Anniston, has shown objective response rates in multiple myeloma and primary brain tumors.

Gene therapy

Gene therapy has figured prominently in the news; especially as the Human Genome Project is nearing completion.

Gene therapy was 1st thought of as a correction of inherited defects with a known single defective gene (sickle cell disease, cystic fibrosis, thalasemma, etc.)

Cancer cells would appear to be poor targets for gene therapy because they contain multiple errors each of which contribute to the growth potential of the cell. However, it may be possible to replace non-functioning tumor suppressor genes or to inactivate genes which promote cancerous growth.

Gene therapy for cancer is probably years away from clinical use.

Gene therapeutics (as opposed to gene therapy) involves transferring a novel gene into a cell. This gene then produces an enzyme that metabolizes a relatively non-toxic drug into a toxic one. The patient is then given the drug. Cells that do not have the gene would be exposed only to the non-toxic precursor drug and therefore would survive. Cells that have the introduced gene would metabolize it to the toxic drug and die.

One major problem with this approach is ensuring that the gene only enters tumor cells - and not normal cells. This obstacle has been dealt with by direct injection into the tumor. Obviously, this approach will not work for a tumor that has already spread to other areas of the body. Primary brain tumors are the subject of most of these trials. Several trials have been reported - these have involved injecting a herpes virus in the tumor and then treating the patient with the antiviral drug glancyclovir.

Response rates have been low, but enough patients have had clinical benefit to show "proof of principle."

Keep tuned - this site will feature new advances as they become available.