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