Manchester, UK – Melanoma cells become drug resistant by using surrounding healthy cells to provide a ‘safe haven’ from treatment, according to new research* published in Cancer Cell recently.

Around half of melanomas are caused by a mutation in a gene called BRAF. Drugs called BRAF inhibitors treat these melanomas by targeting the faulty gene. But these cancers can quickly develop resistance to these targeted treatments.

Scientists at the Francis Crick Institute, funded by Cancer Research UK, and at the Cancer Research UK Manchester Institute have discovered that a side effect of BRAF inhibitors is that they prompt healthy cells to form a ‘safe haven’ shielding melanoma cells from cancer drugs. So even if some cancer cells are destroyed, the protected cancer cells may survive – and the disease can recur in a form that is untreatable.

Francis Crick Institute

Carried out in cells in the laboratory, in mice and in samples from patients’ tumours, the researchers showed this ‘safe haven’ lets melanoma cells turn on a parallel set of cell signals that helps them survive. By adding a second experimental drug that blocks this alternative survival route by targeting a protein called FAK, the researchers discovered that resistance to BRAF inhibitors can be overcome.

This combination of two drugs increased cell death and slowed growth in cell samples, and also stopped tumours from growing larger in mice.

Importantly, while not a cure, adding a second targeted therapy could help improve treatments by overcoming drug resistance and extending the time before the cancer returns.

FAK inhibitors are being tested on their own in early stage cancer clinical trials, but it will be some years before it is known if combining these drugs with BRAF inhibitors could help patients.

Around 13,300 cases of malignant melanoma were diagnosed in 2011 in the UK, that’s 37 people every day. Over the last thirty years, rates of malignant melanoma in Great Britain have risen faster than any of the current top ten cancers.

Study author Dr Erik Sahai, based at the Francis Crick Institute, said: “Skin cancers caused by a faulty BRAF gene typically out-manoeuvre the targeted drugs used to treat them after a few months. Clearly understanding this process is an important first step in improving treatment. We’ve now mapped how melanoma cells exploit their neighbouring cells to survive in the presence of targeted drugs. It’s clear that the ‘safe haven’ offered by the surrounding cells is triggered as a response to the same drugs that target this class of melanoma. Knowing more about this relationship means we can start to improve treatment.”

Co-author Professor Richard Marais, director of the Cancer Research UK Manchester Institute at The University of Manchester, said: “Understanding the complex behaviour of melanoma cells is vital to improving survival. This research helps explain what’s stopping the best drugs we have from working in this deadly skin cancer. This is early laboratory research and the next stage is to see if adding a second drug is safe and effective in patients. That said, we’re making progress, and as our questions are answered we’ll be able to develop and improve cancer treatments.”

Nell Barrie, Cancer Research UK’s senior science information manager, said: “This is an excellent piece of research that adds rich detail to our understanding of how melanoma cells develop resistance to drugs – and how we can tackle this head on. The researchers have worked through the issue with meticulous care to show not just how this happens, but how we can tackle the problem.

“Melanoma survival has been improving for the last 40 years and is now amongst the highest for any cancer. Overall, around nine in 10 people diagnosed with malignant melanoma now survive their disease for at least 10 years, so we’re making great progress, but we have so much more to do. We must develop better and more effective treatments to increase survival. As The Francis Crick Institute begins operation, we look forward to seeing more research like this to help us beat cancer sooner.”

- MFP News Services
- 8/30/15

Patients Wrestle With Extreme Cost of Arthritis Medications

The first national investigation of Medicare coverage of biologic disease modifying drugs (DMARDs) found that in starting a single biologic DMARD, patients face more than $2,700 in copayments each year before receiving relief from catastrophic coverage. Results published in Arthritis & Rheumatology, a journal of the American College of Rheumatology (ACR), show that during the initial phase of coverage, most people are expected to pay a striking 29.6% of total biologic drugs costs (just under one-third) out-of-pocket, creating an enormous financial burden for patients with chronic, rheumatic diseases such as rheumatoid arthritis (RA).

American College of Rheumatology - Arthritis & Rheumatism - Arthritis Care & Research

RA is a chronic autoimmune disease affecting 1.3 million Americans. Medical evidence shows that until the late 1990s, one in three RA patients were permanently disabled within five years of disease onset. Over the last decade there has been significant improvement in treatment, with disease control now possible for many RA patients who receive early, aggressive DMARD therapy.

Treatment with DMARDs is now a standard component of guideline-based care with costs for some the newer drugs topping $20,000 annually. In fact, a recent report by GBI Research estimates that the U.S. market for RA treatment will increase from $6.4 billion in 2013 to $9.3 billion by 2020, driven in part by the increase in RA prevalence–forecasted to reach 1.68 million by 2020.

Regardless of the biologic DMARD, the study found that patients face high initial copayments, then fall into the coverage gap or “donut hole” by February or March. During the donut hole, patients’ cost-sharing increases to 45% of drug costs (for 2015) until they reach catastrophic coverage. Patients generally reach catastrophic coverage between January and July. After that taxpayers, insurers and pharmaceutical companies will pick up 95% of the cost of the biologic DMARD.

A previous study of 1,100 adults with RA found that 1 in 6 decreased their medication because of cost. “While specialty DMARDs have improved the lives of those with chronic diseases like RA, many patients face a growing and unacceptable financial burden for access to treatment,” said Dr. Jinoos Yazdany with the Division of Rheumatology at the University of California, San Francisco and lead author of the present study. “Rather than determining which drug is best for the patient, we find ourselves making treatment decisions based on whether patients can afford drugs,” adds Dr. Yazdany.

The study team analyzed the drug lists (formularies) of 2,737 Medicare Part D plans in 50 states and Washington, DC using the January 2013 Centers for Medicare and Medicaid Services Prescription Drug Plan Formulary and Pharmacy Network Files. Researchers included DMARDS based on the 2012 ACR RA guidelines and the National Committee for Quality Assurance’s DMARD quality measure. Nine biologic medications (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab) and nine non-biologic DMARDs (azathioprine, cuprimine, cyclophosphamide, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, and sulfasalazine were analyzed.

Nationwide, although nearly all Part D plans covered at least 1 biologic DMARD, access was tightly controlled, with 95% of plans requiring prior authorization. Between 81% and 100% of plans required a coinsurance averaging 30% of the drug cost rather than a fixed copayment amount.

“Insurance payment reforms have been suggested by the US government, but are not widely implemented in the health care system,” notes Dr. Yazdany. “With the high cost of biologic DMARDS for RA, many patients are strapped with a substantial financial burden. Americans, especially those patients with chronic conditions such as RA, may be better served by payment and drug coverage reforms that look to decrease rising out-of-pocket costs for patients while keeping total costs in check.”

-MFP News Services
- 7/30/15

‘Good Bacteria’ v ‘Bad Bacteria’ :Dawn of Helpful Immune Cells

The body’s immune system may be the keeper of a healthy gut microbiota, report University of Chicago scientists recently in the journal Immunity. They found that a single binding protein on white blood cells could affect whether or not mice produced a balanced gut microbiota. Without the protein, harmful bacteria were more easily able to cause infection. Why this happens is unclear, but it may be that the immune system has a way to sense the presence of invading intestinal bacteria.

University of Chicago

“Our study reveals how our body’s immune system shapes the gut microbiota to naturally limit infections,” says senior author Yang-Xin Fu, a professor in the University of Chicago Department of Pathology. “Given the rapid rise of harmful bacteria that are resistant to antibiotics, it is paramount that scientists find methods of limiting harmful bacterial infections without the use of antibiotics. For future patients who are infected with harmful bacteria, it might be beneficial to promote the development of good gut microbiota to indirectly kill harmful bacteria, instead of using antibiotics.”

Fu and his collaborators found that intestinal immune cells–called type 3 innate lymphoid cells (ILC3s)–are less able to respond to harmful bacterial infections when they lack a protein called Id2. ILC3s that lacked Id2 were unable to produce a molecule called IL-22 that subsequently stimulates other intestinal cells to produce antimicrobial peptides (AMPs), which help protect the body against pathogenic infections. Notably, normal bacteria seem to be more resistant to AMPs.

When the team transferred microbiota from a mouse with such dysfunctional ILC3s into a completely germ-free mouse, the recipient animal was highly susceptible to infections when later exposed to harmful bacteria. Germ-free mice that received microbiota from animals with functional ILC3s could fight off the bacteria.

How immune cells distinguish between beneficial and harmful bacteria to maintain a healthy microbiota is unknown, although pathogens might produce some molecules that immune cells can sense. After invasion, it has been observed that ILC3s produce higher levels of antimicrobial peptides.

Fu notes that the human body and its microbiota have evolved to live in harmony over millions of years. “This mutually beneficial relationship provides us with the ability to properly receive all of the nutrients from our food, and as shown with this study, the ability to limit harmful bacterial infections,” he says.

-MFP News Services
- 7/29/15