Evaluation of mangafodipir treatment for oxaliplatin-associated neuropathy

An unfortunate side effect of the platinum-chemotherapy drug oxaliplatin is the development of neurotoxicity, which can adversely affect a patient’s quality of life; therefore, the benefit of oxaliplatin-based therapy must be balanced with prevention of neuropathies. Currently, there are no therapeutic interventions available to relieve oxaliplatin-associated neurological symptoms, which are thought to be a result of reactive oxygen species-associated damage.

In this issue of the Journal of Clinical Investigation, Frédéric Batteux and colleagues at the Laboratoire d’Immunologie evaluated use of the MRI contrast agent mangafodipir, which has antioxidant properties, for relief of oxaliplatin-associated neuropathies. In a mouse model of oxaliplatin-induced neurologic damage, administration of mangafodipir reduced neurotoxicity and the presence of oxidized protein products. Furthermore, in a cohort of 22 patients with oxaliplatin-associated neuropathy, mangafodipir treatment appeared to decrease neurological symptoms.

In their accompanying commentary, Charles Loprinzi and colleagues at the May Clinic caution that even though these results seem promising, larger clinical trails have not been able to confirm similar results from other agents that have shown promise for treating chemotherapy-induced neuropathy in animal models and small phase II trials.

Coriat et al., (2014). Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir. J. Clin.Invest., 124:262–272. doi:10.1172/JCI68730 [Article]

Pachman et al., (2014). The search for treatments to reduce chemotherapy-induced peripheral neuropathy. J. Clin. Invest., 124:72-74. doi:10.1172/JCI73908 [Abstract]

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Saving fertility not priority at most cancer centers

Lack of policies to protect cancer patient’s fertility at top cancer centers

Infertility is consistently listed as one of the most distressing long-term side effects of cancer treatment for adolescents and young adults. Yet the leading National Cancer Institute-designated comprehensive cancer centers — which should be leaders in fertility preservation — aren’t doing an adequate job of helping patients protect their fertility, reports a new Northwestern Medicine® study, published this month in the Journal of the National Comprehensive Cancer Network.

Most of these centers around the country do not have policies or procedures in place to consistently identify which patients may be at risk for fertility loss, inform patients of this risk in a timely manner or refer them to fertility specialists, the study found. At the time of the study, there were 39 comprehensive cancer centers that treated adults.

“It can be shocking for patients to find out their fertility was affected when there were potentially options that exist that were not offered to them,” said lead study author Marla Clayman, an assistant professor of medicine at Northwestern University Feinberg School of Medicine and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

“These are the centers that are at the vanguard of research and have the most people and financial resources,” Clayman added. “This should be part of the exemplary cancer care patients get in these centers.”

A patient navigator for fertility preservation sees cancer patients at the Lurie Cancer Center, Clayman noted. Northwestern is the site of the Oncofertility Consortium, a national, interdisciplinary initiative designed to explore the reproductive future of cancer survivors.Survival rates for young cancer patients have steadily increased over the past four decades due to more effective treatments. More women and men look forward to life after cancer and having children is a key part of their hope for the future.

“When you think about having children after cancer, that’s a very strong way to think about surviving and thriving after cancer,” Clayman said. “It’s not just that you want to live, it’s that you want to live a life as close as possible that you could have without cancer.”

Fertility navigators or a designated fertility educator are key to bridge the gap between oncology and fertility. But less than one-third of the centers had someone in this role, the study reports. Fertility navigators or educators reduce the need for oncologists to have in-depth discussions about potential fertility loss and fertility preservation, a rapidly changing field in which they are not experts.

Clayman also pointed out that if these institutions with the most resources have not made fertility preservation a priority, then providing these services to the patients who are seen in community and private clinics cannot be expected to occur. Clayman is a co-editor, along with Northwestern’s Teresa Woodruff and Kate Waimey of the new book Oncofertility Communication. Woodruff, chief of fertility preservation at Feinberg, founded and leads the Oncofertility Consortium.

Clayman et al., (2013). Oncofertility resources at NCI-designated Comprehensive Cancer Centers. J. Natl. Compr. Canc.Netw.11:1504-1509 [Abstract]

Researchers find potential new treatment approach for pancreatic cancer

Scientists from The University of Manchester – part of Manchester Cancer Research Centre believe they have discovered a new way to make chemotherapy treatment more effective for pancreatic cancer patients.

Pancreatic cancer is an aggressive cancer with poor prognosis and limited treatment options and is highly resistant to chemotherapy and radiotherapy. But researchers believe they have found an effective strategy for selectively killing pancreatic cancer while sparing healthy cells which could make treatment more effective.

Pancreatic cancer cells. Credit: The University of Manchester

Dr Jason Bruce, from the Physiological Systems and Disease Research Group, who led the research, said: “Pancreatic cancer is one of the most aggressive and deadly cancers. Most patients develop symptoms after the tumour has spread to other organs. To make things worse, pancreatic cancer is highly resistant to chemotherapy and radiotherapy. Clearly a radical new approach to treatment is urgently required. We wanted to understand how the switch in energy supply in cancer cells might help them survive.”

The research, published in The Journal of Biological Chemistry this month, found pancreatic cancer cells may have their own specialised energy supply that maintains calcium levels and keeps cancer cells alive.

Maintaining a low concentration of calcium within cells is vital to their survival and this is achieved by calcium pumps on the plasma membrane. This calcium pump, known as PMCA, is fuelled using ATP – the key energy currency for many cellular processes.

All cells generate energy from nutrients using two major biochemical energy “factories”, mitochondria and glycolysis. Mitochondria generate approximately 90% of the cells’ energy in normal healthy cells. However, in pancreatic cancer cells there is a shift towards glycolysis as the major energy source. It is thought that the calcium pump may have its own supply of glycolytic ATP, and it is this fuel supply that gives cancer cells a survival advantage over normal cells.

Scientists used cells taken from human tumours and looked at the effect of blocking each of these two energy sources in turn. Their study, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Central Manchester University Hospitals NHS Foundation Trust (CMFT)/National Institute of Health Research (NIHR) Manchester Biomedical Research Centre and AstraZeneca, shows that blocking mitochondrial metabolism had no effect. However, when they blocked glycolysis, they saw a reduced supply of ATP which inhibited the calcium pump, resulting in a toxic calcium overload and ultimately cell death.

Dr Bruce added: “It looks like glycolysis is the key process in providing ATP fuel for the calcium pump in pancreatic cancer cells. Although an important strategy for cell survival, it may also be their major weakness.

“Designing drugs to cut off this supply to the calcium pumps might be an effective strategy for selectively killing cancer cells while sparing normal cells within the pancreas.”

Maggie Blanks, CEO of the national charity, the Pancreatic Cancer Research Fund said: “These findings will certainly of great interest to the pancreatic cancer research community and we’d be keen to see how this approach progresses. Finding weaknesses that can be exploited in this highly aggressive cancer is paramount, so we want to congratulate the Manchester team for their discovery.”

James et al., (2013). Glycolytic ATP fuels the plasma membrane calcium pump critical for pancreatic cancer cell survival. J. Biol. Chem., 288, 36007-36019 [Abstract]

Fatigue, a common side effect of breast cancer treatment, evaluated in novel patient study

Clinical trial aims to identify why some breast cancer patients are at high risk for post-treatment fatigue

Although the prevalence and impact of cancer-related fatigue has been well established, very little is known about its predictors, mechanisms for development, and persistence post-treatment. A new research study at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, in partnership with UCLA, is aimed at identifying breast cancer patients most susceptible to post-treatment fatigue by measuring biological, behavioral and social risk factors.

“Understanding who is at risk for post-treatment fatigue, and why, is the first critical step in the development of personalized, targeted interventions for the treatment and prevention of breast cancer-related fatigue,” said Arash Asher, MD, director of cancer rehabilitation and survivorship at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and the medical center’s primary investigator on the study. “It is our hope to identify the biological and behavioral risk factors that contribute to a patient’s overall risk for fatigue.”

The research study aims to identify biological factors that may cause more severe fatigue in patients post-treatment. Among the biological markers studied, researchers will evaluate the role of inflammation as a key mechanism for cancer-related fatigue. Extensive research has shown a correlation between inflammatory markers in the blood and levels of fatigue among patients during and after breast cancer treatment.

The study also will examine psychological factors, including a history of depression and early-life stressors, that may increase risk for developing post-treatment fatigue in women with early-stage disease.

“By identifying women who are at risk for post-treatment fatigue, our multidisciplinary breast cancer team can work to develop targeted therapies to prevent or ameliorate this disabling symptom,” said M. William Audeh, MD, MS, medical director of the Wasserman Breast Cancer Risk Reduction Program at the Samuel Oschin Comprehensive Cancer Institute breast cancer program. “By providing a deeper understanding of genetic and biological disease characteristics, as well as risk profiles, the study may also lead to highly personalized breast cancer treatments for each individual diagnosed.”

Patients will be evaluated just after diagnosis and surgery and prior to the start of chemotherapy, radiation therapy and hormonal treatments. In this narrow window of time, patients will take part in physical and psychosocial evaluations that examine genetic, biological and psychosocial factors that may cause inflammation and worsen fatigue. Patients will be followed for 18 months after treatment completion and evaluated on a six-month basis.

This study, known as the RISE Study (Research on Inflammation, Stress and Energy Study), was created by principal investigator Julienne E. Bower, UCLA associate professor of Psychology and Psychiatry/Biobehavioral Sciences. The study is funded by the National Cancer Institute.

Patients interested in breast cancer or other clinical trials at Cedars-Sinai may visit http://cancertrialinfo.csmc.edu or contact Jaime Richardson, RN, clinical trial navigator at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, at 310-423-2133 or cancer.trial.info@cshs.org.

Advances in nanotechnology’s fight against cancer

As cancer maintains its standing as the second leading cause of death in the U.S., researchers have continued their quest for safer and more effective treatments. Among the most promising advances has been the rise of nanomedicine, the application of tiny materials and devices whose sizes are measured in the billionths of a meter to detect, diagnose and treat disease.

A new research review co-authored by a UCLA professor provides one of the most comprehensive assessments to date of research on nanomedicine-based approaches to treating cancer and offers insight into how researchers can best position nanomedicine-based cancer treatments for FDA approval.

The article, by Dean Ho, professor of oral biology and medicine at the UCLA School of Dentistry, and Edward Chow, assistant professor at the Cancer Science Institute of Singapore and the National University of Singapore, was published online by the peer-reviewed journal Science Translational Medicine. Ho and Chow describe the paths that nanotechnology-enabled therapies could take — and the regulatory and funding obstacles they could encounter — as they progress through safety and efficacy studies.

“Manufacturing, safety and toxicity studies that will be accepted by the Food and Drug Administration before clinical studies are just some of the considerations that continue to be addressed by the nanomedicine field,” said Chow, the paper’s co-corresponding author.

Compared with other available therapies, nanomedicine has proven to be especially promising in fighting cancer. In preclinical trials, nanomaterials have produced safer and more effective imaging and drug delivery, and they have enabled researchers to precisely target tumors while sparing patients’ healthy tissue. In addition, nanotechnology has significantly improved the sensitivity of magnetic resonance imaging, making hard-to-find cancers easier to detect.

“A broad spectrum of innovative vehicles is being developed by the cancer nanomedicine community for targeted drug delivery and imaging systems,” said Dr. Ho, the paper’s corresponding author and co-director of the Jane and Jerry Weintraub Center for Reconstructive Biotechnology at the UCLA School of Dentistry. “It is important to address regulatory issues, overcome manufacturing challenges and outline a strategy for implementing nanomedicine therapies — both individually and in combination — to help achieve widespread acceptance for the clinical use of cancer nanomedicine.”

Ho’s team previously pioneered the development of a nanodiamond-doxorubicin compound named NDX. In preclinical studies conducted with Chow, NDX was found to be safer and more effective than unmodified doxorubicin, a clinical standard, for treating breast, liver and other cancer models.

Ho and Chow’s new report features multiple studies in which the use of nanoparticles was translated from the preclinical to the clinical stage. In several of the highlighted studies, nanotechnology-modified drugs showed improvements over conventional, drug-only approaches because of their ability to overcome drug resistance (which occurs when tumors reject the drug and stop responding to treatment), to more effective tumor reduction, among other advantages.

The authors also describe how algorithm-based methods that rapidly determine the best drug combinations, and computation-based methods that draw information from databases of drug interactions and side effects, to help rationally design drug combinations could potentially be paired with nanomedicine to deliver multiple nano-therapies together to further improve the potency and safety of cancer treatments.

“This research review by Dr. Ho and his colleagues lays the groundwork for nanomedicine to become a widely accepted cancer therapy,” said Dr. No-Hee Park, dean of the UCLA School of Dentistry. “This blueprint for navigating the process from bench research to mainstream clinical use is invaluable to the nanotechnology community.”

Dr. Ho, also a professor of bioengineering and a member of the Jonsson Comprehensive Cancer Center and California NanoSystems Institute, noted that nanomedicine regulation is still in its early stages, but the clinical use of existing nanoparticle drugs, such as the protein-modified breast cancer drug Abraxane, is a promising start.

“The FDA’s approval of Abraxane provides a strong foundation for the continued acceleration of new cancer nanomedicine therapies and imaging solutions in the fight against cancer,” Ho said.

Chow and Ho (2013). Cancer Nanomedicine: From drug delivery to imaging. Sci. Transl. Med., 5, 216rv4, DOI: 10.1126/scitranslmed.3005872 [Abstract]

Breaking down cancer’s defense mechanisms

A possible new method for treating pancreatic cancer which enables the body’s immune system to attack and kill cancer cells has been developed by researchers.

The method uses a drug which breaks down the protective barrier surrounding pancreatic cancer tumours, enabling cancer-attacking T cells to get through. The drug is used in combination with an antibody that blocks a second target, which improves the activity of these T cells.

Initial tests of the combined treatment, carried out by researchers at the University’s Cancer Research UK Cambridge Institute, resulted in almost complete elimination of cancer cells in one week. The findings, reported in the journal PNAS, mark the first time this has been achieved in any pancreatic cancer model. In addition to pancreatic cancer, the approach could potentially be used in other types of solid tumour cancers.

Pancreatic cancer is the fifth most common cause of cancer-related death in the UK and the eighth most common worldwide. It affects men and women equally, and is more common in people over the age of 60. As it has very few symptoms in its early stages, pancreatic cancer is usually only diagnosed once it is relatively advanced, and prognosis is poor: for all stages combined, the one and five-year survival rates are 25% and 26% respectively. Tumour removal is the most effective treatment, but it is suitable for just one in five patients.

Picture

Left: pancreatic cancer cells (in green) Right: after six days of combined tumour immunotherapy, the cancerous cells had been killed. Credit: Douglas Fearon

Immunotherapy – stimulating the immune system to attack cancer cells – is a promising therapy for several types of solid tumours, but patients with pancreatic cancer have not responded to this approach, perhaps because the human form of the cancer, as in animal models, also creates a protective barrier around itself.

The research, led by Professor Douglas Fearon, determined that this barrier is created by a chemokine protein, CXCL12, which is produced by a specialised kind of connective tissue cell, called a carcinoma-associated fibroblast, or CAF. The CXCL12 protein then coats the cancer cells where it acts as a biological shield that keeps T cells away. The effect of the shield was overcome by using a drug that specifically prevents the T cells from interacting with CXCL12.

“We observed that T cells were absent from the part of the tumour containing the cancer cells that were coated with chemokine, and the principal source of the chemokine was the CAFs,” said Professor Fearon. “Interestingly, depleting the CAFs from the pancreatic cancer had a similar effect of allowing immune control of the tumour growth.”

The drug used by the researchers was AMD3100, also known as Plerixafor, which blocks CXCR4, the receptor on the T cells for CXCL12, enabling T cells to reach and kill the cancer cells in pancreatic cancer models. When used in combination with anti-PD-L1, an immunotherapeutic antibody which enhances the activation of the T cells, the number of cancer cells and the volume of the tumour were greatly diminished. Following combined treatment for one week, the residual tumour was composed only of premalignant cells and inflammatory cells.

“By enabling the body to use its own defences to attack cancer, this approach has the potential to greatly improve treatment of solid tumours,” said Professor Fearon.

Feig et al., (2013).Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. PNAS110, 20212-20217 [pdf]

Keep on exercising, researchers advise older breast cancer survivors

One year of exercise can ensure steady maintenance of bone density to help prevent fractures

To build and maintain muscle strength, it is best for older breast cancer survivors to follow an ongoing exercise program of resistance and impact training. This advice comes from Jessica Dobek of the Oregon Health and Science University, lead author of a study published in Springer’s Journal of Cancer Survivorship. Dobek is part of a research team, headed by Dr. Kerri Winters-Stone, that found that the bone benefit from one year of such training could be maintained, even with less exercise, up to a year later, which could help prevent bone fractures in the long run.

Older women form the largest group of breast cancer survivors. They face many challenges in maintaining a healthy body composition and optimal physical functioning due to the combined effects of cancer treatment, ageing and reduced physical activity. Cancer treatment is associated with loss of bone density, loss of lean body mass and increases in body fat. The associated changes in body composition place older breast cancer survivors at higher risk of obesity-related disease, breast cancer recurrence, frailty and fractures.

Exercise is one way in which to combat the side effects and long-term effects of cancer treatment. In previous research, Dobek and Winters-Stone found that a one-year-long exercise regimen of resistance and impact training helped build muscle strength and stopped bone loss among a group of breast cancer survivors. As they wanted to determine if these benefits continued or were reversed after completing the intervention, follow-up assessments were done one year later on 44 women who were part of the original study. Their bone mineral density of the hip and spine, muscle mass, fat mass and maximal upper and lower body strength were measured.

Their follow-up study is the first to report on long-term changes in body composition and muscle strength in older breast cancer survivors who had previously participated in a supervised resistance and impact training intervention trial.

They found that spine bone mineral density can be preserved in older breast cancer survivors even after formal exercise training stops. Some women continued to engage in exercise, albeit at a lower level, in the year after formal training stopped while others stopped exercising altogether. The sustained prevention of bone loss through moderate levels of exercise might translate to fewer fractures in later life. On the other hand, the findings also show that muscle strength declined more quickly than bone density and may require continued participation in a supervised exercise program where the degree of effort can be sustained at a higher level.

“Exercise programs aimed at improving musculoskeletal health should be considered in the long-term care plan for breast cancer survivors,” advises Dobek. “Though further work is needed, our results may provide a beginning knowledge about the type, volume and length of exercise training needed to preserve bone health among long-term cancer survivors at risk of fracture.”

Dobek et al., (2013). Musculoskeletal changes after 1 year of exercise in older breast cancer survivors, Journal of Cancer Survivorship. DOI 10.1007/s11764-013-0313-7 [Abstract]