TOR signaling and cancer

Another recent development pertinent to the discussion of TOR signaling and cancer (see here), is the announcement of preclinical findings about a potential anti-cancer drug that may act against ovarian cancer. The drug works by inhibiting the mTOR signaling pathway. (mTOR is the mammalian form of TOR.)

This is not at all the first anti-cancer drug that's come along with a similar mechanism of action. But it's still interesting, because any drug that affects TOR signaling has the potential of also causing unwanted side effects, since TOR signaling is involved in so many cell processes. Presumably some effort has been made to find reasons why the effect of the drug should be limited to cancer cells.

The drug is called NV-128, and has been developed by an Australian biotech company called Novogen. Since the drug hasn't yet entered clinical trials in humans, it could take a decade or so (as usual) to perform enough testing to determine that NV-128 is actually effective, and relatively safe.

Anyhow, here's the news release:

Drug Compound Leads To Death Of Ovarian Cancer Cells Resistant To Chemotherapy (4/17/08)

In a discovery that may be useful for maintaining remission in chemo-resistant ovarian cancer, Yale scientists report that pre-clinical studies have shown the drug compound NV-128 can induce the death of ovarian cancer cells by halting the activation of a protein pathway called mTOR.

Many traditional cancer drugs work by triggering cell death via apoptosis. Unfortunately, apoptosis needs enzymes called caspases to work, as explained here. And cancer cells may develop a circumvention of this mechanism by turning down the production of caspases, which are needed to allow mitochondria to respond to apoptosis signals. NV-128, however, is able to overcome this problem by triggering caspase-independent cell death.

In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies. Inhibition of mTOR could shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells.

Here's the Novogen press release:

Novogen’s NV-128 shown to target the akt-mTOR receptor in chemoresistant cancer cells (4/15/08)

NV-128 is unique in that it does not induce caspase-mediated apoptosis which can be non-functional in chemoresistant cancer cells due to accumulated mutations in tumour suppressor/promoter genes and over-expression of anti-apoptotic proteins. Rather, NV-128 uncouples the akt-mTOR­P70S6K signal transduction cascade which has a key role in driving protein translation and uncontrolled cancer cell proliferation. Further, NV-128 induces mitochondrial depolarization via a novel pathway involving the autophagy protein Beclin-1 and Bcl-2, thereby resulting in endonuclease G translocation to the nucleus and cell death.

The same research group that presented the findings just mentioned has also done work on ovarian cancer itself, and been able to locate cancer stem cells for this type of cancer:

Ovarian Cancer Stem Cells Identified, Characterized (4/17/08)

Researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer's recurrence and its resistance to chemotherapy.

As already mentioned, NV-128 is not the only drug under investigation for attacking cancer by targeting the TOR pathway. In fact, almost a year ago, the first anti-cancer mTOR-inhibitor received FDA approval. It's Toricel (temsirolimus), an intravenous drug from Wyeth Pharmaceuticals, for kidney cancer. Novartis has an oral drug (everolimus) for kidney cancer in Phase III trials. (It's already been approved by the FDA as an immunosuppressant to prevent rejection of organ transplants.) Interestingly, and unsurprisingly, everolimus is a derivative of Rapamycin (sirolimus) – an anti-fungal and immunosuppressive compound – which led to the original discovery of mTOR. Everolimus works similarly to Rapamycin as an mTOR inhibitor.

The American biotech company Ariad Pharmaceuticals has a small molecule anti-cancer mTOR inhibitor called deforolimus in intermediate clinical trials for a variety of solid cancers, such as sarcomas, endometrial, prostate, breast and non-small cell lung cancers. The company describes the drug as "a novel small-molecule inhibitor of the protein mTOR, a “master switch” in cancer cells. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis." Last summer Ariad entered into a major partnership with Merck to develop and test the drug, so this is an indication that the drug has definite promise.

Ariad has a nice video you can download, which explains a bit about how their drug works, and about TOR signaling in general. I highly recommend having a look at it, since it covers upstream signals that activate mTOR (growth factors, amino acids, oxygen, energy), downstream effects (synthesis of proteins for cell growth, cell division, metabolism, and angiogenesis). It notes that certain other signaling proteins (PTEN, Akt, PI3K) cause overactivation of mTOR, and it points out that mTOR stimulates the production of the cyclin D cell division protein.

Tags: cancer, TOR signaling

Calorie restriction, TOR signaling, and aging

Now that I've given some pointers to information about how TOR signaling is involved with metabolism (see here), it seems like an opportune time to mention a recent research announcement in this general area.

How Dietary Restriction Slows Down Aging (4/17/08)

University of Washington scientists have uncovered details about the mechanisms through which dietary restriction slows the aging process. Working in yeast cells, the researchers have linked ribosomes, the protein-making factories in living cells, and Gcn4, a specialized protein that aids in the expression of genetic information, to the pathways related to dietary response and aging.

Here's the key background:

Previous research has shown that the lifespan-extending properties of dietary restriction are mediated in part by reduced signaling through TOR, an enzyme involved in many vital operations in a cell. When an organism has less TOR signaling in response to dietary restriction, one side effect is that the organism also decreases the rate at which it makes new proteins, a process called translation.

The researchers investigated various strains of yeast cells that had low rates of protein production, but increased lifespan. They found that a common characteristic of such cells was mutations to one part of the cell's ribosomes, the complex of RNA and certain proteins which manufactures all new proteins in the cell. The result of these ribosome changes was a decrease in the production of most proteins, except for one, called Gcn4, a transcription factor, whose production increased. The effect seems to depend on the same pathway affected by reduced TOR signaling. Gcn4 is associated with control of amino acid synthesis, and is activated when a cell is starved for amino acids.

To make the link between Gcn4 and longevity, the scientists then asked whether preventing the increase of Gcn4 would block life span extension. In every case, cells lacking Gcn4 did not respond as strongly as Gcn4-positive cells.

"The increased production of Gcn4 in long-lived yeast strains, combined with the requirement of Gcn4 for full life-span extension, makes a compelling case for Gcn4 as an important downstream factor in this longevity pathway," Kaeberlein said.

One might speculate that increased Gcn4 production somehow helps the cell cope with lack of nutrients, and one effect is that the cell takes steps to conserve its resources and slow the rate of aging.

Since reduction of TOR signaling is one way to bring about this effect, TOR inhibitors might help slow aging and increase lifespan, at least in yeast. However, since TOR affects so many other cell functions, the chance for harmful side effects of reduced TOR signaling is high.

"The role of TOR and translation in aging is known to be conserved across many different species, so it's plausible that this function of Gcn4 is conserved as well," Kennedy said. Future research will be aimed at testing this hypothesis.

"Clearly TOR signaling is one component, and perhaps the major component, of the beneficial health effects associated with dietary restriction," said Kaeberlein. "The difficulty with TOR as a therapeutic target, however, is the potential for negative side effects. As we learn more of the mechanistic details behind how TOR regulates aging, we will hopefully be able to identify even better targets for treating age-associated diseases in people."

Tags: calorie restriction, TOR signaling

Cancer, metabolism, and oncogenes

I want to call attention (somewhat belatedly) to a series of three very good tutorial blog posts at The Daily Transcript. Although they are nominally about changing views regarding cancer and its causes, they actually provide a nice overview of a number of important topics in molecular biology. Reading these posts will be a big help in understanding a lot of things written about here, in particular topics such as:

• cancer, and how it is "caused" by various factors like metabolism and genetic mutations, and indirectly affected by other biological systems like the immune system
  
• metabolism in general, and how problems with metabolism lead to disease conditions like diabetes and metabolic syndrome, perhaps even Alzheimer's disease
  
• calorie restriction, and how it seems to play a role in longevity
  
• stem cells – what makes them special, how they function biologically and may play a role in the process of cancer
  
• important processes in cell biology, such as apoptosis, autophagy, and (of course) the cell cycle itself
  
• general topics in molecular biology, such as growth factors, transcription factors, signaling cascades, and cell surface receptors
  

So here are the links, with a brief summary of each:

From Metabolism to Oncogenes and Back - Part I (3/17/08)

Historical introduction to the subject. Explains how Otto Warbug had the idea, 100 years ago, that the way to understand cancer was through metabolism. Somewhat later, the discovery of the Rous Sarcoma Virus (1916), and much later, after the revolutionary understanding of DNA and modern molecular biology came about, the focus shifted to the role of oncogenes, tumor suppressors, and genetic mutations in cancer.

From Metabolism to Oncogenes and Back - Part II (3/21/08)

More detailed look at the molecular biology of cancer, protein signaling pathways in general, and TOR signaling in particular. This part includes a great diagram of some of the more important signaling pathways as far as metabolism and cancer are concerned. Besides TOR, it clearly emphasizes the importance of the MAP kinase Ras, and the phosphoinositide signaling proteins PI3K, PTEN, and AKT.

From Metabolism to Oncogenes and Back - Part III (4/2/08)

An even more technical summary of recent discoveries about metabolism, and the peculiar kind of metabolic activity found in cancer cells. It appears that a type of enzyme called pyruvate kinase, which occurs in various forms, plays a big role in cell metabolism and whether a cell uses available energy for making sugars, fats, or DNA.

Tags: cancer, TOR signaling