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Other targeted therapies

Additional targeted therapy approaches against lung cancer

Dr West

Targeting Insulin-Like Growth Factor 1-Receptor (IGF-1R) in Cancer


In addition to several molecular targets that have been well studied for several years, such as the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), new targets are emerging as potentially fruitful approaches to combating cancer. One of these is the insulin-like growth factor receptor, or IGF-1R.

IGF-1R background

IGF-1R is involved in the process of transforming a normal cell into a cancer cell when certain cancer trigger genes, called oncogenes, are activated. Activation of this receptor sets off a complex cascade of effects that promotes tumor survival and growth. There have also been studies that have demonstrated elevated blood levels of IGF in patients with several kinds of cancer. Tumors also tend to express high levels of IGF compared with normal tissues. Continue reading

Dr West

Heat Shock Protein Inhibition as an Anti-Cancer Treatment


There’s a new class of anti-cancer drugs that are being studied, including in lung cancer, known as heat shock proteins, or HSPs. These are sometimes referred to as “stress proteins” because they can be induced to be generated in higher concentrations in response to stresses like heat, cold, low oxygen levels, etc. But HSPs are also present in cells in the absence of significant environmental stress, just as a normal component of the cellular contents. They work as a chaperone protein, alongside of other proteins to ensure that those proteins are in the right shape, which is required to have proteins function properly, as well as the right place when needed. In the context of cancer, HSPs can also assist in the cancer-promoting activities of a wide range of several “client” oncogenic (cancer-inducing) proteins. So inhibiting HSPs, such as one designated HSP-90, is a potential novel mechanism for interfering with the activities of these critical proteins and the overall function of cancer cells.

One such agent that is working its way through clinical testing is IPI-504, from Infinity Pharmaceuticals, the subject of a recent press release. The announcement and another preceding one note that the recent report of phase I work with IPI-504, an IV agent, was associated with stable disease in 7 of 9 patients at the time of first repeat CT evaluation. In addition, two of four patients who happened to have undergone a PET scan on repeat follow-up had a partial response based on European criteria, although it should be noted that PET scanning to assess response is not a standard practice and isn’t anything close to being as established as a CT scan to assess response.

Interestingly, some preclinical work in cell line suggests that the activating mutations of EGFR depend on the HSP-90 protein for stability and that IPI-504 may (bolded and italicized) be useful in EGFR-resistant populations (abstract here). For instance, the T790M mutation is one that has been found in approximately half of the prior EGFR mutation responders to iressa or tarceva once they show progression on these agents, and preclinical lab work suggests that IPI-504 may reverse that proces. However, that’s not human work. But it does lead us to the hypothesis that this agent may be useful in patients who have become resistant to EGFR tyrosine kinase inhibitors despite a mutation.

The new phase II clinical trial with IPI-504 will enroll 20 patients with advanced NSCLC who previously received an EGFR inhibitor, and this group will be equally divided between those with a known activating EGFR mutation and those with a normal or “wildtype” non-mutated EGFR target (the kind we don’t associate with special sensitivity to drugs like tarceva). If responses are seen using the more typical CT-based response assessment criteria for trials, they’ll plan to enroll 19 additional patients on the cohort(s) in which some convincing evidence of activity is seen. The schedule for treatment will be weekly IV administration for two consecutive weeks, followed by a week off, for each cycle this schedule was tested in another phase I trial). According to the press release, this particular trial is now open at Mount Sinai Comprehensive Cancer Center in Miami Beach, FL, and at Yale Cancer Center in New Haven, CT, with some other sites coming on board.

This isn’t the only heat shock protein inhibitor being evaluated, but it may well be one of the first ones for which we get some clinical data in lung cancer. I’ll give updates when new trials are opening up. In the meantime, HSP inhibitors represent an intriguing avenue for targeted therapy in lung cancer that we’ll hear more about in coming years.

Dr West

Thalidomide in Lung Cancer: Answers from Korea


To many outside of oncology, thalidomide is primarily known for causing severe birth defects in women who received it in the 1960s as a sedative and treatment for morning sickness. These birth defects, in which babies were born with no arms or legs but with hands and feet directly attached to their trunks, was likely related to the anti-angiogenic (blood vessel blocking) effects of thalidomide. Over the last several years, however, its anti-angiogenic activity has been employed as an oral treatment for some cancers, and it is an approved treatment for multiple myeloma and has been studied in several other cancer settings, including lung cancer. Specifically, one of the settings in which thalidomide has been the subject of several studies has been extensive disease small cell lung cancer (ED-SCLC), as small cell is a blood vessel rich tumor that has been suspected to be potentially vulnerable to anti-angiogenic drugs (for instance, I covered some early work with Avastin in SCLC in a prior post). In addition, thalidomide appears to have immunostimulatory activity in lab-based work, and this may also contribute to potential anticancer activity.

A friend of mine, Dr. Afshin Dowlati at Case Western Reserve University in Cleveland, recently published on his group’s experience giving thalidomide to patients as a maintenance therapy after initial chemotherapy (abstract here). They enrolled 30 patients who had received 4-6 cycles of initial chemotherapy, which was not specified, who had achieved either a complete or partial response, or else stable disease. (In other words, they enrolled patients who did not demonstrate progression on chemo, which we don’t expect to see after first-line treatment of ED-SCLC.) After 3-6 weeks off of treatment, a total of 30 patients received thalidomide at 200 mg by mouth every evening, with a primary goal of the study to determine the one-year overall survival and overall tolerability of this treatment. Recall that there is no established benefit for maintenance therapy after initial chemotherapy for ED-SCLC (see my prior post on the topic), but we continue to study it because we know that ED-SCLC is often responsive early and then tends to be much more resistant when it returns. The idea of postponing that recurrence with a manageable oral therapy is very appealing, but we still haven’t seen a significant survival benefit despite the compelling rationale behind it. With only 30 patients enrolled, Dr. Dowlati wasn’t going to establish anything definitive, but he did demonstrate that it was a feasible treatment. Patients stayed on thalidomide for a median of 2.4 months, or 79 days. The median survival was pretty encouraging at 12.8 months, and the one-year survival was 52%. The leading side effects were peripheral neuropathy (numbness and tingling in the longest nerves of the body, affecting the fingers and toes, primarily) in about 30%, and constipation in 16% of patients, despite a bowel regimen that was started on everyone at the time of starting thalidomide. The investigators considered the results encouraging enough to warrant further study. Continue reading

Dr West

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:

Bortezomib mechanism (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…).

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…).

   Clinically, velcade is given as a very brief (6 second) IV push, and much of the early work gives it twice weekly for two weeks out of three, a pretty inconvenient schedule. More recently, it’s been studied increasingly on a schedule of a higher dose twice weekly for two weeks, followed by a week off. The most common side effects of velcade have been markedly decreased blood counts and fatigue, which some patients have described as quite profound.

   Several clinical trials have been conducted with velcade in lung cancer, and others are ongoing. Dr. Michael Fanucchi led a randomized phase II trial with 155 patients with advanced NSCLC who had previously received one line of prior chemotherapy to receive either velcade alone or the combination of velcade and taxotere (abstract here).

Fanucci JCO schema

There were several important results from this study. The first point was that velcade has single-agent activity, with a response rate of 8%, which isn’t astounding, but remember that our best agents, and the ones FDA-approved and most commonly used for lung cancer (taxotere, alimta, tarceva) also have a response rate that is essentially identical. But the other arm, receiving the combination of taxotere and velcade, had a response rate of just 9%, the same as what taxotere does on its own. However, the combination did have a much higher stable disease rate, of 45%, compared with 21% for velcade alone. And the combination also had a median time to progression of 4 months, compared with just 1.5 months for the velcade alone:

Fanucchi results

   There have been a few anecdotal reports of impressive results of velcade in some patients with advanced BAC:

Phase I velcade response    Velcade BAC response after several failures

Although not numerous, these results were encouraging enough to lead to dedicated trials of velcade in BAC.  A trial run by the manufacturer, Millenium Pharmaceuticals, in which velcade was given twice weekly, was conducted several years ago. The results have not ever been reported which is usually not a good sign; you don’t keep breakthroughs a secret. Another trial with velcade for BAC is being run by the California and Pittsburgh Cancer Consortium (it’s not just politics that makes strange bedfellows – who would have guessed a cancer research consortium would link several California institutions and the University of Pittsburgh?). In this latter trial, the velcade is being given weekly for two weeks followed by a week off.  So velcade will certainly get the chance to show what it can or can’t do for BAC.

    Velcade has also been studied in recurrent SCLC (abstract here), where SWOG investigators enthusiastically enrolled 60 patients, hoping for another option for this population.  Unfortunately, there was just a single responding patient on the trial, which led SWOG to consider this approach not active enough to pursue further.

    Next, we’ll turn to some combinations of velcade with chemo or targeted therapies.

Dr West

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.

Vascular Disrupting Agents mechanisms (Click to enlarge) Continue reading

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