Monday, September 8, 2008

Rethinking the war on cancer

One of the many disconcerting things about getting cancer -- or having a friend or loved one get it -- is the sudden undermining of your sense of progress. (Literally: I tend to think of "progress" as a good thing, and during one of my early doctor's visit I was pleased when the fellow said something about progress after a CT scan. She meant, of course, that my disease was advancing.) For all the new understanding of the genome, the new smart drugs, the new collaborative research centers and the advances in basic biology made every day, the outlook for many people with metastatic cancer isn't appreciably better than it was 30 years ago. 

In an excellent, if depressing article, Newsweek tries to offer a bracing corrective to the usual puff coverage of new advances, drugs and, er, progress. The idea isn't so much to knock down hope as it it is to suggest that we need a change in how cancer research is approached and funded. The article is here.

A corrective:

She has seen real progress in her 19 years in practice, but the upbeat focus on cancer survivors, cancer breakthroughs and miracle drugs bothers her. "The metaphor of fighting cancer implies the possibility of winning," she said after seeing the last of that day's patients one afternoon. "But some people are just not going to be cured. We've made tremendous strides against some cancers, but on others we're stuck, and even our successes buy some people only a little more time before they die of cancer anyway." She pauses, musing on how the uplifting stories and statistics—death rates from female breast cancer have fallen steadily since 1990; fecal occult blood testing and colonoscopy have helped avert some 80,000 deaths from colorectal cancer since 1990—can send the wrong message.
And some precedent for possible new approaches...
At the same time that molecular biologists were taking the glamorous, "look for the cool molecular pathway," cojones-fueled approach to seeking a cure, pediatric oncologists took a different path. Pediatric cancer had long been a death sentence: in Farber's day, children with leukemia rarely survived more than three months. (President Bush's sister Robin died of the disease in 1953; she was 3.) Fast-forward to 2008: 80 percent of children with cancer survive well into adulthood.

To achieve that success, pediatric oncologists collaborated to such a degree that at times 80 percent of the children with a particular cancer were enrolled in a clinical trial testing a new therapy. In adults, it has long been less than 1 percent. The researchers focused hardly at all on discovering new molecular pathways and new drugs. Instead, they threw everything into the existing medicine chest at the problem, tinkering with drug doses and combinations and sequencing and timing. "We were learning how to better use the drugs we had," says pediatric oncologist Lisa Diller of Dana-Farber Cancer Institute and Children's Hospital Boston. By 1994, combinations of four drugs kept 75 percent of childhood leukemia patients—and 95 percent of those enrolled in a study—cancer-free. Childhood brain cancer has been harder to tame, but while 10 percent of kids survived it in the 1970s, today 45 percent do—a greater improvement than in most adult cancers. (To be sure, some scientists who work on adult cancers are sick of hearing about the noble cooperation of their pediatric colleagues. Childhood cancers, especially leukemias, are simpler cancers, they say, often characterized by a single mutation, and that's why the cure rate has soared. Neutral observers say it's a little of both: pediatric-cancer scientists really did approach the problem in a novel, practical way, but their enemy is less wily than most adult cancers.)


Greg Pawelski said...

To beat down cancer mortality, oncologists need to target all the many cancers that make up a cancer - the dozens of different pathways that cells use to proliferate and spread. That is the leading edge of research today, determining how this patient's tumor cells work and hitting those pathways with multiple drugs, simultaneously or sequentially, each chosen because it targets one of those growth, replication and angiogenesis pathways. The hope is to match tumor type to drug. We need to make the next leap, getting the right drug to the right patient. I agree!

Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes. In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell.

The key to understanding the genome is understanding how cells work. The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one target or pathway. Another challenge is to identify for which patients the targeted treatment will be effective. Screening compounds for efficacy and biosafety.

Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone. You need to measure the net effect of all processes within the cancer, acting with and against each other in real time, and test living cells actually exposed to drugs and drug combinations of interest.

Multi-targeted drugs can be well-predicted by measuring the effect of the drugs on the function (is the cell being killed regardless of the mechansim) of live cells, as opposed to a target (does the cell express a particular target the the drug is supposed to be attacking). While targeted screening tells you whether or not to give one drug, functional screening can find other compounds and combinations and can recommend them from the one analysis.

SG said...

Thanks for your thoughts, greg. The genius of cancer cells is appalling. I'm currently approaching another juncture in my treatment, and I'm wrestling with whether or not I should invest in doing either a chemosensitivity assay or immunohistological analysis of my tumor.

Greg Pawelski said...

Doing half the science is better than doing no science at all, but remember the major differences.

Molecular testing methods detect the presence or absence of selected gene mutations which theoretically correlate with single agent drug activity. Tests are performed using material from dead, fixed or frozen cancer cells, and are never exposed to anti-cancer agents. Established cell line is not reflective of the behavior of "fresh" tumor cells in primary culture in the lab, much less in the patient. You get different results when you test passaged cells compared to primary, fresh tumors.

Cell- based testing methods assess the net effect of all inter-cellular and intra-cellular processes occurging in real-time when cell are exposed to anti-cancer agents. Tests are performed using intact, living cancer cells plated in microclusters. It allows for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.

Paraffin embedded, fixed, minced, or frozen tissue can change over time. One gets more accurate information when using intact RNA isolated from "fresh" tissue than from using degraded RNA, which is present in paraffin-fixed tissue (preserved in paraffin wax).

The consistent and specific control of cancer will require a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness. A sufficient number of independent methods of cell killing must be employed so that it is too improbable for cancer cells to evolve that can escape death or inactivation. It must examine "functional" aspects of every cell in the body and must do so for a prolonged period of time.

Today, we have the ability to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then use two, three, four or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process.