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.

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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.

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Historically, chemotherapy has had a relatively minor role in the management of brain metastases. Although there is a rather low response rate in the brain from some standard lung cancer chemo regimens, we generally conclude that most of our chemo can’t be too effective in the brain because of the blood-brain barrier (BBB) that is relatively impermeable to the majority of our commonly used chemo agents (there is some debate about whether the metastases disrupt that barrier and can allow other chemo agents to get into the brain, but that’s still a murky issue). However, some of the drugs that are routinely used to treat primary brain tumors (cancers that start in the brain tissue) can get through the BBB and reach significant concentrations that can effectively fight cancer. One of the agents that has been shown to be valuable in treating primary brain tumors is temozolomide, or Temodar, an oral chemotherapy drug that is given with radiation to the brain and also on its own off of radiation. Because it’s been shown to improve survival for patients with tumors that start in the brain, and is also helpful for patients with metastatic melanomas, it’s also been an agent that has been the focus of research questioning whether it can improve results when added to radiation, or potentially on its own, in patients with brain metastases from solid tumors like lung cancer. Read the rest of this entry »

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)

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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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Paclitaxel, marketed name Taxol, is among the most commonly used drugs in oncology in general, and definitely also for lung cancer, particularly NSCLC. The combination of carboplatin/taxol is the most frequently prescribed combination for advanced NSCLC in the US and is also employed in many other settings for NSCLC as well. However, there are several potential problems with taxol. It is extremely hard to dissolve and requires a solvent called cremaphor (polyethoxylated castor oil — don’t worry, it’s not on the test!) and special tubing, as well as a three hour infusion time, to administer in its most common schedule. Patients need to take multiple premedications that include steroids, which is a nuisance for lots of patients and a significant problem for some, such as those who have diabetes, because steroids can markedly increase the blood sugar levels of patients. And despite premedications, it’s not uncommon for patients to develop significant hypersensitivity reactions that can be quite serious and, rarely, fatal.

There are several novel formulations of paclitaxel and other chemotherapeutic agents that allow the same paclitaxel molecule to be delivered without the alcohol-based solvent, thereby eliminating the need for steroid premedications and a long “chair time” of patients having to spend most of their day getting chemo because it’s unsafe to give the chemo faster than that. One of these is nanoparticle (tiny little particles) albumin bound (or nab) paclitaxel, which has the scientific name ABI-007 but is commonly known as Abraxane. Not only is this special form of taxol faster to administer and doesn’t require the premedications that solvent-bound taxol does, there is also the possibility that this albumin-bound form may be delivered and picked up by the tumor than standard taxol. In fact, there is some evidence that Abraxane may be superior in some ways to standard paclitaxel in breast cancer, where it has been studied much more than it has been studied in lung cancer thus far. In a large trial with 460 predominantly (86%) chemotherapy pretreated women with breast cancer (abstract here), those who received Abraxane had a significantly higher response rate from Abraxane given every three weeks than standard taxol (21.5% vs. 11.1%), and they also had a significantly longer progression-free survival, but the overall survival was not significantly different. It also had a no hypersensitivity reactions from the Cremaphor solvent, and lower neutropenia rates and severity of neuropathy (although the neuropathy with Abraxane remains a significant side effect challenge). On the basis of this work, Abraxane was approved by the FDA in January, 2005 for recurrent or metastatic advanced breast cancer. Read the rest of this entry »

Sunitinib (SU11248), with the marketing name Sutent, is another multikinase inhibitor, an oral agent that blocks several potentially important anticancer targets in the cell with one drug. This drug is FDA-approved in treating advanced kidney cancer and also a cancer called GastroIntestinal Stromal Tumor (GIST) after progression or intolerance of Gleevec (imatinib). It inhibits the tumor blood supply by blocking the Vascular Endothelial Growth Factor (VEGF) Receptor family, and it can inhibit cancer cell growth by blocking a target called Platelet-Derived Growth Factor (PDGF) Receptor, as well as some other growth signal targets:

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We know that greater expression of both VEGF and PDGF by cancers are associated with worse survival. In fact, you can see the remarkable difference in survival for patients in a European study of 120 stage I patients who underwent surgery and then had their tumors stained for VEGF expression and the functional correlate of it, microvessel density (the density of small blood vessels in the tumor, which are induced by VEGF), divided into levels above or below the median (half-way point):

WOW! Huge difference. This test isn’t routinely available, at least not yet. Read the rest of this entry »