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Novel Agents for Lung Cancer: Proteasome Inhibition with Velcade (Bortezomib)
Much of the focus on novel agents has been on strategies like inhibition of the epidermal growth factor receptor (EGFR) that can stimulate tumor growth, or anti-angiogenesis, blocking the tumor blood supply. But there are other, novel therapies that are also being tested in lung cancer as well. One of these is proteosome inhibition, with an agent like Velcade (bortezomib), which is approved for treating the plasma cell (blood) cancer multiple myeloma and also has activity in lymphomas.
Sometimes referred to as the “cellular housekeeper”, proteasomes are a set of proteins that are inside the nucleus of the cell and regulate the concentrations of multiple important regulatory proteins, primarily by degrading proteins beyond what are required in the cell. Because proteasomes affect a wide range of regulatory proteins, inhibiting the proteasome can lead to downstream effects that control many cell systems:
(Click to enlarge)
The proteins listed on the slide aren’t ones that are well known to many people, but they have effects on the cell cycle of growth and division, can induce programmed cell death (a normal cell function often lost in cancerous cells), and (of course, in keeping with so many novel agents) can have anti-angiogenic properties. In some preclinical (lab-based) research, velcade can enhance the effects of chemotherapy against many cancer cell lines. In several models, adding velcade can overcome resistance to chemotherapy, although this work has been in the lab and not the clinic, and it has focused on different cancer types than lung cancer (bladder, pancreas, prostate, colon
Vascular Disrupting Agent AS1404/ ASA404/ DMXAA: A Variant on Anti-Angiogenesis
First, I want to thank members Jim (dadawg001) and Neil (neilb) for bringing up this topic in the Discussion/Q&A Forum yesterday. Amazingly, yesterday morning I happened to be reviewing slides in my collection on a novel agent and approach that I thought would make a good topic for a post here: the drug DMXAA, which is a “vascular disrupting agent”. Later that same day, Jim raised a question about a new agent, ASA404, which had promising results reported in a press release by its manufacturer, Antisoma, based in London. I noted that I was unfamiliar with the agent, which was only partly true. In fact, it has been known previously as AS1404 and DMXAA, so even though I was thinking about this agent for reasons other than the press release (which I’ll get to), we were all circling around the same drug yesterday. Definitely worthy of a full discusison now. (Antisoma also needs to work on it’s brand identity so that people can actually figure out that ASA404 is AS1404 and also DMXAA.)
Anti-angiogenic drugs like Avastin (bevacizumab) are felt to work largely by causing regression of new blood vessels to tumors as well as inhibition of a new blood supply to a tumor that would otherwise be growing and is now limited by an inability to receive nutrients and oxygen and also to dispose of waste products. In contrast, ASA404 is a vascular disrupting agent that works directly on the endothelial (blood vessel inner wall) cells to cause apoptosis (programmed cell death). In addition, it causes release of the glycoprotein Von Willebrand factor in blood that can lead to clotting of blood vessels (potentially a good feature, also potentially bad) and also a cascade of cytokines, basically proteins with hormonal activities that often contribte to making people with cancer feel terrrible, such as tumor necrosis factor, another focus of cancer treatment modalities. The end result is that this agent can cause the breakdown of existing (not just newly forming) blood vessels and destruction of cancer cells.
(Click to enlarge) Continue reading
DCA Revisited: Is It A Breakthrough Yet?
I’m surprised to find that I’m moving to a topic that may actually be more controversial than a Michael Moore movie, but in fact, I think that’s where I’m headed.
Several months ago, I wrote a post about dichloroacetate, or DCA, which is a chemical used to treat a childhood disease called congenital lactic acidosis, and which has been the study of some more recent study by Dr. Evangelos Michelakis at the University of Alberta in Edmonton, Alberta in Canada. DCA can increase the activity of mitochondria, which produce energe in the cell and can be suppressed in cancer cells; restoring that function can lead the cells to undergo programmed cell death, or apoptosis, that is supposed to occur when a cell recognizes that it has dysfunctional mutations. Recent work by the group in Edmonton (summary here) suggested that DCA was effective in killing tumor cells in test tubes and some animal models, and the authors suggested that DCA should move readily into clinical trials for cancer. One problem is that DCA is a generically available product that no pharmaceutical company stands to profit from, so it does not have a readily available source of funding for the millions of dollars needed to run clinical trials that might lead to a proper demonstration of effectiveness of not. The University of Alberta has established a charitable fund that has thus far raised signficant financial support in order to test DCA in clinical trials despite the absence of a big pharma beneficiary. Trials are reportedly in development.
At the time that this came out, in a real media frenzy, my post covered some of the news and used the occasion to temper some of the extreme enthusiasm about this agent being a likely miracle for the broad treatment of cancer. I described the huge gap between promising preclinical drug that kills cancer cells in test tubes and rodents and the demonstration of clinical benefit in large trials with real patients. The majority of drugs are abandoned along the way for being too toxic or not living up to the early promise of efficacy. We would do well to remember that back in 1998, when emerging work on angiogenesis by Dr. Judah Folkman was hailed as a certain miracle, again based on very promising work in mice. Dr. Folkman was very circumspect and avoided overpromising what his research could accomplish in humans: “if you’re a mouse and you have cancer, we can take good care of you” and, “Going from mice to people is a big jump, with lots of failures” (basically summarizing my first DCA post in one sentence). In contrast, in that same front-page article in the New York Times that featured this reported breakthrough, Dr. James Watson (who along with Francis Crick discovered the molecular structure of DNA and was awarded the 1962 Nobel Prize in Physiology and Medicine) was quoted as saying, “Judah is going to cure cancer in two years”. I cringed when I heard that, fearing that it would feed a media machine and lead to incredible hype, and it did. But nearly ten years later, we have not cured cancer, at least not nearly enough, even though a few antiangiogenic drugs like Avastin (bevacizumab) have recently been shown to improve outcomes for colon, lung, breast, and some other cancers. Continue reading
Vorinostat/SAHA: Another Targeted Therapy Being Tested in Lung Cancer
I’ve got a lot of things on my list of things to cover in the near future…patient sex differences in lung cancer and estrogen, an update I’m trying to generate on DCA (dichloroacetate), the concept of pharmacodynamic separation of chemo and EGFR inhibitors, more on the trials from ASCO that may be changing our practice in treating locally advanced NSCLC, not to mention the discussion I’d like to start on Michael Moore’s new movie Sicko, which I went to see with my wife this past weekend. And then there’s the long list of topics I’ve been meaning to get to for several weeks before ASCO. Yikes. Well, at least we all know we’re not going to run out of things to talk about anytime soon.
Today, since member Spanky3 is starting a trial with the agent vorinostat (you can offer encouragement at the end of this forum thread), I’ll provide some introduction about this new agent. It’s also known as SAHA, which stands for suberoylanilide hydroxamic acid, which is why we always want to call it vorinostat or SAHA or its marketed name, Zolinza. Vorinostat is an oral medication that is approved for treating cutaneuous T-cell lymphoma, or CTCL, and it works as a histone deacytylase (HDAC) inhibitor. A what? Basically, DNA is wrapped up in a form better designed for compact storage rather than use for transcribing genes when it’s not being used, and those histones are what bind DNA into the storage form. Whether they release the DNA for transcription of genes on that DNA into protein depends on whether the histones have an acetyl group (iwhich you don’t need to know — it’s not on the quiz — but if you’re really interested or very bored, info is here) is added or not, so HDAC controls gene expression, and inhibition of this enzyme can inhibit some cancer cells. This is part of a whole new field called epigenetics, which is basically the study of how DNA is modified, in terms of the packaging that leads to more or less use, without changing the underlying instructions.
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If you look at the figure above and a big light bulb doesn’t go on over your head, don’t fret if you still don’t understand it — the scientists are also not sure out it works. In fact, HDAC inhibitors may have other anticancer effects by acetylating proteins other than histones, and they may also interfere with the proteins controlling cell division by acetylating the centromeres, which are important cellular machinery for mitosis.
Axitinib: New Drug with Activity in Lung Cancer
A few new agents emerged from the ASCO 2007 meeting as very real potential players in lung cancer. Probably at the lead of that list, in my opinion, was axitinib (AG-013736, now a Pfizer product). Similar to agents like sunitinib and sorafenib, this is an oral agent that blocks a target called the Platelet-Derived Growth Factor Receptor (PDGFR) and also is a potent, and selective inhibitor of three different receptors in the Vascular Endothelial Growth Factor (VEGF) family: VEGFR-1, VEGFR-2, and VEGFR-3 (scientists are very clever and original with such names, as you can see). As is typical for any complex biological process, there isn’t just one ligand, the protein that fits fits the target, and a single receptor for it, but rather a family of ligands and receptors that act in a coordinated fashion to balance a mechanism like blood vessel and lymphatic channels (the vessels that move lymph, a plasma-based filtering fluid, between lymph nodes). Here’s a basic schema of the VEGF ligands and receptors (VEGFR-2 is the dominant one):
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Axitinib connects to the intracellular, back end portion that has kinase activity, which basically means that it turns on an enzymatic signalling pathway inside the cell with multiple activities, which in this case ultimately promote blood vessel production that can benefit a growing tumor. Like lots of promising drugs, it inhibits cancer cells in test tube and animal models, but more encouragingly, it’s been studied and looks like it has anti-cancer activity human patients with kidney cancers and some other oncology settings. This year, Dr. Joan Schiller, who heads the oncology program at the University of Texas-Southwestern Medical Center and also chairs the ECOG Lung Cancer Committee, presented results of axitinib as a single agent in previously treated patients with advanced NSCLC (abstract here). Continue reading
Selecting Chemo by Extreme Drug Resistance
My recent post about selecting the right treatment for an individual tumor is part of a long history of trying to tailor cancer therapy. Many companies offer such services, and in fact advertise them heavily. However, the oncology community as a whole has not enthusiastically embraced such approaches, as many patients suggesting these tests may have found when they raise the question. This is based on decades of general disappointment, on marketing of ideas ahead of the clinical research to really prove the value of lab-based selection of optimal treatment. Because of these issues, there are no management guidelines that include recommendations for these types of tests, certainly not in lung cancer management.
In fact, there are good reasons to be suspicious that a treatment that looks promising in a test tube model of cancer is actually going to work in real live people. This is exactly the cautionary point I raised in a prior post about the difference between pre-clinical and actual patient-based testing of cancer treatments. Many, many more cancer treatments have looked sensational in test tube and animal models than in the clinic, which should be expected because the human experience depends on absorption of the drug, and delivery through the bloodstream, while cancer cells are constantly mutating, developing resistance to our treatments all too quickly. The lab models can’t quite capture the dynamic and more challenging nature of actual living cancer in human patients. Consequently, a lab report saying drug X will work for Mr. Smith’s lung cancer often falls short on that promise. If the companies that made broad claims actually backed up their contentions with clinical data, the way investigators are trying to follow up on the MADeIT trial with a larger direct comparison of tailored vs. standard unselected chemotherapy, the oncology community would likely be much more eager to adopt such testing as a standard of care. Continue reading
COX-2/EGFR Inhibitor Therapy: Hope or Hype?
While there have been studies of the COX-2 inhibitor celebrex in combination with chemo for treating NSCLC, the palpable buzz about celebrex in treating lung cancer has been from a trial by my friend Karen Reckamp, formerly at UCLA, now recently moved to City of Hope Cancer Center in nearby Duarte, CA. Several studies have shown that EGFR expression is associated with increased cell growth, increased angiogenesis, increased tissue invasion and metastasis, and a worse survival compared with patients who have tumors that don’t overexpress EGFR. And as I wrote in my introductory post on COX-2 inhibition, high expression of this enzyme can also lead to worse patient outcomes among folks with NSCLC (COX-2 actually hasn’t been shown to be expressed significantly in SCLC). In fact, these two pathways interact to regulate cell proliferation, migration, and invasion (reference article here).
(complex, isn’t it? Click to enlarge — but it won’t help, unless you’ve got a PhD in biochemistry)
Xyotax: A New Taxane Targeted for Women Only
Similar in concept to Abraxane, paclitaxel poliglumex (PPX, or Xyotax) is another novel formulation of paclitaxel in which the taxane is bound to a biodegradeable polymer utilizing a polyglutamate drug delivery system. As with Abraxane, this allows administration without solvents over a recommended infusion time of 10-20 minutes and potentially allowing for improved delivery of the agent to the tumor target with a greater relative sparing of normal tissues. The idea is that the release of the paclitaxel molecule from the polymer backbone by lysosomal proteases (enzymes that cut apart proteins), some of which are overexpressed by tumor cells.
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Xyotax has been studied in several phase III randomized trials in the performance status 2 (PS2) patient population . In the STELLAR 3 trial (abstract here), the combination of carboplatin/PPX was compared with carboplatin/paclitaxel q3weeks, while the STELLAR 4 trial compared single-agent PPX to gemcitabine or vinorelbine as a single-agent (abstract here).
Each of these first-line trials demonstrated no significant differences in survival or other efficacy endpoints favoring the Xyotax arm in either trial, but an exploratory analysis of the female patients in both of these trials revealed a markedly superior survival in recipients of PPX.
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