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EGFR Molecular Markers and the Impact of Gene Mutations
We’ve been talking about the potentially relevant molecular markers for EGFR, and the importance of EGFR as a cancer target (see prior post), without really describing what these markers are. There are three main aspects of EGFR biology that have been studied for their potential predictive value in consideration of EGFR inhibitor therapy, whether the oral tyrosine kinase inhibitors like tarceva (erlotinib) or iressa (gefitinib), or the monoclonal antibodies against EGFR such as erbitux (cetuximab). What are these markers?
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Loss of Appetite and Weight Loss: A Very Common and Difficult Problem for Cancer Patients
Loss of appetite and the weight loss that accompanies it are very common problems, seen in up to 80% of patients with advanced cancers, and this issue certainly appears as an issue on the discussion boards. In many cases, it’s one issue on a list of problems, and indeed we’ve gone far too long without a good discussion of this topic that deserves some attention.
A more formal definition of what we see so frequently in the clinic is “anorexia-cachexia syndrome” (ACS). In oncology terms, anorexia just means “loss of appetite”, not the psychiatric focus on being overweight (anorexia nervosa), and cachexia (pronounced “ka-KEK-see-ah”) is a significant concerning weight loss. The ACS syndrome is typically defined as a loss of 5% of the pre-illness weight over a 2-6 month period, but the term “cachectic” is a term health care workers generally use to describe someone who is quite underweight. As you might suspect, the ACS syndrome that also includes nausea, early satiety (feeling full), and fatigue is associated with a shorter survival than is seen in people who eat better and maintain their weight.
Easing the Strain of Cancer-Related Fatigue and “Chemo-Brain”
In recent years, more people are cured or living with cancer as a chronic illness because cancer treatments have improved. As a result, treatment after effects and the challenges they present are becoming increasingly apparent. Two common after effects are cancer-related fatigue (CRF) and cognitive impairment, also known as “chemo-brain.” The National Comprehensive Cancer Network defines CRF as “a persistent sense of tiredness related to cancer or cancer treatment that interferes with usual functioning.” It is different from the every-day tiredness that can affect anyone, and is not readily relieved by rest or sleep.
“Chemo-brain” may occur after chemotherapy and can include difficulties with memory, concentration, language, attention, reaction time, organizational skills and other mental functions. It’s becoming increasingly recognized as a very real and significant medical problem. Many patients experience excessive fatigue or cognitive difficulties following their cancer treatments, which can be very distressing. Fatigue is the most common side effect of cancer and cancer treatment. And we know that cancer-related fatigue can compound the effect of chemo-brain and, likewise, that chemo-brain can increase cancer-related fatigue.
New Effective Treatment for Opioid-Induced Constipation
It’s not a glamourous topic, but severe constipation due to opioid (narcotic) medications is a major issue in managing pain from cancer. Opioid medications like morphine, oxycodone, dilaudid, and fentanyl are often needed to manage cancer-related pain effectively, but they come with some baggage. Although I strongly encourage my patients who need narcotics to not worry about becoming addicted (you can become dependent, which may be unavoidable with appropriate use but is a physiologic effect, not a desire or need to abuse these agents), but opioid-induced constipation is the most common and challenging side effect we encounter as the downside of achieving good pain control that many cancer patients need. In fact, there’s an old quote in medicine, “The hand that writes the narcotic prescription is the hand that writes the laxative prescription.” Not exactly poetry, but I think of it every time I write a prescription for a needed narcotic, and I also write for one or more bowel medications to counter-balance the constipating effects of narcotics. Otherwise, you’re pretty much asking for trouble.
Even with many of the agents available, from stool softeners to laxatives to suppositories and enemas and more, some patients who need significant amounts of narcotics can get pretty miserable from constipation, and we find ourselves sometimes wondering how to balance the competing problems of pain and severe constipation. So when a new and effective treatment for opioid-induced constipation is tested and becomes commercially available, it can represent a major benefit for the people who need it.
That new agent is called relistor, or methynaltrexone, and unfortunately it is only able to be administered as an injection under the skin, like insulin, but it was the subject of a recent randomized study published in the New England Journal of Medicine that showed the benefit it can offer (abstract here). This drug blocks a subset of the opioid receptors, called mu receptors, that are along the gut and cause constipation when turned on by opioids, but this drug also can’t get through the blood brain barrier to reverse the pain control effects of opioids.
New Treatment Being Developed for EGFR Inhibitor Skin Rash
The leading side effect of EGFR inhibitors, both the oral tyrosine kinase inhibitors (such as tarceva (erlotinib)) and the IV monoclonal antibodies (such as erbitux (cetuximab)), is rash, dryness, and other skin side effects. While a rash sounds modest to many people compared to many of the leading problems with chemo, many of the members here can attest that while an EGFR rash can range be as mild as a pimple or two, it can also be itchy, painful, and be as severe as a skin rash covering large amounts of the body, sometimes with open lesions. And for some patients, the skin side effects can require dose reductions or even lead patients to discontinue their EGFR inhibitor, even if it might help against their lung cancer.
As described in a press release last week, Hana Biosciences, based in South San Francisco, has initiated a study of topical menadione, a precursor to forms of vitamin K that also activates EGFR. This topical medication is being studied in the setting of both a prophylactic treatment and as a treatment for skin side effects that emerge on treatment. This research is being led by Dr. Mario Lacouture at Northwestern, who I’d consider to be the leading expert in EGFR rash treatment right now.
There have been several posts and forum threads on managing the rash, but it’s very encouraging to see that not only is more attention being paid to this problem, there are actually trials being run, even with new agents, that are trying to reduce a side effect that can significantly worsen the quality of life for patients on EGFR inhibitors, sometimes even keeping them from getting the drug, or perhaps a dose that could be managed chronically if the rash was controlled more effectively.
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 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
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.
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
DCA and the Journey from In Vitro Studies to Cancer Treatment
I received a question on the discussion forum, in the setting of a lot of internet discussion, about an an agent called dichloroacetate, or DCA, as a potential anticancer therapy. This excitement is based on a study out of the University of Alberta in Canada, that appeared in the journal Cancer Cell (article here). This is a very novel molecular therapy approach, and one about which I don’t have a lot of insight yet, but it does provide an opportunity to discuss the gap between a promising result in preclinical studies and a proven anticancer therapy.
DCA is an unpatented small molecule that has been used for decades to treat children with rare molecular disorders associated with mitochondrial problems, but it’s not a drug that I have had occasion to use. Mitochondria are a component of every cell that create energy for the cell, and mitochondrial disorders have been known to be seen with cancer but have been believed to be an effect rather than a key contributing cause of the cancer process.
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The idea is basically that cancer cells suppress their mitochondria, making the cells resistant to apoptosis, or the normal process of programmed cell death, a sort of self-destruct program built into all cells of the body for certain normal developmental processes but also as a defense mechanism in case the cells mutate too much to work properly. The work described in the paper demonstrated that multiple types of cancer cells in test tube (in vitro) and animal models could be suppressed and killed after DCA restored the normal ability of mitochondria and led to apoptosis that destroyed cancer cells. This research suggests it would have no effect on normal non-cancer cells, so it is believed that DCA would not be assocaited with significant side effects. Overall, these results were considered very encouraging for a drug that it inexpensive and orally available. Continue reading
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