Complexity

We put Max on IV Topotecan for 5 days January 28-February 1. Since then, his blood counts hit the ground and haven't gotten up to any reasonable level since. Look at his numbers in January and February and you can see the cliff dive they took right after the 5 days of Topotecan:


Legend: VMA/HVA=urine markers indicative of tumor cell activity - disregard HVA. WBC=white blood cell. RBC=red blood cell. PLT=platelets. ANC=absolute neutrophil count

His VMA level shot up to a recent high - 17.4. And just today I was admiring the nice downward trend. We'll measure again late in the week to see (hopefully) if it was a fluke. If not, it probably means that the cancer is getting active. For reference's sake, at official relapse in November '06, his VMA was only at 22 so it doesn't have much higher to go before alarm bells start to be sounded in the Mikulak household.

His VEGF, a blood factor that is an inflammatory marker signalling new blood vessel growth (angiogenesis) and thus tumor growth, has gone up from 40 on 1/14 to 113 on 2/12. The normal range is 31-86 pg/ml so something is going on. Sickness and/or an inflammatory response (ankle sprain, etc) can also raise VEGF, so its not entirely isolated to cancer activity.

Nevertheless I am personally very nervous - more so than usual. It's probably due also to the fact that we lost two precious kids the past few weeks (Eden Bruskow and Michael Haley) who were very similar to Max in that they were both taking nifurtimox for relapse and had been doing so for a while (Michael since before Max).

So, we continue to wait for Max's counts to climb so that he can get on his oral cytoxan again. In an attempt to get his counts up, we are pulling out all the stops - shark liver oil for platelets, and calf liver for RBC. The trouble is these remedies take time and he needs to get back on his chemo now.

On a more positive front, in today's WSJ an article about newer cancer drugs and some trends which these indicate medicine is heading, all of which favor the approach we are taking with the projects we are funding through MagicWater:

• Personalized medicine - our first project in this area soon to be announced.
  
  "Now that we understand that everything is doggone different, I think we have to look at each patient completely," Dr. Sugarbaker says. "What we need to do is pair up the right patient with the right drug."
  
  
• Looking at drugs developed for other, large-population (ie, adult) cancers and other diseases and testing them in neuroblastoma.
  
  ...progress in developing cancer drugs may require targeting them to tiny groups of patients.

There are many things in this article I disagree with also. Such as the notion that the only way to fight cancer effectively, is to do gene testing on an individual's cells to determine the appropriate treatment. But a counter-point in the article was also rendered.

"Finding a mutation in a tumor doesn't prove the mutation caused the tumor."

In the end, the only thing that matters if you are battling cancer is, "does it work?"


Study: More Complexity In Tailoring Cancer Drugs
By KEITH J. WINSTEIN
February 26, 2008; Page B1

The genetic mutations in cancer cells may vary in every patient, a study found, suggesting that drugs will need to be tailored more finely to small groups.

The small study, by doctors at the Brigham and Women's Hospital in Boston and scientists from a gene-reading unit of Roche Holding AG, is among the first to look comprehensively at the genes in cancerous tumors to find which genes went awry. It's part of a new wave of medical studies using cheaper ways of reading DNA -- the chemical blueprint found in every cell -- that promise to change the understanding of disease.

The doctors, led by David Sugarbaker, a surgeon, examined four patients with a rare and deadly lung-sac cancer called pleural mesothelioma, which strikes about 3,000 people a year. The results were cause for hope and chagrin: of four patients studied, each patient's tumor had between two and six genes that had mutated, when compared with healthy cells from the same patient. Such mutations are thought to be causes of cancer. But every patient's tumor had a different group of mutated genes, and no gene was mutated in more than one patient.

That could explain why chemotherapy drugs work well in some patients and not at all in others, the doctors say. But it also means that progress in developing cancer drugs may require targeting them to tiny groups of patients. The study was published online yesterday by the journal Proceedings of the National Academy of Sciences.

The findings suggest that companies may find more success with drugs like Genentech Inc.'s Herceptin, which targets a genetic mutation found in about 20% of breast cancers; and Novartis AG's Gleevec, which attacks a particular mutation found in certain kinds of leukemia.

But it also raises the uncomfortable prospect that cancers in some patients may be so unusual that the cost of developing drugs to treat them might be prohibitively high based on the market that could benefit from them.

Dr. Sugarbaker argues that comprehensively surveying the mutated genes of patients' tumors might help in figuring out which existing cancer drugs can work on which patients. "Now that we understand that everything is doggone different, I think we have to look at each patient completely," Dr. Sugarbaker says. "What we need to do is pair up the right patient with the right drug."

But some geneticists say that approach isn't yet cost-effective. In the study, it cost more than
$100,000 per patient to read out a tumor's genes and compare them with healthy cells from the same person -- and that was using newer, cheaper methods of DNA reading from Roche's gene-reading division, called 454 Life Sciences. Roche is one of several companies trying to make gene-reading technology more affordable. Others, considered less reliable, offer similar technology that could, if verified, bring the cost to around $12,000 per patient, the authors of the study say.

"Whether it's at all clinically useful is way premature," says Bert Vogelstein, a cancer researcher at Johns Hopkins University who published similar research, on breast and colorectal cancers, in 2006. "The problem is interpreting the results." Finding a mutation in a tumor doesn't prove the mutation caused the tumor, Dr. Vogelstein says.

The study published yesterday said the genes examined "could be causally related to cancer." The study didn't look at every single piece of DNA in the tumor cells -- just pieces that were active.

Cancer is believed to occur when a body's DNA, or deoxyribonucleic acid, changes during the many generations of cell replication that occur as a person ages. Each of the six billion letters that make up DNA have to be copied to make a new cell.

The copying process isn't perfect, so the DNA of two different cells in the same person might have 10,000 differences, according to various estimates. Normally those copying errors are harmless, but if enough changes, or mutations, occur, a cell can turn into a cancerous tumor that takes over the body.

The National Institutes of Health is spending $100 million to fund a much larger study, called the Cancer Genome Atlas Pilot Project, that aims to map out mutated genes in brain, lung and ovarian cancers. Preliminary results may be released later this year.

Dr. Sugarbaker contends that understanding the bad genes in tumors will change the way they are classified and described. Today, physicians examine a tumor under a microscope to figure out what kind of cancer it is -- a process known as biopsy. But in the future, "that biopsy will not go under a microscope," Dr. Sugarbaker says. Instead, he says, "every patient is going to need a [DNA] sequence done on their tumor" and cancers will be classified by their mutations, rather than broad categories such as lung cancer or breast cancer.

However, Jason Bielas, a researcher at the University of Washington who has written skeptically about such studies, questions whether DNA reading is worth it. "It doesn't seem like at this point that it is cost-effective to go down any route that uses this type of data to design drugs," he says.

Yet some believe that yesterday's study and others like it suggest a future where individual physicians could order a custom drug that attacks the particular mutations in a tumor without harming healthy cells. Even today, scientists can go to the Web site of the Ambion division of Applera Corp., a gene-reading company, input the DNA code of an undesirable gene and buy a chemical that can "silence," or neuter it, in a test tube. Several companies are working on such "gene silencing" techniques -- also called RNA interference -- including Merck & Co., Alnylam Pharmaceuticals1 Inc. and Silence Therapeutics PLC. But they are far from being ready to be used on cancer patients.

"The RNA interference strategies are actually showing quite spectacular results in the laboratory," says Richard Gibbs, director of the Human Genome Sequencing Center at the Baylor College of Medicine. "This is precisely the kind of study that opens up the prospect of using these tools for intervention."

Write to Keith J. Winstein at keith.winstein@wsj.com

URL for this article:http://online.wsj.com/article/SB120399752255692957.html