Study finds how diabetes drug metformin inhibits progression of pancreatic cancer

Metformin-induced suppression of metastasis-promoting tumor microenvironment may be most prevalent in overweight, obese patients

Massachusetts General Hospital (MGH) investigators may have uncovered a novel mechanism behind the ability of the diabetes drug metformin to inhibit the progression of pancreatic cancer. In their report that has been published in the open access journal PLOS One, the research team describes finding that metformin decreases the inflammation and fibrosis characteristic of the most common form of pancreatic cancer. Their findings in cellular and animal models and in patient tumor samples also indicate that this beneficial effect may be most prevalent in overweight and obese patients.

We found that metformin alleviates desmoplasia – an accumulation of dense connective tissue and tumor-associated immune cells that is a hallmark of pancreatic cancer – by inhibiting the activation of the pancreatic stellate cells that produce the extracellular matrix and by reprogramming immune cells to reduce inflammation,” says Dai Fukumura, MD, PhD, of the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology, the study’s co-senior author. “We also found these effects only evident in tumors from overweight or obese individuals, who appear to have tumors with increased fibrosis.”

The study focused on pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, which accounts for almost 40,000 cancer death in the U.S. ever year. Half of those diagnosed with this form of pancreatic cancer are overweight or obese, and up to 80 percent have type 2 diabetes or are insulin resistant. Diabetic patients taking metformin – a commonly used generic medication for type 2 diabetes – are known to have a reduced risk of developing pancreatic cancer; and among patients who develop the tumor, those taking the drug may have a reduced risk of death. But prior to the current study the mechanism of metformin’s action against pancreatic cancer was unclear, and no potential biomarkers of response to metformin had been reported.

The researchers first found that levels of hyaluronan, a component of the extracellular matrix, were 30 percent lower in tumor samples from overweight or obese patients who were taking metformin to treat diabetes than in those who did not take the drug. In an obese animal model of pancreatic cancer, those that received metformin had reduced expression of both hyaluronan and collagen-1 and fewer activated pancreatic stellate cells (PSCs). Studies in cultured cells identified the signaling pathway by which metformin reduces the production of hyaluronan and collagen-1 by PSCs and also prevents the recruitment of tumor-associated macrophages, which increase the inflammatory environment.

In obese mouse models, the researchers found that metformin treatment reduced levels of tumor-associated macrophages by 60 percent and reduced expression of genes involved in remodeling the extracellular matrix of tumor tissue. The tumors of animals treated with metformin also had reductions in a metastasis-associated change in cellular characteristics called epithelial to mesenchymal transition (EMT) and in the overall level of metastasis. These tumor-related effects of metformin appear to be independent of the drug’s effects on metabolic pathways involved in glucose metabolism and body weight.

Nearly 200 clinical trials are currently underway investigating the effect of metformin on tumors in both diabetic and non-diabetic patients,” say co-senior author Rakesh K. Jain, PhD, director of the Steele Laboratory. “Understanding the mechanism behind metformin’s effects on pancreatic and other cancers may help us identify biomarkers – such as patient body weight and increased tumor fibrosis – that can identify the patients for whom metformin treatment would be most beneficial.” Fukumura is an associate professor of Radiation Oncology, and Jain is the Cook Professor of Tumor Biology at Harvard Medical School. Later this year Jain will be among nine recipients of the 2016 National Medal of Science.

Incio et al. Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. PLOS one. 2015;DOI: 10.1371/journal.pone.0141392 [Article]


Palliative care initiated in the emergency department is associated with improved quality of life

A palliative care consultation initiated in the emergency department (ED) for patients with advanced cancer was associated with improved quality of life and did not seem to shorten survival, according to an article published online by JAMA Oncology.

Visits to the ED are common for patients with advanced cancer and it is during these visits that decisions are often made about the intensity of care. Although the availability of palliative care services continues to increase, consultation typically does not happen until a week into a patient’s hospital stay. A consultation initiated from the ED may be an opportunity to ensure that care is congruent with a patient’s wishes and to interrupt the cascade of intensive, end-of-life care that may be a marker of low-quality care.

Corita R. Grudzen, M.D., M.S.H.S., of New York University, and coauthors conducted a randomized clinical trial to compare quality of life, depression, health care utilization and survival in ED patients with advanced cancer randomly assigned to an intervention with an ED-initiated palliative care consultation vs. usual care.

The study included 136 patients: 69 in the palliative care consultation intervention and 67 in usual care, who also may have received a palliative care consultation if it was requested by the admitting team or an oncologist. Among the 69 patients in the intervention, 41 died by the one-year mark, as did 44 of the 67 patients who received usual care.

The authors report that the palliative care consultation intervention was associated with increased quality-of-life scores from study enrollment to week 12 (average increase of 5.91 points in the intervention vs an increase of 1.08 in the usual care group).

Median survival was longer for patients in the intervention (289 days) compared with the usual care group (132 days), although the difference was not statistically significant. The lack of statistical significance was due to the highly variable length of survival in the study group, the authors note.
The authors found no statistically significant differences in depression, admission to the intensive care unit and discharge to hospice. The authors suggest the impact of palliative care on health care utilization was “more nuanced” in their study.

Emergency department-initiated palliative care consultation improved QOL [quality of life] in patients with advanced cancer and does not seem to shorten survival; the impact on health care utilization and depression is less clear and warrants further study,” the study concludes.

Grudzen et al. Emergency Department–Initiated Palliative Care in Advanced Cancer: A Randomized Clinical Trial. JAMA Oncol. Published online January 14, 2016. doi:10.1001/jamaoncol.2015.5252 [Article]

Racial disparity lies at the intersection of HIV and Hodgkin lymphoma

A new study finds a significant racial disparity within a doubly troubled population of patients: those with HIV and Hodgkin lymphoma. In such cases, blacks are at significantly higher risk than whites of not receiving treatment for the cancer that in many cases would be effective.

Black patients have higher rates of not receiving treatment,” said lead author Dr. Adam Olszewski, associate professor of medicine in the Alpert Medical School of Brown University and a physician in the Cancer Center of Memorial Hospital in Pawtucket, R.I. “Hodgkin lymphoma is generally believed to be highly curable. We have an expectation to cure over 90 percent of early stage patients and even 70-80 percent of quite advanced cases.”

Olszewski’s study in the journal AIDS, conducted with Dr. Jorge Castillo of Dana-Farber Cancer Institute, identified the racial disparity in data from nearly 2,100 cases in the National Cancer Data Base between 2004 and 2012.


​While the disparity is clear, Olsewski said, the root cause of it is not. Several closely entangled epidemiological, socioeconomic, and medical factors are at play.Heading into the study, researchers knew that people with HIV have a risk of Hodgkin lymphoma that is five to 20 times greater than people who do not have HIV. They also knew that HIV incidence has remained relatively high among blacks, while it has dropped significantly for whites. As a result, the new study found that between 2004 and 2012, blacks surpassed whites as the largest racial group with simultaneous HIV infection and Hodgkin lymphoma, making up 49 percent of such cases in 2012.

Meanwhile, doctors have had a muddy sense of whether HIV-positive people with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. Many HIV-positive patients didn’t tolerate an older treatment regime for the lymphoma, Olszewski said, but chemotherapy treatment has vastly improved in more recent years. While some small studies, particularly in Europe, have found that HIV status makes no difference to survival, observations in the U.S. population suggest that being HIV-positive makes survival less likely.

The new study, the largest to date, may reconcile that conflict. It shows that in the United States the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

Specifically, the study ostensibly showed that HIV-negative people had an 80 percent Hodgkin lymphoma survival rate five years after diagnosis, but HIV-positive people survived at a rate of only 66 percent over the same timeframe. But among HIV-positive patients, 16 percent went untreated. Among people in the study who did get lymphoma treatment, HIV-positive people were statistically just as likely to survive as HIV-negative people. The results apply to the majority of cases in which the subtype of Hodgkin lymphoma is determined.

Importantly, further statistical analysis showed that one of the main risk factors for an HIV-positive person going untreated was being black. Statistically adjusting for possibly confounding factors, HIV-positive blacks were 67 percent more likely than HIV-positive whites to go untreated for the lymphoma. Other risk factors, which are often related to race, were low income and lacking health insurance. Another was being over 60 years of age.

Olszewski acknowledged it’s not clear how the racial disparity arises. It could correlate with more advanced or poorly controlled HIV infection. It could also be a lingering assumption that HIV-positive patients (who are increasingly likely to be black) won’t tolerate the treatment well. Some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself. Another possibility is that the often-related socioeconomic status of being black and poor and uninsured makes it hard for patients to remain connected to care after diagnosis.

For patients who have HIV and Hodgkin lymphoma, treatment can be effective and tolerated, especially when the lymphoma subtype is known, Olszewski said, but doctors should understand that some patients many need extra assistance or attention to ensure they connect with that care.

To date, this study suggests, it’s apparent that some people who should get treatment aren’t getting it.

Olszewski et al., Outcomes of HIV-associated Hodgkin lymphoma in the era of antiretroviral therapy: analysis of the National Cancer Data Base. AIDS, 2016; doi: 10.1097/QAD.0000000000000986 [Abstract]

Mapping cancer’s ‘social networks’ opens new approaches to treatment

Cancer Research UK-funded scientists have designed a computer model that applies techniques used to analyse social networks to identify new ways of treating cancer, according to research published in PLOS Computational Biology. The model analyses the unique behaviours of cancer-causing proteins – spotting what makes them different from normal proteins, and mapping out molecular targets for new potential drugs that could be developed to treat cancer.

Scientists at The Institute of Cancer Research, London, compared proteins inside cells to members of an enormous social network, mapping the ways they interact. This allowed them to predict which proteins will be most effectively targeted with drugs.The researchers have made this map publicly available. It could provide drug discovery scientists with a shortcut to finding new drugs for many different types of cancer.

The team found that there are many molecular pathways that interact to affect the development of cancer. Cancer-causing proteins that have already been successfully targeted with drugs tended to have particular ‘social’ characteristics that differ from non-cancer proteins – suggesting that previously unexplored cancer proteins with similar characteristics could also make good drug targets.

‘Hub-like’ proteins which ‘communicate’ with lots of other proteins – like a super-Facebook user with thousands of friends – were more likely to cause cancer.This information could provide a wide range of potential targets for drug development.

Study leader Dr Bissan Al-Lazikani, Team Leader in Computational Biology and Cancer Research UK-funded scientist at The Institute of Cancer Research, London, said: “Our study is the first to identify the rules of social behaviour of cancer proteins and use it to predict new targets for potential cancer drugs. It shows that cancer drug targets behave very differently from normal proteins and often have a complex web of social interactions, like a Facebook super-user.

Finding new targets is one of the most important steps in drug discovery. But it can be a lengthy, expensive process. The map that we’ve made will help researchers design better new drugs, more quickly, saving time and money. It also sheds light on how resistance to treatments may occur, and in just a few years could help doctors choose the best drug combinations to suit individual patients.”
Nell Barrie, Cancer Research UK’s senior science information manager said: “Thanks to research, cancer survival has doubled in the last 40 years. But we urgently need to develop better, more effective treatments so that in the future no one has to fear a cancer diagnosis. Research like this, that’s made publicly available, will help speed up crucial advances in drug discovery to save more lives from cancer.

Mitsopoulos et al. Distinctive Behaviors of Druggable Proteins in Cellular Networks.  PLoS Comput Biol. 2015; 11(12): e1004597. doi:10.1371/journal.pcbi.1004597 [Article]

Financial burden of cancer survivorship varies by age

Survivors of cancer pay thousands of dollars in excess medical expenditures every year, with the excess financial burden varying by age and cancer site, according to a new American Cancer Society study. The study, appearing early online in the Journal of the National Cancer Institute, says targeted efforts will be important to reduce the economic burden of cancer.

As a group, cancer survivors (estimated to number 14.5 million in the United States in 2014) face greater economic burden, including medical expenditures and productivity losses. But relatively little is known about whether that burden varies by cancer site compared to similar individuals without a cancer history.

​Researchers led by Zhiyuan ‘Jason’ Zheng, PhD, senior health services researcher in the Surveillance and Health Services Research program at the American Cancer Society, used 2008 to 2012 Medical Expenditure Panel Survey data to measure excess economic burden attributable to the three most prevalent cancers. They calculated excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed) for colorectal (n = 540), female breast (n = 1568), and prostate (n = 1170) cancer survivors, and for those without a cancer history (n = 109,423). They stratified the data by cancer site and age (nonelderly: 18-64 years vs elderly: >65 years), and controlled for age, sex, race/ethnicity, marital status, education, number of comorbidities, and geographic region.

They found cancer survivors experienced annual excess medical expenditures compared with individuals without a cancer history. For the nonelderly population, annual excess expenditures were $8657 for colorectal cancer; $5119 for breast cancer; and $3586 for prostate cancer. For the elderly population, annual excess expenditures were: colorectal: $4913; breast: $2288; prostate: $3524.

Nonelderly colorectal and breast cancer survivors were more likely to have employment disability as well as productivity loss at work (7.2 days) and at home (4.5 days). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history.

This study helps us quantify the excess economic burden associated with the three major cancer sites,” said Dr. Zheng. “Understanding this burden is an important step to shape health care policies to target areas where cancer survivors are most vulnerable.”

​Zheng et al. Annual Medical Expenditure and Productivity Loss Among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States. J Natl Cancer Inst. 2016; 108 (5): djv382 doi: 10.1093/jnci/djv382 [Abstract]