A majority of patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor mutations in the anaplastic lymphoma kinase (ALK) gene responded to treatment with a novel ALK inhibitor despite progressing on earlier ALK inhibitor therapy, according to new results from a phase I study (Shaw AT et al.). The trial highlights the potential role of second-line ALK-targeted therapy in the treatment of ALK-positive NSCLC.
Approximately 3% to 7% of patients with NSCLC have ALK rearrangements, which occur more commonly in nonsmokers, younger patients, and adenocarcinomas. ALK-mutated tumors become dependent on ALK signaling, and as a result, are highly susceptible to ALK inhibition. Crizotinib, a first-generation ALK inhibitor, can induce response rates of 60% in patients with advanced ALK-positive NSCLC, but most patients develop resistance to crizotinib within one to two years.
In general, ALK rearrangements do not overlap with other oncogenic drivers such as EGFR and KRAS mutations in patients with NSCLC (Gainor JF et al.). New options for ALK-targeted therapy, therefore, expand treatment options for patients who are not candidates for other targeted therapies, and for those who progress on current ALK inhibitor therapy.
Alice T. Shaw, MD, PhD, Assistant Professor at Harvard Medical School in Boston, presented findings from a multicenter, open-label, single-arm study of 122 patients with locally advanced or metastatic ALK-positive NSCLC. Of these, 63% had progressed on prior crizotinib therapy, and 31% were ALK-inhibitor naïve. All patients received LDK378, an oral next-generation ALK inhibitor that has shown 20-fold greater potency against ALK compared with crizotinib.
Response rates to LDK378 400-750 mg once daily were high in 114 evaluable patients, with 75% demonstrating some degree of tumor regression. The complete response rate was 58% for all patients, with no apparent differences between those with crizotinib resistance (57%) and those with no prior exposure to an ALK inhibitor (60%). Responses were durable, with a prolonged median duration of response (8.2 months) and median progression-free survival (8.6 months). Imaging studies also demonstrated the activity of LDK378 against central nervous system (CNS) metastases.
“CNS relapses are a major cause of morbidity and mortality in patients treated with crizotinib, so establishing the CNS activity of LDK378 is extremely important,” Dr. Shaw said.
Treatment with LDK378 was generally well tolerated. The most common adverse events included mild gastrointestinal symptoms in 58%-73% of patients. Grade ≥3 adverse events included elevated ALT (19%), elevated AST (10%), diarrhea (8%), and elevated lipase, hypokalemia, and nausea in 5% of patients. Three patients (2%) discontinued LDK378 due to adverse events. No treatment-related deaths were reported.
The current gold standard for detecting ALK rearrangements is fluorescence in situ hybridization (FISH). Many institutions, however, are exploring the use of immunohistochemistry screening with ALK-specific antibodies, reserving ALK FISH to confirm ALK positivity (Tsao MS et al.; Lantuejoul S et al.).
Based on early findings from this trial, the FDA recently designated LDK378 as a breakthrough therapy, a designation intended to expedite the development and review of new therapies for serious or life-threatening conditions. LDK378 is currently under evaluation in phase II and III trials of patients with advanced NSCLC who have received prior chemotherapy and crizotinib and in patients who are crizotinib-naïve.
Another investigational ALK inhibitor, CH5424802, showed antitumor activity in in a phase I/II study of patients with ALK-positive NSCLC and no prior exposure to ALK-inhibitor therapy (Nakagawa K et al.). AP26113, a dual inhibitor of ALK and EGFR, is also under development for the treatment of ALK-positive NSCLC.
Source: The oncologist
ine-hei�j1.#0ground:white’>In females, there was a marked deterioration of glucose tolerance, which may be related to the 2-fold induction of estrogen sulfotransferase and reduced expression of estrogen receptor α (25%) and estrogen target genes (>34%).
Because of the very low doses of pollutants used in the mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in food in the development of metabolic diseases.”
The chemical contaminants used in the study were chosen not only because they’re pervasive in the food supply, but also because they’re known endocrine disruptors. The glands of your endocrine system and the hormones they release influence almost every cell, organ, and function of your body. It is instrumental in regulating mood, growth and development, tissue function, metabolism, as well as sexual function and reproductive processes.
Endocrine disrupters are substances or mixtures that alter the functions of your endocrine system and consequently cause adverse health effects, either in your body or in your offspring. These types of chemicals can exert their effects by:
- Mimicking the biological activity of your hormones by binding to a cellular receptor. This can initiate your cell’s normal response to the naturally-occurring hormone at the wrong time or to an excessive extent (agonistic effect).
- Binding to the receptor but not activating it. Instead the presence of the chemical on the receptor prevents binding of the natural hormone (antagonistic effect).
- Binding to transport proteins in your blood, thus altering the amounts of natural hormones that are present in your blood circulation.
- Interfering with the metabolic processes in your body, affecting the synthesis or breakdown rates of your natural hormones.
The strongest evidence showing that exposure to these types of environmental chemicals can lead to disruption of endocrine function comes from the bizarre changes seen in a number of wildlife species, such as male fish transforming into females, frogs developing a variety of defects like multiple testes or ovaries, and hermaphrodite bears, just to name a few.
Yet, it’s commonly stated that these chemicals are not dangerous to humans because they exist at such low levels, even as research suggests otherwise. For instance, of 115 published animal studies, 81 percent found significant effects from even low-level exposure to BPA.
And the latest study only adds to this undeniable knowledge:
“With this study, we have succeeded in providing proof-of-concept that low doses of contaminants, even at levels normally considered to be without health impacts in humans, do in fact affect humans when subjected to chronic exposure, and when the contaminants are combined with a high-calorie diet,” the researchers said.2
What Are the Long-Term Health Risks from Exposure to Common Food Contaminants?
A typical American comes in regular contact with some 6,000 chemicals and an untold number of potentially toxic substances on a less frequent basis. There are about 75,000 chemicals regularly manufactured and imported by US industries, so you could be exposed to any number of them. Disturbingly, many of them have never been fully tested for safety, and virtually none have been studied in combination with one another, which is how real-world exposure occurs and where their toxicities can be amplified exponentially.
Upwards of 20 environmental chemicals, most of them endocrine-disrupting chemicals, have been shown to cause weight gain when exposure occurs during fetal and infant development, although some are also linked to adult exposures. Others, including BPA, PCBs, phthalates and agricultural pesticides can lead to health problems including:
|Non-descended testes in young males
||Breast cancer in women
||Prostate cancer in men
|Developmental effects on the nervous system in children
||Attention deficit hyperactivity in children
According to a World Health Organization (WHO) and United Nations Environment Program (UNEP) report:3
“The diverse systems affected by endocrine-disrupting chemicals likely include all hormonal systems and range from those controlling development and function of reproductive organs to the tissues and organs regulating metabolism and satiety. Effects on these systems can lead to obesity, infertility or reduced fertility, learning and memory difficulties, adult-onset diabetes or cardiovascular disease, as well as a variety of other diseases.”
Specifically, health problems linked to some of the most common food contaminants include:
- BPA: Plasticizing chemicals like BPA, found in plastics and canned food linings, disrupt embryonic development and are linked to heart disease and cancer. Beware that many manufacturers of ‘BPA-free’ products have simply replaced BPA with bisphenol-S (BPS), an equally toxic chemical. More recently, research has found that other bisphenols used in the production of consumer products, namely, bisphenols M, AP and P, are actually more toxic to DNA than BPA.4
- Phthalates: Phthalates dysregulate gene expression and cause genital anomalies, especially in baby boys, that may pass down several generations. Phthalates are found in vinyl flooring, detergents, automotive plastics, soap, shampoo, deodorants, fragrances, hair spray, nail polish, plastic bags, food packaging, garden hoses, inflatable toys, blood-storage bags, and intravenous medical tubing.
- Dioxins: Dioxins are a byproduct of industrial processes, such as chlorine bleaching of paper products and the manufacturing of some pesticides. Because they are persistent environmental pollutants, they accumulate in the food chain and more than 90 percent of human exposure is through foods like meat, dairy products and fish. According to WHO, “Dioxins are highly toxic and can cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer.”5
- PCBs: Like dioxins, PCBs are persistent organic pollutants (POPs) that persist in the environment and resist breaking down, accumulating in the food chain and posing serious risks to human health and the environment. For instance, even though PCBs have been banned in the US for decades, they are still present in your environment. PCBs and other POPs have caused birth defects and other abnormalities among wildlife, along with damage to virtually every human bodily system.
Tips for Finding the Purest Foods Possible
When it comes to staying healthy, avoiding processed foods and replacing them with fresh, whole foods is the “secret” you’ve been looking for. The more steps your food goes through before it reaches your plate, the greater your chances of contamination becomes. If you are able to get your food locally, you eliminate numerous routes that could expose your food to contamination with not only disease-causing pathogens but also with the chemical contaminants noted above, which often exist in food packaging.
It’s also important to choose your fresh foods wisely, as you’ll want to focus on those grown in non-polluted areas using organic farming methods. Whatever food you’re looking to eat, whether organic or locally grown, from either your local supermarket or a farmer’s market, the following are signs of a high-quality, healthy food. Most often, the best place to find these foods is from asustainable agricultural group in your area. You can also review my free nutrition plan to get started on a healthy eating program today:
|It’s grown without pesticides and chemical fertilizers (organic foods fit this description, but so do some non-organic foods)
||It’s not genetically engineered
||It contains no added growth hormones, antibiotics, or other drugs
|It does not contain artificial anything, nor any preservatives
||It is fresh (if you have to choose between wilted organic produce or fresh conventional produce, the latter may still be the better option as freshness is important for optimal nutrient content)
||It was not grown in a concentrated animal feeding operation (CAFO)
|It is grown with the laws of nature in mind (meaning animals are fed their native diets, not a mix of grains and animal byproducts, and have free-range access to the outdoors)
||It is grown in a sustainable way (using minimal amounts of water, protecting the soil from burnout, and turning animal wastes into natural fertilizers instead of environmental pollutants)