There’s a new report in Molecular Cell (29, 541-551) from Gokhan Hotamisligil’s group suggesting that cellular stress might actually be helpful in certain contexts.

The Hotamisligil lab has published numerous reports on the importance of endoplasmic reticulum (ER) stress in metabolic dysfunction. Their previous data have suggested that insulin resistance (pre-diabetes, if you will) leads to a greater demand for insulin from the pancreatic beta cells. But this increased demand means more protein production, which can stress the ER and result in apoptosis. If this occurs in the islets overt diabetes can result.

In addition to his basic science experience, Gokhan also has a clinical background and he mentioned to me once that he used to see tuberous sclerosis complex (TSC) patients and was struck by the numerous benign tumors that form throughout their bodies. Now his interests are coming full circle as his group is reporting on ER stress in TSC and a potential therapy angle that could result from this insight.

The normal versions of the disease genes of TSC, TSC1 and TSC2, encode for proteins that form a complex that inhibits mTOR, the mammalian target of rapamycin. mTOR is a critical protein that integrates the nutritional state of the cell and cell growth by activating nuclear factors that control protein translation in response to increased amino acid levels. So TSC deficiency results in hyperactivation of mTOR, which leads to increased cell growth and is probably an explanation for the high number of benign tumors in these patients. While rapamycin, an inhibitor of mTOR, is a possible therapeutic treatment for TSC sufferers, it also has many nasty side-effects, especially over the long-term, so its potential in this regard is rather limited.

Given the increased protein production that results when mTOR is hyperactivated, it is possible that ER stress could occur in TSC-deficient cells. In this new report, Umut Ozcan et al. now show that lack of TSC does result in ER stress, including in the tumors that form in the Tsc2 KO mouse, as well as in a resected human TSC-derived tumor. They also show that this ER stress results in insulin resistance, tying in these results with the lab’s previous studies.

Clearly the level of ER stress caused by the defect in TSC, however, is not sufficient to cause apoptosis given the high number of benign tumors that form in this disease. But the team reasoned that if TSC1- or TSC2-deficient cells were treated with thapsigargin, a chemical inducer of ER stress, then perhaps they could tip the balance towards cell death. They were able to show this and, importantly, at the dosage of thapsigargin used normal cells were not killed. This result indicates the absence of TSC makes cells more vulnerable to ER-stress-induced apoptosis, which the group then used to their advantage in vivo. They injected Tsc2+/- mice, which develop kidney adenomas after 1 year, with thapsigargin once a day for a week and that resulted in apoptosis in the tumor cells but not in nearby healthy tissue. It wasn't reported, however, if this treatment was sufficient to shrink the tumor or return normal kidney function.

These findings are summarized in this schematic from the paper:

These results suggest a possible way to treat TSC. Unfortunately thapsigargin is too toxic and too blunt a tool to be used in the clinic. For example, pancreatic beta cells, even healthy ones, are quite vulnerable to ER stress-induced apoptosis. But nonetheless this study does point in a new direction for the development of a future therapeutic option in treating cancers that involve hyperactivation of mTOR.

Posted by Randy Levinson at 04:42 PM | Permalink | Comments (1)

People being treated for cancer often become anemic, meaning their blood oxygen levels fall too low, which is partly why they feel exhausted during treatment. To ease the anemia — and the fatigue — doctors prescribe erythropoietins, which stimulate the production of red blood cells.

On Friday, the Food and Drug Administration warned that these drugs, sold under the brand names Epogen, Procrit and Aranesp, are doing more harm than good in some cases. Doctors have apparently been over-prescribing the drugs, using them to reverse anemia, instead of just alleviating it enough to avoid blood transfusions.

The agency says that the drugs carry a higher risk of blood clots in the legs and the lungs, could make tumors grow faster, and could even cause people being treated for cancer to die more quickly. The drugs will now be sold with a black-box warning that highlights these risks.

Here's what I don't understand: we first reported on the risks with these drugs in 2003, when a couple of trials unexpectedly showed that people taking erythropoietin died faster than those taking the placebo.

We quoted experts who had found that many tumor cells have receptors for erythropoietin and that the cells grow faster in response to erythropoietin, and we reported — perhaps naively, in retrospect — that the mounting evidence might have an effect on how the drugs are prescribed.

As I said, that was in December 2003, more than three years ago.

Why has it taken so long for the FDA to act?

Posted by Apoorva Mandavilli at 03:27 PM | Permalink | Comments (3)

The Stanley Medical Research Institute, a Maryland-based philanthropy, is donating $100 million to uncover the genes important in mental illnesses such as bipolar disorder and schizophrenia, according to an article in today's Boston Globe.

The money is going to the Broad Institute, led by genome bigwig Eric Lander, who was one of the driving forces behind the cancer genome. I've already noted the criticisms against that project, and some of the same apply here. Sure, technology now allows us to find the genetic variations between different people and the researchers will no doubt find masses of data.

But these are extremely complex disorders, each involving multiple genes. What roles do those genes play in the disease? Without understanding how the different genes interact and what the impact is of the different variations, the data will be all but meaningless. For example, scientists from the cancer genome project are reporting in this week's Nature that the number of mutations that drive cancer is much larger than they expected.

To the institute's credit, the mental illness project's results will be publicly available — the more scientists who can analyze the data the better. Lander is quoted in the Globe as saying, "If you're looking for a needle in a haystack, and you can sift the whole haystack, you'll find the needle."

Hmmm.... I don't think that was the message of the idiom.

Posted by Apoorva Mandavilli at 03:40 PM | Permalink | Comments (3)

Our former intern Emily Waltz points out that Scientific American's March issue has given Francis Collins and Anna Barker, who lead the Cancer Genome Atlas initiative, several pages to, as Emily puts it, "make their case" for the project.

The cancer genome atlas, which is supposed to catalog all the mutations found in human cancers, is ambitious in scope--it's expected to cost about $1 billion over the next decade. Just the pilot phase, which began a year ago, has a tab of $100 million. That's no small sum when individual researchers are feeling the pinch of tightening budgets.

Emily is understandbly skeptical. Her reporting of the project last year uncovered serious practical hurdles facing the project, including the lack of enough tumor samples with the required informed consent. Privately, many scientists also complain that this is a vanity project and is unlikely to do much beyond run up masses of data.

As if in direct response to that criticism, Collins and Barker say, "Piles of data are, of course, not worth much without evidence that comprehensive knowledge of cancer's molecular origins can actually make a difference in the care of people."

Collins and Barker are right to note that drugs like Gleevec, which is what scientists like to call a "rational drug," can result from identifying the molecular origins of a cancer. But the article isn't really clear on how the project is likely to deliver those drugs--at least, not enough to make it worth the hefty price tag.

Posted by Apoorva Mandavilli at 03:08 PM | Permalink | Comments (0)

The most popular news item on Yahoo yesterday was a Reuters article about a potential new cancer drug. Intrigued, I read the article but couldn't understand why it was news.

The article is a cutesy account of how the researcher, Katherine Schaefer, had mistakenly added massive amounts of a PPAR-gamma modulator to a cancer cell line and killed them. That apparently led Schaefer to test this substance as a cancer drug in various other cancer cell lines and in mice.

As most biologists can tell you, almost anything added in massive amounts will kill cells. It's fortunate that this one does seem promising, but let's be realistic. So far, it seems effective in mice, which are a far, far cry from humans. Even if everything works well, a less than 10% chance, it will be at least 15 years before a drug version sees the light of day.

This particular article was published in the International Journal of Cancer--and not in the fictitious International Cancer Research as the Reuters article said--but a quick PubMed search reveals that Schaefer first published a link between PPAR-gamma and cancer in 2005. So even that aspect wasn't new.

Although scientists do often hype their findings, Schaefer herself seems perfectly reasonable. When I told her I was surpised her paper had been covered so widely, she said, "You and me both." Apparently, this was the work of an energetic PR person at her university who, I must say, deserves to be congratulated. She spun the story admirably well as a tale of lucky accidents, a wire service journalist bit and bingo! I could say something here about the dangers of over-hyping science, but I'll restrain myself.

At least the publicity has already had one good outcome. Schaeffer says she's had emails from people she hasn't heard from in 15 years or more. Happy accident indeed!

Posted by Apoorva Mandavilli at 03:44 PM | Permalink | Comments (2)