Chemotalk Newsletter

Chemotalk Newsletter, Vol. 33: January 1, 2011

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Happy New Year!  I don't care how bad it is out there, we're still here, and for a lot of us, that's the best news of all.  After doing this newsletter for almost three years, I think I've discovered that nobody needs the information this newsletter provides, until they do need it.  So for that reason, it will keep going as long as I do...and I plan on being here awhile ...

This piece came in just as I was finishing last month's newsletter.  I knew then it was important enough to lead the next issue:


By Andrew Pollack

For the last decade cancer drug developers have tried to jam the accelerators that cause tumors to grow.  Now they want to block the fuel line.

Cancer cells, because of their rapid growth, have a voracious appetite for glucose, the main nutrient used to generate energy.  And tumors often use glucose differently from healthy cells, an observation first made by a German biochemist in the 1920s.

That observation is already used to detect tumors in the body using PET scans.  A radioactive form of glucose is injected into the bloodstream and accumulates in tumors, lighting up the scans.

Now, efforts are turning from diagnosis to treating the disease by disrupting the special metabolism of cancer cells to deprive them of energy.

The main research strategy of the last decade has involved so-called targeted therapies, which interfere with genetic signals that act like accelerators, causing tumors to grow  But there tend to be redundant accelerators, so blocking only one with a drug is usually not enough.

In theory, however, depriving tumors of energy should render all the accelerators ineffective.

"The accelerator still need the fuel source," said Dr. Chi Dang, a professor of medicine and oncology at Johns Hopkins University.  Indeed, he said, recent discoveries show that the genetic growth signals often work by influencing cancer cells' metabolism.

The efforts to exploit cancer's sweet tooth are in their infancy, with few drugs in clinical trials.  But interest is growing among pharmaceutical companies and academic researchers.

"Nutrient supply and deprivation is becoming potentially the next big wave," said Dr. David Schenkein, chief executive of Aglos Pharmaceuticals, a company formed two years ago to develop drugs that interfere with tumor metabolism.  Among its founders was Dr. Craig B. Thompson, the new president of Memorial Sloan-Kettering Cancer Center in New York.

Other small companies, like Cornerstone Pharmaceuticals and Myrexis, are pursuing the approach, and big drug companies are also jumping in.  Earlier this year, AstraZeneca agreed to work with Cancer Research UK, a British charity, on drugs that interfere with cancer metabolism.

One factor spurring interest in cancer metabolism is the intriguing interplay between cancer and diabetes,  metabolic disease marked by high levels of blood glucose.  The possible link between the two great scourges has garnered so much attention that the Diabetes Association jointly published a consensus statement this summer summarizing the evidence.

People with Type 2 diabetes tend to have a higher risk of getting certain cancers.  And preliminary evidence suggests that metformin, the most widely used diabetes pill, might be effective in treating or preventing cancer.

It is still not clear if high blood glucose is the reason diabetics have a higher cancer risk.  A more likely explanation is that people with Type 2 diabetes have high levels of insulin, a hormone that is known to promote growth of certain tumors, according to the consensus statement.

Similarly, metformin might fight cancer by lowering insulin levels, not blood sugar levels.  But there is some evidence that the drug works in part by inhibiting glucose metabolism in cancer cells.

Even if blood sugar levels fuel tumor growth, however, experts say that trying to lower the body's overall level of blood sugar - like by starving oneself - would probably not be effective.  That is because, at least for people without diabetes, the body is very good at maintaining a certain blood glucose level despite fluctuations in diet.

"When a patient with cancer is calorically restricted, the amount of glucose in the blood until they are almost dead is close to normal," said Dr. Michael Pollak, professor of medicine and oncology at McGill University in Montreal.  Also, Dr. Pollak said, tumors are adept at extracting glucose from the blood.  So even if glucose is scarce, he said, "the last surviving cell in the body would be the tumor cell."

So efforts are focusing not only on reducing the body's overall glucose level but on interfering specifically with how tumors use glucose.

This gets to the Warburg effect, named after Otto Warburg, the German biochemist and Nobel Prize winner who first noticed the particular metabolism of tumors in the 1920s.

Most healthy cells primarily burn glucose in the presence of oxygen to generate ATP, a chemical that serves as a cell's energy source.  But when oxygen is low, glucose can be turned into energy by another process, called glycolysis, which produces lactic acid as a byproduct.  Muscles undergoing strenuous exercise use glycolysis, with the resultant buildup of lactic acid.

What Dr. Warburg noticed was that tumors tended to use glycolysis even when oxygen was present.  This is puzzling because glycolysis is far less efficient at creating ATP.

One theory is that cancer cells need raw materials to build new cells as much as they need ATP.  And glycolysis can help provide those building blocks.

"You can have energy that turns on the lights in your house, but that energy can't build anything," said Matthew G. Vander Heiden, assistant professor of biology at the Massachusetts Institute of Technology.

Still, as with everything else about cancer, metabolism is complex.  Not all tumors cells use glycolysis, and some normal cells do.  So it could be challenging to develop drugs that can hurt tumors but not normal cells.

Two early efforts by a company called Threshold Pharmaceuticals to interfere with glucose metabolism did not work well in clinical trials.  One of Threshold's drugs, called 2DG, is the same form of glucose used in PET imaging, but without radioactivity.  Because of a slight chemical modification, this form of glucose cannot be metabolized by cells, so it accumulates.

But much less 2DG buildup is needed to spot a tumor on a scan than to destroy it by gumming up its works.  Large amounts of the drug were needed because 2DG lasted only a short time in the body and because it had to compete with the natural glucose that is abundant in the bloodstream.

Efforts have not ended, however.  Waldemar Priebe, a professor of medicinal chemistry at the M.D. Anderson Cancer Center, said he had developed a way to deliver up to 10 times as much 2DG to a tumor.  It has been licensed to a startup called Intertech Bio.

The other Threshold drug, glufosfamide, consisted of glucose linked to a standard chemotherapy agent.  The idea was that, as with the Trojan horse, the tumors would eagerly ingest the glucose only to then be poisoned.

In a late-stage clinical trial involving more than 300 patients with advanced pancreatic cancer, glufosfamide prolonged loves compared with no treatment, but not by a statistically significant amount.

A new company, Eleison Pharmaceuticals, plans to repeat the trial.  Dr. Forrest Anthony, Eleison's chief medical officer, said the original trial would have succeeded had it excluded 43 diabetics who were taking insulin which is known to impede PET scanning for tumors.  Insulin "sends glucose into skeletal muscle and fat tissue and away from the cancer," he said.

Many other companies and scientists are trying to develop drugs that inhibit enzymes -- for example, pyruvate kinases M2, involved in tumor metabolism.

Yet another approach is not to starve a tumor of energy but to give it more energy, and that is the idea behind a substance called dichloroacetate, or DCA.  Dr. Evangelos Michelakis of the University of Alberta, who came up with the idea, says there is a mechanism by which cells that become defective can commit suicide for the greater good of the body.

But cancer cells usually do not kill themselves.  Dr. Michelakis says this could be because they lack sufficient energy.

DCA, a simple chemical that is formed in small quantities when drinking water is chlorinated, has long been used to treat certain rare diseases in which lactic acid builds up in the body.  DCA inhibits an enzyme called pyruvate dehydrogenase kinase.  The effect of that inhibition is to move metabolism away from lactic acid-producing glycolysis and toward more normal oxidation of glucose in the mitochondria, the energy factories of the cell.

In 2007, Dr. Michelakis and colleagues published a paper showing the DVCA, when put in drinking water, could slow the growth of human lung tumors implanted into rats.  It seemed the DCA did not affect normal cells.

Some patients began clamoring for it.  Within days, an amateur chemist had synthesized DCA and began offering it for sale.  Some clinics still offer it.  Dr. Michelakis cautioned that in high doses DCA can cause nerve damage and that it takes months for enough to build up in the body to have any effect.

This spring, in the journal Science Translational Medicine, Dr. Michelakis reported results of the first human testing of DCA, in five patients with glioblastoma multiforme, a deadly brain caner.  There was no control group, making it hard to judge the drug's effectiveness, though some patients lived longer than might have been expected.  There was evidence that the drug bolstered the activity of mitochondria and promoted cell suicide.

Since DCA is not a novel compound, it cannot be patented, making it unlikely a pharmaceutical company would pay for clinical trials.  So Dr. Michelais has been raising money from foundations and governments to conduct larger clinical trials.

"We have only assumptions and theoretical excitement," Dr. Michelakis said.  Still, he added, "there's no question that this is a new direction that is logical and very appealing."

* * *

Also of interest to researchers:


New research suggests that many CANCER cells are equipped with a kind of suicide pill: a protein on their surfaces that gives them the ability to send an "eat me" signal to immune cells.  The challenge now, the researchers say, is to figure out how to coax cancer cells into emitting the signal rather than a dangerous "don't eat me" signal.

A study published in Science Translational Medicine reports that the cells send out the enticing "eat me" signal by displaying the protein calreticulin. But another molecule, called CD47, allows most cancer cells to avoid destruction by sending the opposite signal: "Don't eat me."  In earlier research, Stanford University School of Medicine scientists found that an antibody that blocks CD47 -- turning off the signal -- could help fight cancer, but mysteries remained.

"Many normal cells in the body have CD47, and yet those cells are not affected by the anti-CD47 antibody," said Mark Chao, a Stanford graduate student and the study's lead author. "At that time, we knew that anti-CD47 antibody treatment selectively killed only cancer cells without being toxic to most normal cells, although we didn't know why."

Now, the new research has shown that calreticulin exists in a variety of cancers, including some types of LEUKEMIA, NON-HODGKIN'S LYMPHOMA and BLADDER, BRAIN and OVARIAN cancers. "This research demonstrates that the reason that blocking the CD47 'don't eat me' signal works to kill cancer is that leukemias, lymphomas and many solid tumors also display a calreticulin 'eat me' signal," said Dr. Irving Weissman, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and a co-principal investigator of the study. "The research also shows that most normal cell populations don't display calreticulin and are, therefore, not depleted when we expose them to a blocking anti-CD47 antibody."

The next step is to understand how calreticulin works. "We want to know how it contributes to the disease process and what is happening in the cell that causes the protein to move to the cell surface," said Dr. Ravindra Majeti, an assistant professor of hematology and study co-principal investigator.  "Any of these mechanisms offer potential new ways to treat the disease by interfering with those processes."

* * *

In keeping with my mandate to include as many pieces as possible about transplants ...


In a rare case, a man living in Germany who had both LEUKEMIA and AIDS no longer has any detectable HIV cells in his blood following a STEM CELL TRANSPLANT for his leukemia three years ago.

Experts were quick to caution that the case does not have practical implications for the treatment of AIDS worldwide.

As it turns out, the donor for that transplant carried a rare mutation in a gene that increases immunity against the most common form of HIV. First reported in 2009, this follow-up study, published in the journal Blood, confirms that the recipient patient is still free of both leukemia and HIV three years after the transplant.

One expert issued strong words of caution in interpreting the finding. "Our phones have been ringing off the hook," said Dr. Margaret Fischl, director of the AIDS clinical research unit at the University of Miami Miller School of Medicine. "We are having patients calling us and asking if they can stop their antiretroviral therapy -- and the answer is uncategorically no."

The theory is that if you could wipe out every infected cell you could cure HIV, Fischl said, but this is a unique case.  The patient had intense chemotherapy and radiation, then relapsed and was given a second transplant from the same donor. The donor was unique in that he had a gene that could fight the most common form of HIV. This mutation is seen in about one in every million people, Fischl explained.

"How much did a second transplant contribute to the slow takeover of the donor cells that are resistant to one form of HIV? The extent that that happened is remarkable," she said.  However, this patient also was infected with another form of HIV as well. "What they are hoping is that the chemotherapy and radiation therapy wiped out that form, too. Could that patient still rebound with HIV in the future? Yes," said Fischl.

This treatment also carries with it a 30% risk of death.  "That he was young and got through it is quite remarkable," she said. "I would never give this to a healthy patient. I could never justify it. If you use this therapy, 30% of your patients could die from the intervention."

Fischl said the study does present new ways to look for an HIV cure, however. "This is leading to looking at gene therapy in a totally different way.  We tell our patients that this was a very particular situation. What made this work was that he got a very rare donor. It opens doors for us, but we are years away from potentially making gene therapy more broadly available.  It shows us the hurdles we have to get over to get to the cure."

Rowena Johnston, director of research at the Foundation for AIDS Research, also added a note of caution but said that the case "speaks to the promise of research.  We need to be clear that what was done for this patient was not something that can be done on a wide scale," Johnston said. "It really was a lucky case for this one guy that all the stars aligned and that all of the factors that needed to come together really did."

However, gene therapy might be an avenue to pursue, Johnston said. "We're a long way from that. There's a lot of technology that needs to be perfected, there's a lot of issues that need to be considered in terms of how you would deliver this to patients in a safe way and how the long-term effectiveness of that treatment might pan out," she said.

But the man's example has given gene therapy a "shot in the arm," Johnston said. "It's not just a pipe dream any more, somebody has been cured and we need to work out how we can come up with a cure that will be more readily available to everybody out there who needs it. That's over 30 million people living with HIV."                                 * * *


Genes that predict length of survival and help guide treatment for patients with non-small cell lung cancer have been identified by U.S. researchers.

The investigators took samples of lung tumors and nearby healthy lung tissue from 30 patients and examined the samples for the presence of messenger ribonucleic acid (mRNA) associated with 48 known genes for molecules called nuclear hormone receptors.  They then compared the active genes with patient outcomes and found that the expression of genes for certain nuclear hormone receptors helped predict patient survival. According to the results, patients with two specific nuclear hormone receptors in their tumor tissue lived the longest. The two "biomarkers" were the short heterodimer partner and the progesterone receptor.

"Patient responses to cancer treatment vary widely and often depend on subtle biological differences among tumors," said study co-lead author Dr. David Mangelsdorf, chairman of pharmacology at the University of Texas Southwestern Medical Center.  "These findings are important because the ability to determine which genes are being expressed in each person's tumor, as well as a patient's likely survival time, can guide physicians to the most effective and appropriate personalized treatments," he added.

The study was published in the journal PLoS Medicine.                                 * * *


A gene mutation that is present in one of every four patients with glioblastoma brain cancer has been identified by researchers.  The mutation -- a gene deletion known as NFKBIA -- contributes to tumor development, promotes resistance to treatment and significantly worsens the chances of survival of patients with GLIOBLASTOMA, the most common and deadly type of adult brain cancer, said senior author Dr. Griffith Harsh, a professor of neurosurgery at the Stanford University School of Medicine.

For this study, researchers analyzed several hundred tumor samples collected from glioblastoma patients and found NFKBIA deletions in 25 percent of the samples.  The study, which appears in the New England Journal of Medicine, is the first to link the NFKBIA deletion with glioblastoma.

Previous research has found that defects in NFKBIA -- normally present on chromosome 14 -- are linked with a wide range of cancers, including MELANOMA, MULTIPLE MYELOMA, HODGKIN'S LYMPHOMA, and BREAST, LUNG and COLON CANCERS.

It was already known that a genetic defect in the coding for epidermal growth factor receptor (EGFR), a cell-surface receptor for a hormone known as epidermal growth factor, plays a role in about one-third of glioblastoma cases. In these cases, there are either too many copies of EGFR or its receptor is stuck in the "on" position, so it sends out messages for cells to multiply continuously. This can spark the development of tumors.

Patients with NFKBIA or EGFR abnormalities have significantly shorter survival times than glioblastoma patients with tumors that have neither defect, the researchers noted.

The discovery may aid the development of targeted therapies. "If we can determine that a patient's glioblastoma has the NFKBIA deletion, we can target that tumor for treatment" with drugs that take the gene deletion into account, according to study principal investigator Dr. Markus Bredel. Background material for the study notes that some drugs, such as bortezomib, which now treat other cancers, may even have that capability, and an early-stage clinical trial using bortezomib for glioblastoma is currently taking place at Northwestern.

* * *

"I'm Hot!...and I'm Bald!": CHEMOTHERAPY FOR WINNERS doesn't touch upon childhood cancers, but this newsletter does:


U.S. scientists have unraveled the genetic code for the most common type of BRAIN CANCER in children.  Gene sequencing reveals that this tumor, medulloblastoma, or MB, possesses far fewer genetic abnormalities than comparable adult tumors.

The discovery that MB has five to 10 times fewer mutations than solid adult tumors could further attempts to understand what triggers the cancer and which treatment is most effective.

"The good news here is that for the first time now we've identified the broken genetic pieces in a pediatric cancer, and found that with MD there are only a few broken parts," said lead author Dr. Victor E. Velculescu, associate professor with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.  "And that means it's potentially easier to intervene and to stop it," he said, likening the cancer to a train that's speeding out of control.

Velculescu and his colleagues, who report their findings in an issue of Science, say this is the first time genetic decoding has been applied to a non-adult cancer.

Each year this cancer strikes about 1 in every 200,000 children younger than 15 years old. Before migrating through the patient's central nervous system, MBs begin in the cerebellum portion of the brain that is responsible for controlling balance and complicated motor function.

Focusing on 88 childhood tumors, the research team uncovered 225 tumor-specific mutations in the MB samples, many fewer than the number found in adult tumors. This surprised the researchers, given that prior work had not suggested a large genetic difference between childhood and adult malignancies.  The discovery could help improve the way MB is classified and treated. "We now have the pieces of the puzzle which are altered in this particular tumor type," noted Velculescu. "And what we have to do is figure out how these pieces can be put together and come up with new avenues for targeted therapies that take advantage of these differences."

At least one expert, Dr. Isabelle M. Germano, director of the brain tumor treatment program at Mount Sinai Medical Center in New York City, agrees that the finding gives researchers a new leg up on a killer disease. "Theoretically this study -- which postulates that because there are fewer mutations it might be easier to target those mutations -- could raise hope for finding a more successful way of dealing with MB," Germano said.  "So this is an improvement in our understanding of what we're dealing with. And once we understand better the mechanisms at the base of this illness, it becomes more possible to develop treatment options ... or, if possible, even prevent it from occurring in the first place," she said.

While not a common disease, MB accounts for 10 to 20% of all primary tumors among children, Germano said. "And outcomes have actually been improving as we come to know more about it, with five-year survival around 80% for patients older than 3.  "But for infants [the five-year survival rate] is just 30%," she said. "So at the present time mortality can be pretty high."

* * *

Because chemo is the standard of care for MS, RA and for anyone who has an organ transplant, I try not to focus solely on news about cancer.  However, most of the medical information relating to chemotherapy does center on cancer.  The next piece is interesting, although the leap to a "cure" is, I believe, a dangerous one:


Combinations of targeted therapies for an especially aggressive type of BREAST CANCER could potentially usher the majority of affected patients into remission.

Presenting results from three trials at the annual San Antonio Breast Cancer Symposium, scientists explained that administering two or more drugs designed to treat HER2-positive tumors resulted in much higher remission rates than doses of any one drug or standard CHEMOTHERAPY alone.  Given to patients several weeks before cancer surgery, with or without chemotherapy, the medications often shrank tumors dramatically or eradicated them altogether.

HER2-positive cancer is receptive to a protein called human epidermal growth factor receptor 2, which promotes the growth of malignant cells. Drugs that specifically target HER2 cells -- including Herceptin, Tykerb and Omnitarg -- have been proven effective on these types of tumors, which tend to be more aggressive than other breast cancers.

"I think it's a very exciting era, because we've gone from a very lethal era . . . to a point where we might be able to cure this disease," said Dr. Neil Spector, a professor of medicine at Duke University Medical Center, who moderated the symposium session.

Using Tykerb and Herceptin combined with chemotherapy before surgery, researchers followed 2,500 women with early breast cancer at 85 facilities throughout Germany. About half of these patients achieved remission before surgery, said Dr. Michael Untch, head of the multidisciplinary breast cancer department at Helios Clinic in Berlin.  "In a majority of these patients, we could do breast-conserving surgery where previously they were candidates for mastectomy," Untch said.  The team will continue following the patients to see if remission at surgery affects their outcome.

Another study showed the combination of Omnitarg and Herceptin, when given with the chemotherapy drug docetaxel, eradicated 46 percent of tumors, 50 percent more than the results achieved without Omnitarg. Also, 17 percent of tumors were eradicated by combining the two targeted drugs and skipping chemotherapy, the researchers said.

"Our study is the only one that has tested the hypothesis that (Omnitarg and Herceptin) could work without chemotherapy in these women," said lead researcher Dr. Luca Gianni, director of medical oncology at the Fondazione IRCCS Istituto Nationale TumoriFondazione IRCCS Istituto di Milano in Italy.

The third study, which included 455 patients followed at 99 sites for nearly two years, indicated that a combination of Tykerb, Herceptin and the chemotherapy drug Taxol improved tumor response rates significantly more than any of the drugs alone.  The mix led to a 51 percent remission rate, compared to 29 percent for a single therapy, said lead researcher Dr. Jose Baselga, chief of the division of hematology and oncology and associate director of the Massachusetts General Hospital Cancer Center.

"With these new therapies, we could easily go to curing over 90 percent of these patients, which is remarkable since this was the most lethal kind of breast cancer 10 years ago," said Baselga.

"This is a very fast advancement of new therapies," Untch agreed.

Researchers countered negative side effects of the drugs, which included diarrhea, liver function abnormalities, skin disorders and a low white blood cell count, by lowering patients' dosages or administering additional medications to alleviate specific symptoms.

Describing targeted therapies as a "HER2 blockade," Spector said if cost was not an issue, he would use all three drugs on HER2-positive breast cancer patients.

Discussing the high cost of treatment at the session, the researchers noted that spending more money on faster-acting, more effective treatments could save other treatment expenditures down the line.  "I do think we need to be creative in the ways we (run through) this data to make things more affordable," Spector said.

Because this study was presented at a medical meeting, the findings should be viewed as preliminary until they are published in a peer-reviewed journal.                               

* * *


Researchers have identified a gene mutation that may offer a target for new treatments for a type of lymphoma.  The team found that a mutation of the MYD88 gene is one of the most frequent genetic abnormalities in patients with this cancer, known as LARGE B CELL LYMPHOMA.

The MYD88 gene encodes a protein that is crucial for normal immune response to invading microorganisms. The mutation identified in this study can cause uncontrolled cellular signaling, resulting in the survival of malignant cells.  A subgroup of the large B cell lymphoma that has a dismally low cure rate -- known as the activated B cell-like (ABC) subtype -- appears particularly susceptible to the gene.

Lymphoma is a cancer of the blood that starts in white blood cells. Diffuse large B cell lymphoma, in turn, is a type of non-Hodgkin lymphoma, in which white blood cells known as lymphocytes multiply out of control. There are three subtypes of diffuse large cell lymphoma: Patients with the ABC form have the lowest rate of three-year survival, with only 40 percent reaching that milestone.

The researchers, led by scientists at the U.S. National Cancer Institute (NCI), found that the mutant form of MYD88 allowed the ABC lymphoma cells to survive but the non-mutated version did not.  One more piece of the puzzle was unraveled through another cell-signaling protein called IRAK4. The researchers found it functioned as an enzyme to modify a substance called IRAK1, which was required for the mutant MYD88 protein to promote lymphoma cell survival.

"We believe the results of this study may provide a method to identify patients with the [ABC subtype] whose tumors may depend upon MYD88 signaling," study author Louis M. Staudt, of NCI's Center for Cancer Research, said in an NCI news release.  These patients, he said, may thus benefit from therapies targeting "regulatory pathways that sustain the survival of these lymphoma cells."

The study appears in the journal Nature.                          

* * *

Finally, from The New York Times:


By Amy Harmon

They had told him on his last visit: the experimental drug that had so miraculously melted his tumors was no longer working.  His legs were swollen, the MELANOMA erupting in angry black lumps.  The patient, a computer consultant in his 40s, had little time left.

And now the man's doctor, Roger Lo, of the cancer center at the University of California Los Angeles, was calling to ask whether they could harvest a slice of one of his resurgent tumors for research he would almost certainly not be alive to benefit from.  He would need to fly to Los Angeles from Northern California at his own expense, subject himself to an injection of anesthetic and the slight risk of infection, and spend yet another afternoon in the hospital.

"I was hoping," Dr. Lo said that day last spring, "you would come in for a biopsy."

`The hope lies in a new breed of cancer drugs that work by blocking the particular genetic defect driving an individual tumor's out-of-control grown - in the case of Dr. Lo's patient, a single overactive protein.  If researchers can pinpoint which new genetic alteration is driving the cancer when it evades the blockade - as it nearly always does - similarly tailored drugs may be able to hold it off for longer.  The crucial evidence resides in the tumor cells of patients who, like Dr. Lo's, have relapsed.

But the need to ask those who know their time is short to undergo another invasive procedure in the name of science is just one obstacle to what many oncologists see as the best chance to give future cancer patients a more permanent reprieve.

A regulatory process that can take years to approve a drug for sale means that instead of thousands of patients to draw on, only a few hundred who receie the drug through clinical trials are available for such research. Ethical review boards frown on any procedure that exposes patients to unnecessary risk, like the rupturing of a blood vessel or puncturing of a lung.  Some hard-won tumor samples prove unsuitable for research. Then there is the question of who will pay for the biopsies, which cost as much as $5,000 and typically cannot be billed to insurance.  Dr. Lo, for one, covered the costs when there was no other means to pay.

As drugs tailored to the genetics of particular tumors make their way through early clinical trials, similar quests to improve on them are being undertaken by researchers in the various forms of a disease that kills more than a half-million Americans and millions more people worldwide every year.

Dr. Lo's quest to understand how melanoma forges its resistance to the drug PLX4032, made by Roche, illustrates the Herculean effort required to tae even a baby step toward a cure for cancer.  Finding a single clue that could lead to the testing of one new drug that might help a small fraction of patients took two long years.

But it also shows how such progress emerges, from a complex mix of academic ambition, collaboration and competition among scientists, and, especially, the willing participation of dying patients.

When the man Dr. Lo had called arrived in his office a week later, tumors covered his legs from the bottom of his feet to his groin.  Some of them were infected, their odor so overwhelming that the doctor put on a mask before administering an anesthetic and cutting into his left thigh.A Researcher's Trials

Dr. Roger Lo, 38, was an unlikely player in the scramble to improve on the Roche drug, which had been given to only a handful of patients when its successes began to grab the fields attention in late 2008.

An assistant professor in dermatology, he had started his own laboratory only a few months earlier and had been advised by senior colleagues to avoid high-risk projects until he secured a steady source of financial support.

But like others in the field, he was galvanized by watching melanoma patients respond to the Roche drug, the first to reliably slow a disease that typically kills within a year of diagnosis, and rarely responds to CHEMOTHERAPY.

Studying how to prevent a relapse, he argued in a grant proposal in early 2009, was "of paramount importance."

Impressed by his drive, and equally eager to realize the full promise of the drug's approach, Dr. Antonio Ribs, the melanoma oncologist running U.C.L.A.'so arm of the drug's clinical trial, agreed to collaborate with Dr. Lo.  Bigger, better-financed laboratories pursuing the same question might reach an answer first, Dr. Ribas warned.

But Dr. Lo had reason to hope the results would be published in a leading journal if he was the first to find the culprit responsible for reigniting the cancer, among the many possibilities.  That could prompt drug companies to speed the development of a new therapy

Lacking tumor samples fro patients in the Roche trial, Dr. Lo instead sought to replicate the cancer's resistance to the drug by feeding a steady diet of the drug to melanoma cells taken from three previous patients who had never received it.  When the few cancer cells that survived the onslaught began to grow in their petri dishes, he used those, now resistant to the drug, to begin his search.

It could have been straightforward.  Many researchers believed the answer would be that the gene whose mutation initially made the protein that drove the cancer's uncontrolled growth had mutated again, as had happened in other cancers.  In a few cases, a new drug tailored to the new mutations had lengthened remissions.

But Dr. Lo found no evidence of this.  Nor did he find the smoking gun in several other genes linked to the growth of other cancers.

Instead, he began the painstaking process of measuring the activity of hundreds of proteins that might have driven the cancer's uncontrolled growth.  The experiments required modifying the levels of each protein in the drug-resistant cells, dosing them with the drug and checking every few hours to see how fast they were growing.  With only two junior scientists and a technician in his laboratory, Dr. Lo performed much of the work, himself.

Even so, he knew, nothing he found in the cells whose resistance he had artificially bred in the lab would matter unless he also found it in the patients who had relapsed.One Patient's Contribution

Those who wonder whether a single patient can help cancer research should know the case of Lee Reyes.

Thirty years old when his advanced melanoma was diagnosed in early 2008, Mr. Reyes was distraught at how little he had accomplished.  Introverted and a perfectionist, he had dropped out of college and lived with his parents in Fresno, Calif.  He cycled through video game systems, favoring the Xbox.  He loved flying and thought about getting a helicopter pilot's license, but never pursued it.

"For the better part of about 10 years I did close to nothing," he said two years ago.  "I just always felt I had so much time."

One of Dr. Ribas's first patients in the trial of the Roche drug, Mr. Reyes was selected because he was among the half of melanoma patients whose tumors carried the overactive protein the drug blocked.  As it would for nearly every patient in the trial, the drug held his cancer at bay for several months.  But as would happen with the others, his response did not last.

With his life at immediate risk because of a melanoma tumor that had metastasized to his heart, Mr. Reyes traveled to U.C.L.A. for surgery in May 2009, agreeing to let his tumor be used for research.

On Dr. Ribas's instructions, a technician stood in Mr. Reyes's surgery room and, as soon as the surgeon extracted the tumor, ran with it to the nearby laboratory to reduce the chance to expose to contamination.  To coax the cancer cells to thrive so that Dr. Lo could run them through a battery of tests, it was sliced up with sterile knives and deposited, in a flask with sugar solution, in an incubator.

"Let's hoe it grows," Dr. Ribas said to Dr. Lo.

On a visit to Mr. Reyes's room after the surgery, Dr. Ribas did not discuss the future with his patient.  They both knew the options were limited.  Instead, they talked animals: Mr. Reyes's affinity for monkeys - he was clutching a stuffed one from a hospital gift shop - and Dr. Ribas's for sea otters.

When Mr. Reyes died a few months later, Dr. Ribas called his mother to offer his condolences, as is his custom.  Then he told her something else.

"He said Lee is helping them," Ellen Reyes told her husband.

Mr. Reyes cells were growing.A Breakthrough

It would take months or Mr. Reyes's cells to multiply to the numbers Dr. Lo needed to perform his tests.  And that summer, the foundation he had hoped would finance his research judged his grant proposal "too ambitious" for a junior investigator.

But by late September 2009, using the laboratory cells he had earlier bred to resist the Roche drug, he had narrowed his search.  The cancer's new driver, he believed, was one of 42 proteins on the surface of the cell.  A few weeks later, he closed in.  An experiment that could detect all 42 found a single culprit, appearing as twin dots of black on the translucent background of the film: the resistant cells contained 10 times more of the protein than those that were still responding to the Roche drug in Dr. Lo's petri dishes.

And, he noted with excitement, a drug designed to block that protein was already being prescribed or other cancers.  Perhaps a solution for patients was available already.

But as he prepared to see whether Mr. Reyes's cells bore out the observation, Dr. Lo tried to restrain his hopes.

"We have a likely candidate," he told Dr. Ribas carefully.

It was probable, he reminded himself, that this protein was not the source of the cancer's resistance in all patients.  In fact, the cancer could reroute itself differently in every patient.  Even if the theory was right, Mr. Reyes's tumor might not reflect it.

In October, as the precious cells grew close to the number required for the experiment, Dr. Ribas received a box in the mail.  In it was a stuffed sea otter, and a note from Mr. Reyes's mother.

They had visited the Monterey Aquarium over the summer, she wrote.  Mr. Reyes had bought the otter to take to Dr. Ribas on his next trip.

On a Saturday night in mid-November, Dr. Lo called Dr. Ribas.  He was looking at the film showing the results of the experiment on Mr. Reyes's cells.  On the translucent background, the same twin dots showed black.

The patient's cells, still living, harbored levels of the protein far higher than even Dr. Lo's laboratory models.

"Toni," he said.  "You have to see this for yourself.The Scramble for Donors

To be confident that his find was not a fluke, Dr. Lo needed more samples from other patients.  Their goal would be 10, he and Dr. Ribas agreed in late-night e-mail exchanges.  The best would be "before" and "after" snapshots from patients at the beginning of their treatment and after they had relapsed.  But those were in short supply.

Only 48 patients had been treated in the drug's first trial, eight at each of six leading cancer centers.  Many had not been biopsied when their cancer returned.  Some of the biopsies had been sent to Roche, which had not yet shared its own research with the academic researchers.

Briefly, researchers at the six sites contemplated pooling the few samples in their possession, and sharing authorship of their results.  But the tissues could be subjected to only so many tests before being used up.  And success in academia can hinge on being listed as a paper's lead author.  When several group discussions failed to yield even a complete accounting of who had how many samples, researchers agreed to stay in touch, but go it separately.

Still, in late 2009, Dr. Ribas approached two of the oncologists he knew to ask if they would share samples with Dr. Lo.

"I think he really has something," he told the two, Dr. Jeffrey Sosman and Dr. Grant McArthur.

Four tumor samples, two from each doctor, arrived a few days later by FedEx.  One, from a retired math teacher in Tennessee, tested positive for high levels of Dr. Lo's protein.

The sample protein was hyperactive in another sample, which came from a Croatian patient of Dr. Ribas's who had been commuting to Los Angeles for treatment.  The patient had surgery in Croatia to remove a tumor in his abdomen an requested that it be sent to Dr. Ribas.

Like everyone treating the patients in the Roche trial, Drs. Lo and Ribas were growing increasingly tormented by the knowledge that they could not promise more than a few months' reprieve to the patients enrolled in the drug trial.

They also knew that other researchers were close to publishing their own findings.  One had given a presentation at a conference, and there was a rumor that his paper had been tentatively accepted by Nature, a premier science journal.

Over the first six months of this year, the doctors renewed their efforts to perform biopsies.  Dr. Lo sent gentle e-mail reminders to the other oncologists with patients on the Roche drug, who might forget to ask or sidestep the difficult conversation.

He juggled his schedule to be available whenever the opportunity arose, borrowing exam rooms to squeeze patients in.  He scraped exposed tumor off the neck of a dance teacher in her 60s, and sliced into the lower back of a mortgage broker in his 50s.

Roche's rules for how biopsy samples would be stored in the next, larger trial of its drug made it impossible to perform many of the tests Dr. Lo wanted to try.  So the U.C.L.A. doctors asked patients to sign a separate consent form, authorized by the university's ethical review board, for research that would be conducted independent of the drug company.

There were some biopsies they did not get.  One patient's family volunteered an autopsy if it would help, but the timing made it impossible: Dr. Lo needed living tissue for the studies he was conducting.  The doctors decided against asking another patient, a young mother whose tumor was in her liver.  The risk of complications did not justify the benefit.

A prominent immunologist from San Diego was willing to subject himself to a biopsy of a tumor near his knee, but the U.C.L.A. surgeon turned him away on the operating table, judging it too painful to remove.  Still, when the immunologist Dr. Norman Klinman, underwent surgery in San Diego after relapsing, his son raced to deliver his tumor sample, strapped into the front seat of his car in a container of dry ice, to Dr. Ribas's laboratory.

By early May, they had nine samples.  Dr. Lo's three lab workers had worked nearly every weekend for a year, and he lacked the money to hire more.  Another of his grant proposals had been turned down because a reviewer said the Roche drug was too early in its testing to warrant a search for the cause of resistance to it.

When the machine they used to measure cell growth broke down that moth and dozens of experiments had to be redone, Dr. Los postdoctoral trainee mentioned a long-postponed trip to see relatives on the East Coast."Put it on hold," Dr. Lo urged.  "We're almost there."An Elusive Target

When Dr. Lo submitted his paper to Nature last July, he had collected tumor samples from 12 patients.  Of the four that contained his suspect protein, three of the patients had died by the time he had identified it in their biopsy.

But the last one came from a 54-year-old Canadian named Wes Coyle, who was alive, but barely, when Dr. Lo confirmed the protein's presence through a biopsy of a tumor in his pelvis.  It was the first time that, using his and Dr. Lo's research, Dr. Ribas could try to help a patient who had relapsed.  He warned Mr. Coyle's sister Peggy Coyle Seaver, who was caring for her brother, that it was a long shot.  But he prescribed the drug, made by Pfizer, that was known to block the protein in some other cancers.

For two weeks, Ms. Seaver reported to the doctor, her brother was able to eat again.  Yet he died soon after that.

Another opportunity arose with a fifth patient who contributed tumor samples to Dr. Lo's collection, an avid gardener in Los Angeles.  Her sample carried a gene mutation that suggested a second possible escape route for the cancer.  But on a clinical trial for a drug specifically designed to block it, she quickly deteriorated.

Most likely, the two doctors knew, single drugs would not alone block the resurgent cancer, even if they were hitting the right targets.

"Damn it!" Dr. Ribas exploded, calling Dr. Lo when he saw the tumors growing on her scans.  Of the 12 patient samples, Dr. Lo had identified the likely source of the cancer's resurgence in five.  In August, with a grant he received from the Melanoma Research Alliance, along with researchers at other institutions, Dr. Lo began to probe the rest.

And in late November, after requesting another round of experiments, Nature published his paper, along with one from a competing researcher.

Mrs. Seaver scanned the copy Dr. Ribas sent her, her breath catching when she recognized her brother, listed in a table as the 54-year-old male who had a 78-day response.  "It feels like Wesley is still alive," she told her husband.

Brian Lewis, a paramedic whose wife Dr. Lo had decided against asking for a liver biopsy, read about his paper on the Internet, and contacted the doctor to ask whether providing one now would help him.  His wife was doing poorly, but they had two young children, he wrote, "and I would hate to see them fight the same battle their mom is fighting."

A researcher at Sloan-Kettering Cancer Center consulted his own batch of five tumor samples from patients who had relapsed.  One of them, he told colleagues on a conference call, had the second mutation Dr. Lo had found.

In early December, Dr. Ribas visited Roche's offices in San Francisco.  The data in the paper, he argued, made a case for clinical trials of combinations of drugs the company was already developing.  Researchers would need to take biopsies from patients in those trials, too, they all agreed.  Because the cancer, even if blocked a second time, might find another way through.

"We have a lot more to do," Dr. Lo tells his laboratory staff every day.                               

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Here's to a Happy, Healthy, and Stress-Free New Year, for us all!

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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