How certain drugs alter metabolism of pancreatic cancer cells

UT Southwestern Medical Center researchers have found that cancer drugs known as CDK4/6-inhibitors alter the metabolism of pancreatic cancer cells, revealing a biologic vulnerability that could be exploited for therapeutic gain. The findings were published today in Cell Reports.

Because pancreatic cancer has one of the worse prognoses of any cancer and is the third leading cause of cancer deaths in the U.S., according to the National Cancer Institute, researchers for years have sought to find better treatment options.

Last year, the FDA approved the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for treating a certain type of advanced breast cancer. This class of drugs has been widely studied in clinical trials for many other types of cancer, including pancreatic cancer. CDK 4/6 inhibitors are cytostatic, meaning they work by preventing cancer cells from growing and dividing.

“On the one hand, that’s great, because the tumor won’t grow, but on the other hand, the patient still has a tumor, which will eventually become resistant to those drugs,” said study senior author Dr. Erik Knudsen, Professor of Internal Medicine in the Eugene McDermott Center for Human Growth and Development at UT Southwestern.

“There’s a lot of interest in better understanding the biology behind CDK4/6 inhibitors — and in finding out whether we can use that information to kill tumors instead of simply stopping their growth,” added Dr. Agnieszka Witkiewicz, also in the McDermott Center and an Associate Professor of Pathology.

In this study, the research team treated human pancreatic cancer cells and tumors grown in mice with CDK4/6-inhibiting drugs. Surprisingly, they found that when tumor cells were treated with CDK4/6 inhibitors, the cells’ metabolism — the way cancer tumors get energy — became more active.

“Now we can try attacking specific aspects of CDK4/6-induced metabolic programming,” said Dr. Knudsen, also a member of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, along with Dr. Witkiewicz. “For example, by targeting altered tumor metabolism, we could potentially turn the cytostatic effect of CDK4/6 inhibitors into a cytotoxic effect that actually kills the cancer cells.”

The upshot is that by disrupting a tumor’s cell cycle with CDK4/6 inhibitors and then targeting the altered metabolism with other drugs — such as mTOR inhibitors — it may be possible to positively impact cancer treatment.

“These data yield valuable new insights into the cross talk between CDK inhibitors, signaling pathways, and tumor metabolism in pancreatic cancer, opening up some interesting new possibilities for treatment that could be evaluated in clinical trials,” Dr. Witkiewicz said. “The real goal is that this work — as well as ongoing studies — will benefit patients with pancreatic cancer.”

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*credit verbatim via provided by UT Southwestern Medical Center


Scientists discover how diabetes drug Metformin slows down pancreatic cancer

Researchers at the Massachusetts General Hospital (MGH) might have stumbled upon the mechanism of how the diabetes drug metformin can slow down the progression of cancer of the pancreas.

The details of the study are published in the journal PLOS One, where the team describes that this common diabetes drug decreases the inflammation and fibrosis seen commonly in pancreatic cancer. However, based on their findings in patient tumor samples as well as cellular and animal models, the researchers add that in overweight and obese patients might benefit more from this surprising metformin discovery.

The study focused on the most commonly occuring pancreatic cancer – pancreatic ductal adenocarcinoma (PDA) – which kills almost 40,000 people in the U.S. ever year. Half of those diagnosed with PDA are overweight or obese, and almost 80 percent are insulin resistant or have type 2 diabetes.

Previous analyses have revealed that Diabetic patients taking metformin have a lower risk of developing PDA; and those who do have PDA have a reduced fatality rate. But before the current study nobody knew how or why this drug inhibited the progress of pancreatic cancer.

The team discovered that metformin increases a collection of tumor-associated immune cells and a dense connective tissue which are both characteristic of pancreatic cancer. According to the lead author of the study, Dai Fukumura, MD, PhD, of the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology, metformin does this by slowing down the activation of the pancreatic stellate cells (cells that cause fibrosis and interact closely with cancer cells to create a tumor friendly environment) and by reprogramming immune cells to reduce inflammation.

However the team observed that hat these changes were more pronounced in the tumors of obese and overweight individuals, in whom the tumors had increased fibrosis.

In fat mice, the researchers found that metformin treatment reduced levels of tumor-associated macrophages by 60 percent. The tumors of animals treated with metformin also had showed a reduction in metastasis, suggesting a lower risk in the spread of the cancer.

This new evidence is part of a wave of findings that suggest that regular everyday drugs can play a huge role in preventing and fighting cancer. In fact an organization called ReDo has been set up solely for this purpose of finding regular drugs with anti-cancer properties.

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*credit verbatim via and Mohan Garikiparithi*

Merck, BioLineRX to study drug combo to fight #PancreaticCancer

Israeli biopharmaceutical company BioLineRX Ltd said on Tuesday it would collaborate with U.S. industry heavyweight Merck to test a combination of drugs for the treatment of pancreatic cancer.

The companies will partner in a mid-stage study to evaluate the safety and efficacy of the combination of BioLineRx’s BL-8040 and Merck’s Keytruda in patients with metastatic pancreatic adenocarcinoma.

“Because certain tumors exhibit only a modest response to existing immunotherapies, we are increasingly seeing clinical studies involving combinations of immuno-oncology agents with other classes of drugs,” said Kinneret Savitsky, BioLineRx’s chief executive.

BL-8040 acts against CXCR4 receptors that are involved in tumor progression, the company said. It has been shown in several clinical trials to mobilize immune cells and to be effective at inducing direct tumor cell death.

Keytruda, an antibody, works by increasing the ability of the body’s immune system to help detect and fight tumor cells, said Merck, which is known as MSD outside the United States and Canada.

Pancreatic adenocarcinoma accounts for most cases of pancreatic cancer, according to the American Cancer Society. Specific symptoms often do not develop until the disease has reached an advanced stage, which is reflected in a low five-year survival rate.

The study is due to start by mid-2016 and both companies will have the option to expand the collaboration to include a pivotal registration study, BioLineRX said.

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*credit verbatim via , Ari Rabinovitch, reporter; David Clarke, editing*



More magnesium may lower risk of pancreatic cancer

Magnesium intake may be an effective way to prevent pancreatic cancer, a new study suggests.

Pancreatic cancer is the fourth leading cause of cancer-related death in both men and women in the United States. The overall occurrence of pancreatic cancer has not significantly changed since 2002, but the mortality rate has increased annually from 2002 to 2011, according to the National Cancer Institute.

“Pancreatic cancer is really unique and different from other cancers,” says Ka He, chair of the epidemiology and biostatistics department at Indiana University. “The five-year survival rate is really low, so that makes prevention and identifying risk factors or predictors associated with pancreatic cancer very important.”

Previous studies have found that magnesium is inversely associated with the risk of diabetes, which is a risk factor of pancreatic cancer. But few studies have explored the direct association of magnesium with pancreatic cancer and those that did had inconclusive findings, says lead author Daniel Dibaba, a PhD student in the School of Public Health.

Using information from the VITamins and Lifestyle study, the researchers analyzed an enormous trove of data on more than 66,000 men and women, ages 50 to 76, looking at the direct association between magnesium and pancreatic cancer and whether age, gender, body mass index, non-steroidal anti-inflammatory drugs use, and magnesium supplementation play a role.

Of those followed, 151 participants developed pancreatic cancer. Every 100-milligrams-per-day decrease in magnesium intake was associated with a 24 percent increase in the occurrence of pancreatic cancer.

The study, published in the British Journal of Cancer, also found that the effects of magnesium on pancreatic cancer did not appear to be modified by age, gender, body mass index, or non-steroidal anti-inflammatory drug use, but was limited to those taking magnesium supplements either from a multivitamin or individual supplement.

“For those at a higher risk of pancreatic cancer, adding a magnesium supplement to their diet may prove beneficial in preventing this disease,” Dibaba says.

“While more study is needed, the general population should strive to get the daily recommendations of magnesium through diet, such as dark, leafy greens or nuts, to prevent any risk of pancreatic cancer.”

Other researchers from Indiana University and from the University of Washington, and the Jikei University School of Medicine in Tokyo contributed to the study.

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* credit verbatim via and
April Toler of Indiana University *

Researchers Focusing on Early Detection, Immunotherapy for Pancreatic Cancer

The challenge with pancreatic cancer has always been to catch it early. Because of its subtle, variable symptoms, the disease often isn’t diagnosed until an advanced stage, when it is particularly difficult to treat.

Researchers are investigating not only how to detect the disease earlier but also how to better understand its causes and develop more effective treatments.

Pancreatic cancer arises in a series of steps that occur over a number of years. At the earliest stages, pancreas cells begin to acquire mutations or other abnormalities in a small number of genes. As abnormalities arise in additional genes, the cells of the pancreas begin to look abnormal. One of the most common genes to be affected is KRAS, which regulates cell growth. Researchers are developing new diagnostic tests that can detect this change using fluid extracted from the pancreas, although such tests aren’t yet ready for general use.

In recent research, scientists at Dana-Farber and other institutions recently found that an upsurge in certain amino acids often occurs before pancreatic cancer is diagnosed and symptoms appear. Although the increase isn’t large enough to be the basis of an early-detection test, the discovery will help researchers better understand how pancreatic cancer affects the rest of the body, particularly how it can trigger the sometimes deadly muscle-wasting disease known as cachexia.

Efforts to improve the treatment of pancreatic cancer include the development of new surgical and radiation therapy techniques, new combinations of chemotherapy drugs, targeted therapies, and therapies that harness the immune system to attack the disease.

In the surgical field, investigators are exploring whether laparoscopic procedures – which involve inserting surgical instruments through small cuts in the abdomen – to remove cancerous pancreatic tissue are as effective as traditional, large-incision techniques and whether they improve the recovery process. Some studies are also examining whether delivering a large dose of radiation therapy to the pancreas during surgery is beneficial.

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*credit verbatim via Dana-Farber Cancer Institute*

Only 1 in 5 US #PanCan patients get key blood test at diagnosis

Study: Only 1 in 5 US pancreatic cancer patients get this key blood test at diagnosis

CA 19-9 tumor marker test especially important for early-stage patients, Mayo finds

NAPA, Calif. — Only 1 in 5 U.S. pancreatic cancer patients receive a widely available, inexpensive blood test at diagnosis that can help predict whether they are likely to have a better or worse outcome than average and guide treatment accordingly, a Mayo Clinic study shows. People who test positive for elevated levels of a particular tumor marker tend to do worse than others, but if they are candidates for surgery and have chemotherapy before their operations, this personalized treatment sequence eliminates the elevated biomarker’s negative effect, researchers found.

The findings will be presented at the Western Surgical Association annual meeting Nov. 7-10 in Napa.

“This is another argument for giving chemotherapy before surgery in all pancreatic cancer patients and ending the old practice of surgery followed by chemo,” says senior author Mark Truty, M.D., a gastrointestinal surgical oncologist at Mayo Clinic in Rochester, Minn. “The study answers an important clinical question and applies to every pancreatic cancer patient being considered for surgery.”

The Mayo study, which used the National Cancer Data Base, is the first on the subject based on national data and is the largest of its kind, Dr. Truty says.

Researchers analyzed outcomes for 97,000 patients. The tumor marker whose impact they studied is known as CA 19-9. It is associated with several cancers, including pancreatic cancer, and can be measured in the blood of most people: 10 percent do not produce it. Pancreatic cancer patients who didn’t secrete CA 19-9 were also studied.

Pancreatic cancer patients whose blood showed higher-than-normal CA 19-9 levels tended to have worse outcomes than others at the same stage of cancer, the study found. Surprisingly, the elevated tumor marker’s negative effect on survival was most pronounced in patients diagnosed at an early stage, the researchers wrote.

“When we looked at how these patients did after surgical removal of their cancers, the only treatment sequence that completely eliminated the increased risk posed by CA 19-9 elevation was chemotherapy followed by surgical removal of the tumor,” Dr. Truty says.

Another key finding was that only 19 percent of pancreatic cancer patients nationally have their CA 19-9 checked at diagnosis, far fewer than anticipated, he says. The CA 19-9 blood test has been standard for pancreatic cancer patients at Mayo Clinic for years.

Failing to test for and address elevated CA 19-9 means that many patients with above-normal levels may undergo significant surgeries that may not be as beneficial long term as anticipated, Dr. Truty says.

About 50,000 people are diagnosed with pancreatic cancer each year in the U.S. Historically, only about 7 percent of pancreatic cancer patients have lived at least five years after diagnosis. But advances such as the CA 19-9 test and improved chemotherapy, radiation and surgical techniques are improving survival odds for many patients, Dr. Truty says.

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FDA approves new treatment for advanced #PancreaticCancer

The U.S. Food and Drug Administration today approved Onivyde (irinotecan liposome injection), in combination with fluorouracil and leucovorin, to treat patients with advanced (metastatic) pancreatic cancer who have been previously treated with gemcitabine-based chemotherapy.

According to the National Cancer Institute, there will be 48,960 new cases of pancreatic cancer diagnosed in the U.S. in 2015, and nearly the same number of deaths caused by the disease (40,560). Pancreatic cancer can be difficult to diagnose early and treatment options are limited, especially when the disease has spread to other parts of the body (metastatic disease) and surgery to remove the tumor is not possible.

“Many FDA staff who review drug applications are clinicians as well, so it’s especially rewarding when we are able to expedite access to new treatments for patients with unmet needs,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “By using the Priority Review designation for the application for Onivyde, patients will have earlier access to a drug that helps extend survival.”

The FDA granted Priority Review and orphan drug designations for Onivyde. Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

The effectiveness of Onivyde was demonstrated in a three-arm, randomized, open label study of 417 patients with metastatic pancreatic adenocarcinoma whose cancer had grown after receiving the chemotherapeutic drug gemcitabine or a gemcitabine-based therapy. The study was designed to determine whether patients receiving Onivyde plus fluorouracil/leucovorin or Onivyde alone lived longer than those receiving fluorouracil/leucovorin. Patients treated with Onivyde plus fluorouracil/leucovorin lived an average of 6.1 months, compared to 4.2 months for those treated with only fluorouracil/leucovorin. There was no survival improvement for those who received only Onivyde compared to those who received fluorouracil/leucovorin.

The safety of Onivyde was evaluated in 398 patients who received either Onivyde with fluorouracil/leucovorin, Onivyde alone or fluorouracil/leucovorin. The most common side effects of treatment with Onivyde included diarrhea, fatigue, vomiting, nausea, decreased appetite, inflammation in the mouth (stomatitis) and fever (pyrexia). Onivyde was also found to result in low counts of infection-fighting cells (lymphopenia and neutropenia). Death due to sepsis following neutropenia has been reported in patients treated with Onivyde.

The labeling for Onivyde includes a boxed warning to alert health care professionals about the risks of severe neutropenia and diarrhea. Onivyde is not approved for use as a single agent for the treatment of patients with metastatic pancreatic cancer.

Onivyde is marketed by Merrimack Pharmaceuticals Inc. of Cambridge, Massachusetts.

The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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