Ancient sea bacteria byproduct modiefied for use as potential cancer drug

University of Florida pharmacy researchers have modified a toxic chemical produced by tiny marine microbes and successfully deployed it against laboratory models of colon cancer. 

Light microscope view of the cyanobacterium Microcoleus chthonoplastes [Credit: NASA Microbes Image Gallery]

Writing today in ACS Medicinal Chemistry Letters, UF medicinal chemists describe how they took a generally lethal byproduct of marine cyanobacteria and made it more specifically toxic — to cancer cells. 

When the scientists gave low doses of the compound to mice with a form of colon cancer, they found that it inhibited tumor growth without the overall poisonous effect of the natural product. Even at relatively high doses, the agent was effective and safe. 

“Sometimes nature needs a helping human hand to further optimize these products of evolution to treat human diseases,” said Hendrik Luesch, Ph.D., an associate professor of medicinal chemistry at UF’s College of Pharmacy. “Based on what we learned about apratoxins’ mechanism of action, we knew this compound class had great potential for use in anticancer therapies; however, the natural product itself is too toxic to become a therapeutic.” 

The researchers synthesized several apratoxin compounds that were similar to the original except for slight differences in composition, designing one that proved to be extremely potent against the cancer cells in cultures and in mice, but without the overwhelming toxicity. 

The compound acts as a single agent to reduce levels of two types of proteins that are targeted by cancer research labs around the world — growth factors, and enzymes called tyrosine kinases, which act as receptors for the growth factors. 

Known as apratoxin S4, the compound strips colon cancer cells of their ability to both secrete and use naturally occurring factors that fuel growth — something that Luesch, postdoctoral chemist Qi-Yin Chen, Ph.D., and assistant scientist Yanxia Liu, Ph.D., say is a powerful “one-two punch” against mushrooming populations of cancer cells. 

The trio describes apratoxin’s dual action for the first time in today’s online publication, although Luesch presented early findings in May at the New York Academy of Sciences. 

“This is an extremely interesting discovery that may have the potential to lead to a novel drug, but an extraordinary amount of additional research is needed before we will know. We can hope,” said David J. Newman, D.Phil., chief of the National Cancer Institute’s Natural Products Branch, who was not involved in the research. “Luesch has found a novel compound and a novel mechanism of action that stops the secretion of the receptor and the growth factor — as far as I am aware, this mechanism has only been shown in apratoxin at this time. If nothing else, he has shown us a new way to kill tumor cells and has revealed a new chemistry, and those are important steps.” 

Apratoxin is produced by cyanobacteria, microbes that have evolved toxins to fend off predators and cope with harsh conditions in a marine environment. Collectively known as blue-green algae — a misnomer because the single-celled organisms are not algae or members of the plant kingdom — a wide variety of cyanobacteria species exists in both sea and freshwater environments. 

Like plants, cyanobacteria convert sunlight into energy through a process known as photosynthesis. But where plants exclusively use a green pigment called chlorophyll to capture light to make food, cyanobacteria also use a bluish pigment called phycocyanin. 

In addition, cyanobacteria have the unique ability to use respiration as well as photosynthesis to acquire energy, making these organisms tiny chemical factories capable of producing many as-yet unidentified molecules that may be useful for health applications. 

“Marine cyanobacteria produce a huge diversity of compounds,” said Luesch, who is also a member of the UF Shands Cancer Center. “About half of anticancer drugs are based on natural products. All but a couple of them are derived from terrestrial organisms, yet more than 70 percent of the Earth is covered by oceans, which presumably contain a number of therapeutic molecules with potentially novel biological activities. When we studied the biological effects of apratoxin, we predicted it would be particularly useful against colon cancer if we could engineer it to be more selective.” 

Chen synthesized the apratoxins, while Liu carried out the biology and pharmacology experiments. More lab work is required before a drug based on apratoxin can be tested in patients with colon cancer, but Luesch believes apratoxin S4 is the first candidate to show the needed tumor selectivity, antitumor effects and potency to be effective. The UF Research Opportunity Fund and the Bankhead-Coley Cancer Research Program supported the study. 

Author: John Pastor  | Source: College of Pharmacy - University of Florida [August 31, 2011]

Read more »

Computer-based tool to improve diagnosis and prognosis for cancer patients

A computer-based tool could help GPs to speed up the diagnosis and treatment of patients suffering from two of the most common forms of cancer, potentially saving thousands of lives every year. 

Researchers at The University of Nottingham and ClinRisk Ltd have shown that the algorithm is successful in identifying those suffering with gastro-oesophageal cancer and lung cancer at an earlier stage by 'red-flagging' potentially worrying combinations of symptoms and risk factors. 

Their results, published in the British Journal of General Practice on Monday October 31, showed that the 10 per cent of the patients that the algorithm predicted as most at risk of developing one of the two diseases accounted for 77 per cent of all the gastro-oesophageal and lung cancers diagnosed over the following two years. 

The research was led by Professor Julia Hippisley-Cox, in the University's Division of Primary Care. She said: "Earlier diagnosis of cancer is a major challenge and we hope this new research will help doctors identify patients for earlier referral and investigation." 

The tool could help GPs to improve their record on early diagnosis in line with current Government policy and the National Awareness and Early Diagnosis Initiative (NAEDI) — a public sector/third sector partnership between the Department of Health, National Cancer Action Team, and Cancer Research UK. Evidence suggests that simply raising awareness of symptoms and speeding up diagnosis could save 5,000 lives a year without any new advances in medicine. 

Two simple web calculators have been produced — one for lung cancer (www.qcancer/lung) and the other for gastro-oesophageal cancer (http://www.qcancer.org/gastro-oesophageal) — which are designed for use by doctors but a simpler version could also be made available on the internet to raise awareness among the general public and to prompt patients with high risk factors or symptoms to seek advice from their doctor. 

Lung cancer is the most common cancer worldwide, with 1.3 million new cases diagnosed every year. It has one of the lowest survival rates because two-thirds of patients are diagnosed too late to be successfully treated. 

It presents a huge challenge for family physicians because the symptoms can be common and non-specific. While smoking is a well-known risk factor, evidence suggests that other factors including age, social deprivation, and chronic obstructive airways disease also have an important part to play. 

The presence of the disease can be indicated by 'red flag' symptoms such as new onset of coughing, coughing up blood (haemotypsis), weight loss, loss of appetite and anaemia. Currently, doctors focusing on just one of these symptoms without taking into account other risk factors are likely to miss 80 per cent of current lung cancer cases. 

Similarly, gastro-oesophageal cancer is one of the most common cancers worldwide and earlier diagnosis could improve treatment options and improve five-year survival. 

Alarm symptoms for gastro-oesophageal cancer include vomiting blood (haematemesis), difficulty swallowing (dysphagia), appetite loss, weight loss, or abdominal pain but focusing on one symptom alone in diagnosis can mean that up to 40 per cent of cases are missed. Other underlying factors which could also alert doctors to patients at risk include heavy smoking. 

The study aimed to develop and test the success of a computer algorithm that would incorporate both the symptoms and underlying risk factors of patients to flag those in need of urgent investigation or referral. 

It used 375 general practices in the UK already using the QResearch® database system — a not-for-profit partnership between The University of Nottingham and leading GP systems supplier EMIS — to collect anonymised patient information. 

It included patients aged 30 to 84 years who were free from a diagnosis of the cancers at the start of the study. For lung cancer it ruled out those patients who had previously seen their GPs within the previous 12 months with symptoms of coughing up blood, loss of appetite or weight loss, while the gastro-oesophageal study looked at those patients at the beginning of the study free from difficulty swallowing, vomiting blood, abdominal pain, appetite loss or weight loss. 

The study then identified those patients with the highest associated risk factors for the cancers to predict which were most likely to develop the disease and then validated their results by looking at which patients had been diagnosed with the cancers at the end of two years. 

The study found that the new algorithm worked so well it could identify 10 per cent of the population in which around 77 per cent of all new cases of cancer arose over the two years. 

The algorithm could be incorporated into existing GP computer records to alert doctors to patients who are potentially at a higher risk of developing the diseases. 

In the case of the lung algorithm, it could also be used to inform National Institute of Clinical Excellence (NICE) guidelines on investigation and referral of patients with suspected cancer. For example, NICE guidance recommends an urgent referral for a chest x-ray for patients with persistent symptoms such as coughing up blood, chest pain, shortness of breath, cough or weight loss but not for appetite loss, despite the fact that the study showed that patients with this symptom is four or five times more likely to develop the cancer. 

Dr Clare Gerada, Chair of the Royal College of General Practitioners that publishes the BJGP, said: "The University of Nottingham studies will create great excitement for those of us working in primary care. Early diagnosis has a huge impact on the treatment and survivorship of patients with lung and stomach-related cancers. Incorporating this simple calculation into the consultation could give GPs a two-year headstart on investigation and treatment, with the potential to save thousands of lives. 

"This is exactly the sort of research that the British Journal of General Practice was set up to highlight — practical measures that GPs can take to improve the care they give to their patients. The publication of these vitally important studies by Professor Julia Hippisley-Cox, Dr Carol Coupland and their colleagues could prove a defining moment for cancer diagnosis. I hope the Department of Health and others will take heed." 

Similar QResearch® tests have already proven effective in previous research in identifying patients at most risk of developing heart disease, fracture, kidney disease and serious blood clots. 

Source: University of Nottingham [October 31, 2011]

Read more »

Doctors can learn empathy through a computer-based tutorial

Cancer doctors want to offer a sympathetic ear, but sometimes miss the cues from patients. To help physicians better address their patients' fears and worries, a Duke University researcher has developed a new interactive training tool. 

The computer tutorial includes feedback on the doctors' own audio recorded visits with patients, and provides an alternative to more expensive courses. In a study appearing Nov. 1 in the Annals of Internal Medicine, the research team found that the course resulted in more empathic responses from oncologists, and patients reported greater trust in their doctors – a key component of care that enhances quality of life. 

"Earlier studies have shown that oncologists respond to patient distress with empathy only about a quarter of the time," said James A. Tulsky, M.D., director of the Duke Center for Palliative Care and lead author of the study. "Often, when patients bring up their worries, doctors change the subject or focus on the medical treatment, rather than the emotional concern. Unfortunately, this behavior sends the message, 'This is not what we're here to talk about.'" 

Tulsky said cancer doctors have many reasons for avoiding emotionally fraught conversations. Some worry that the exchanges will cause rather than ease stress, or that they don't have time to address non-medical concerns. 

Neither is true, Tulsky said, noting his research shows that asking the right questions during patient visits can actually save time and enhance patient satisfaction. 

"Oncologists are among the most devoted physicians -- passionately committed to their patients. Unfortunately, their patients don't always know this unless the doctors articulate their empathy explicitly," Tulsky said. "It's a skill set. It's not that the doctors are uncaring, it's just that communication needs to be taught and learned." 

The current gold standard for teaching empathy skills is a multi-day course that involves short lectures and role-playing with actors hired to simulate clinical situations. Such courses are time-consuming and expensive, costing upwards of $3,000 per physician. Tulsky's team at Duke developed a computer program that models what happens in these courses. The doctors receive feedback on pre-recorded encounters, and are able to complete the intervention in their offices or homes in a little more than an hour, at a cost of about $100. 

To test its effectiveness, Tulsky and colleagues enrolled 48 doctors at Duke, the Veterans Affairs Medical Center in Durham, N.C., and the University of Pittsburgh Medical Center. The research team audio-recorded four to eight visits between the doctors and their patients with advanced cancer. 

All the doctors then attended an hour-long lecture on communication skills. Half were randomly assigned to receive a CD-ROM tutorial, the other half received no other intervention. 

The CD taught the doctors basic communication skills, including how to recognize and respond to opportunities in conversations when patients share a negative emotion, and how to share information about prognosis. Doctors also heard examples from their own clinic encounters, with feedback on how they could improve. They were asked to commit to making changes in their practice and then reminded of these prior to their next clinic visits. 

Afterward, all the doctors were again recorded during patient visits, and the encounters were assessed by both patients and trained listeners who evaluated the conversations for how well the doctors responded to empathic statements. Oncologists who had not taken the CD course made no improvement in the way they responded to patients when confronted with concerns or fears. Doctors in the trained group, however, responded empathically twice as often as those who received no training. In addition, they were better at eliciting patient concerns, using tactics to promote conversations rather than shut them down. 

"Patient trust in physicians increased significantly," Tulsky said, adding that patients report feeling better when they believe their doctors are on their side. "This is exciting, because it's an easy, relatively inexpensive way to train physicians to respond to patients' most basic needs." 

Although the CD course is not yet widely available, efforts are underway to develop it for broader distribution.  

Source: Duke University Medical Center [October 31, 2011]

Read more »

Key driver of metastasis identified

Scientists at Dalhousie University in Nova Scotia have identified a key mechanism of metastasis that could lead to blocking tumor growth if their findings are confirmed.

Metastasis of a cancerous cell. Coloured scanning electron micrograph (SEM) of an ovarian cancer cell, showing pseudopodia protrusions, a prominent feature of actively motile cells. The role of pseudopodia in metastasis (the spread of cancer cells around the body) is poorly understood but it appears that a protein, named autocrine motility factor (AMF), causes pseudopodia to extend prior to cell movement. Locomotion is integral to the entire process of metastasis. Magnification: x2500 when printed 10 centimetres wide [Credit: STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY]

In a recent issue of Cancer Research, a journal of the American Association for Cancer Research, lead researcher David Waisman, Ph.D., professor in the Departments of Biochemistry and Molecular Biology and Pathology, and Canada Research Chair in Cancer Research at Dalhousie University, detailed the key role the macrophage cell surface protein S100A10 plays in allowing macrophages to move to the site of tumor growth – a process that is essential to tumor development.

Waisman said the findings are an example of the complicated biology of cancer.

"We used to think that the only cells that mattered in a tumor were the cancer cells, and that's it, but now we are beginning to see that other cells must collaborate with cancer cells to drive tumor growth and permit an evolution of the cancer cells into metastatic cells. This change is what causes poor prognosis and ultimately what kills the patient," he said.

Waisman and colleagues discovered that tumors will not grow without macrophage assistance. These macrophages must come from the blood or from other locations in the tissues. How they are able to move through the tissues or from the blood supply into the tumor had always been a mystery.

These macrophages need to chew their way through the tissue that forms a barrier around the growing tumor in order to move into the tumor site and combine with the cancer cells. The researchers found on the outside surface of the macrophage is a protein called S100A10, which enables the macrophage to remove the tissue barriers retarding migration to the tumor site.

Theoretically, blocking either the macrophages or S100A10 chemically could slow, or even stop, tumor growth.

"We found that the protein, S100A10, acts like a pair of scissors on the outside of the macrophages that empowers the macrophages with the ability to chew their way through tissues and enter the tumor site where they release substances that stimulate cancer cell growth and metastatic evolution," said Waisman.

He said the next step is to figure out exactly how S100A10 functions as a molecular scissor and also to identify pharmaceutical agents that can block the action of S100A10, thereby preventing the movement of macrophages to the tumor site. By understanding exactly how S100A10 works at the molecular level, it may even be possible to design agents which block its activity.

Source: American Association for Cancer Research [October 31, 2011]

Read more »