SEPTEMBER / OCTOBER 2003

AROUND HARVARD

This article originally appeared in the August 2003 Harvard Health Letter and is provided courtesy of Harvard Health Publications.

Can smart bombs win the war on cancer?

By pinpointing abnormalities specific to tumor cells, a novel generation of cancer drugs may usher in a whole new era of cancer treatment.

Chemotherapy for cancer is proof that good can come of bad. During World War I, doctors noticed soldiers exposed to mustard gas had low white blood cell counts, a clue that the poison might preferentially attack bone marrow. Secret research during World War II led to the development of nitrogen mustard, a chemical cousin of mustard gas. After a scientist noticed that the new chemical was especially lethal to lymphoid tissue and dividing cells, cancer researchers figured it might be used to treat leukemias and lymphomas (lymph cancer). They were right — and the era of chemotherapy was born.

Through trial and error, dozens of other anticancer drugs have been discovered since (methotrexate, cyclophosphamide, and fluorouracil [5-FU], to name just a few). Often these drugs are much more effective when given together. The cure for cancer hasn’t been found, but amazing progress has been made with the right mixes of well-established agents. For example, more than 75% of children with leukemia and virtually all Hodgkin’s disease and testicular cancer patients can be treated so they’re free of cancer for a decade or more and don’t suffer late recurrences. Cancer specialists consider these cures.

But conventional chemotherapy leaves much to be desired. Cancer cells do become resistant to its effects. Many of the most common tumors (lung, breast, colorectal, prostate) are harder to treat. And the older drugs tend to attack all dividing cells, not just the cancerous ones. That’s why anemia, hair loss, immune suppression, and a variety of gastrointestinal problems (cells in the mouth and gut are among the fastest dividing cells in the entire body) are common side effects. Ut wise enim ad minim veniam, quis nostrud exerci tation ullamcorper suscipit laboris nisl ut aliquip ex ea commodo con sequat. Duis autem vel eum irure dolor in henderit in vulputate velit esse consequat.

Jamming the signal
Now cancer chemotherapy may be entering a phase with agents that are “smarter” than their predecessors. Rather than poison the cancer — and other cells with it — the strategy is to find a weakness in the armor. These novel agents can be grouped into four categories.

The receptor blockers
Receptors are molecules that jut out from a cell’s surface like stubby antennae. Cancer cells sometimes have too many of them or some that are stuck in an “on” position. By blocking receptors, a drug can cut a cancer cell off from the molecules that stimulate it to go into reproductive overdrive and spread. Examples include Herceptin (trastuzumab), a breast cancer drug and the first of this wave of drugs to be approved by the FDA, and Erbitux (cetuximab), a colorectal cancer drug that has had good results in several early trials but hasn’t yet been approved by the FDA (2003). Erbitux has been in the news because it was developed by ImClone Systems, the scandal-plagued company that Martha Stewart had stock in.

Tyrosine kinase inhibitors
Signaling pathways are elaborate chains of chemical reactions that run from a cell’s surface to its nucleus and the DNA within. They carry “messages” that activate genes, so they’re a major influence on cell growth and division. Several of the newer cancer medications are designed to jam these pathways by inhibiting tyrosine kinase, a crucial enzyme. The star tyrosine kinase inhibitor is Gleevec (imatinib mesylate). Approved by the FDA in 2001, it has been remarkably effective against chronic myeloid leukemia (CML), an adult blood cancer. It’s now the first-line treatment for CML. Iressa (gefitinib), an oral lung cancer drug approved by the FDA in May 2003, and Tarceva (erlotinib), an unapproved lung cancer drug (2003), are also tyrosine kinase inhibitors.

Anti-angiogenics
Angiogenesis is the growth of new blood vessels. Like any other tissue, tumors need blood, so cancer cells churn out proteins that recruit and grow new blood vessels. The idea that cancer could be treated by blocking angiogenesis and starving cancer cells of their blood supply was proposed in the 1970s by Dr. Judah Folkman, a Harvard researcher. He’s still the person most closely identified with the theory. The first positive results for an anti-angiogenic compound in a Phase III trial — the type of large, controlled study used for FDA approval — were announced in June 2003 at the annual meeting of the American Society for Clinical Oncology (ASCO). However, whether the drug works because of its anti-angiogenic effects or for some other reason is still open to question. The trial compared conventional chemotherapy plus anti-angiogenic Avastin (bevacizumab) with conventional therapy plus a placebo in people with metastatic colorectal cancer. People who took Avastin lived about 5 months longer (20.3 months vs. 15.6 months) than people who took the placebo.

Proteasome inhibitors
The proteasome is a complex of enzymes often compared to the cell’s garbage disposal. The theory is that cancer cells have more “garbage” proteins to dispose of than healthy cells, so the defective proteins will pile up and harm the cell if proteasome is disabled. The first proteasome inhibitor approved by the FDA is Velcade (bortezomib), a treatment for multiple myeloma, a bone marrow cancer.

Chemotherapy: Older Style and Newer Wave
	Conventional chemotherapy often damages DNA or other parts of the cellular machinery necessary for cell division.
	Newer medications act outside the nucleus, interfering with receptors and signaling pathways to the nucleus.

Some clouds in the silver lining
The newer drugs may be smarter, but they’re also more specialized and may prove to be less versatile than mainstay agents. Herceptin, for example, is used only in metastatic breast cancer patients — and then only in the 25%–30% whose cancer cells “overexpress” the HER2 protein on their surface. Gleevec has made headlines with some spectacular results, but it’s a proven therapy only in cancers that are relatively rare: CML, gastrointestinal stromal tumors (GIST), and a form of pediatric leukemia that accounts for 2% of all leukemias in children.

The newer agents don’t necessarily replace the older drugs. Erbitux, for example, is more than twice as effective when used with another conventional drug, irinotecan, than it is alone. As mentioned above, Avastin was tested in combination with other drugs.

Side effects haven’t gone away. Herceptin causes serious damage to heart muscle in some patients, although by adjusting the conventional chemotherapy drugs used with Herceptin some doctors say that problem can be avoided. Six of the 800 patients given Avastin suffered perforations of their intestines, and one died. Erbitux causes acne; indeed, acne is a sign that the drug is working. The numbers affected are small and, in the case of Erbitux, the problem isn’t serious compared with the benefit. Still, the side effects show that other cells also have the targets that these targeted agents hit.

Finally, so far, many of the positive results for the newer drugs have been in the sickest, most desperate patients — people whose cancer has spread and for whom other therapies have failed. That makes halting the cancer or keeping the person alive longer impressive. On the other hand, treatment at that late stage means that any sign of “activity” — the tumor shrinks just a little or stays the same size — or the addition of a few months of life gets hailed as a success, particularly by the private companies behind the drug. The hope, though, is that drugs with even the most modest effects on late cancer will eventually prove to be effective in earlier cases when a true cure is possible.

Copyright 2003-2004 Harvard Medical International   •   http://hmiworld.org/