Chemotalk Newsletter

Chemotalk Newsletter, Vol. 78: October 1, 2014

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October...and here we go.  The first story has a lot of unanswered questions, but it's a step in the right direction:


A protein named p66ShcA shows promise as a biomarker to identify breast cancers with poor prognoses, according to research published in the journal Molecular and Cellular Biology.

Cancer is deadly in large part due to its ability to metastasize. The vast majority** of cancer deaths are associated with metastasis.  In BREAST CANCER, a process called "epithelial to mesenchymal transition" aids metastasis. Epithelial cells line surfaces which come into contact with the environment, such as skin and the gastrointestinal tract. Mesenchymal cells are a type of cell in embryonic tissue and in connective tissue, where they form very loose contacts with one-another.  Tumor cells lose mature epithelial characteristics, such as the ability to adhere to their neighbors, and gain those of the mesenchymal cells which enable them to move easily through the cellular matrix and into the blood stream. That enables their metastatic migration to distant organs and tissues.

In this study the researchers, led by Josie Ursini-Siegel of McGill University, show that the protein p66ShcA is highly enriched in breast cancers that have undergone epithelial to mesenchymal transition.  "We showed that elevated p66ShcA expression levels are strongly associated with expression of numerous epithelial to mesenchymal transition genes in all breast cancer subtypes," says Ursini-Siegel. "Thus, p66ShcA may serve as one of the first prognostic biomarkers to identify poor outcome breasts cancers regardless of their molecular subtype."

The ability to predict prognosis is critical to management of treatment. A patient with a good prognosis can be spared aggressive treatment, with its oft-unpleasant side effects. But failure to apply aggressive treatment to an aggressive tumor can lead to death.

Breast cancers stratify into at least five subtypes, each of which is associated with a different outcome. Nonetheless, earlier research showed that there is heterogeneity within the subtypes, which makes predictions of outcome based on subtype less reliable than they might otherwise be. "By understanding the underlying mechanisms that contribute to tumor heterogeneity and metastatic progression, including the epithelial to mesenchymal transition, we hope to be better able to guide the development of prognostic and therapeutic strategies to improve patient care," says Ursini-Siegel.

*  Because cancer is made up of our own cells run amok, biomarkers are not so definitive that they alone determine the outcome of a cancer diagnosis.

** As far as I know, only metastatic cancer kills you.  If I'm wrong, would a professional in the field please contact me and teach me otherwise?

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By Denise Grady

Doctors have taken an important step toward a long-sought goal: harnessing a person's own immune system to fight CANCER.

An article published in Science describes the treatment of a 43-year-old woman with an advanced and deadly type of cancer that had spread from her bile duct to her liver and lungs, despite CHEMOTHERAPY.

Researchers at the National Cancer Institute sequenced the genome of her cancer and identified cells from her immune system that attacked a specific mutation in the malignant cells.  Then they grew those immune cells in the laboratory and infused billions of them back into her blood stream.

The tumors began "melting away", said Dr. Steven A. Rosenberg the senior author of the article and chief of the surgery branch at the cancer institute.

The woman is not cured: Her tumors are shrinking, but not gone.  And an experiment on one patient cannot determine whether a new treatment works. But the report is noteworthy because it describes an approach that may also be applied to common tumors -- like those in the digestive tract ovaries, pancreas, lungs and breasts -- and that cause more than 80% of the 580,000 cancer deaths in the United States every year.

Dr. Rosenberg agreed, saying that in April 2012, when Ms. Bachini received the first immune treatment, her life expectancy was probably a mattr of months.

Related techniques involving immune cells have brought lasting remissions for people with LEUKEMIA, a blood cancer, and the aggressive SKIN CANCER MELANOMA.  But until now researchers had not found a way to use the cells against the so-called solid tumors that cause so many deaths.

Other researchers said th treatment used by Dr. Rosenberg's team, known as adoptive cell therapy, had promise for these common cancers.  But they also cautioned that the report was early and based on just one patient.

Dr. Carl June, who directs similar research at the University of Pennsylvania, said the research addressed an important issue by showing that adoptive cell therapy could have an effect on commonly lethal solid tumors.

Another expert, Dr. Michel Sadelain of the Memorial Sloan-Kettering Cancer Center in New York, said the report showed that carefully selected immune cells could be a powerful tool against bile-duct cancer.  But he also said it was too soon to tell if the same approach would work for other patients or could be scaled up or could be scaled up to treat all those who might need it.

Dr. Rosenberg acknowledged that there were limitations.  The technique required highly sophisticated techniques in immunology, and produced a treatment tailored to only one patient.  He said his team was working around the clock to streamline the process, and added, "Potentially, if we could reduce the complexity, it's something that could get out into commun usage eventually."

Researchers have hoped for decades to find some unique marker on cancer cells, something not present on healthy cells, that could be used as a targt so that cells of the immune system could home in on it and leave the good ones alone.

The goal has been elusive, but Dr. Rosenberg's team has helped some patients with melanoma by treating them with immune cells - a type of T-cell called a tumor-infiltrating lymphocyte - that were extracted from samples of the patients' tumors.  The team decided to study whether this type of T-cell could help people with other types of cancer.

Ms. Bachini learned in 2009 that she had BILE-DUCT CANCER, or cholangiocarcinoma.  It had already spread to her liver.  She had surgery to remove about two-thirds of her liver, but within a few months the disease had turned up in her lungs.  She went through one grueling regimen of chemotherapy, then another.  She had nerve damage, nausea and hearing loss from the drugs.  Her tumors began growing again.  She started to cough.

"I knew chemotherapy was not going to kill this," she said.  She quit the drugs.

Searching the Internet for clinical trials, she came across Dr. Rosenberg's T-cell study.  "I looed at my husband and said, 'This is what I want to do,'" Ms. Bachini said.

In March 2012, Dr. Rosenberg's team removed tumors from her lungs to extract tumor-infiltrating T-cells, then cultured the cells in a lab.  A month later, Ms. Bachin was given chemotherapy to wipe out her immune system, and more than 42 billion T-cells were infused through an intravenous line.  She was also given a drug called interleukin-2, which helps activate T-cells.

The treatment was arduous: The chemotherapy left her vomiting, weak and bald, and the interleukin-2 made her swell up with fluid.

By the end of April, 2012, her cough was gone and her strength returning She went bak to the cancer institute once a month for checkups.  The study, paid for by the government, was free, even including her airfare.

"Life was good," she said.  "Everything kept shrinking."

But by last summer, the lung tumors were growing again.

By then, the team had sequenced the genome of her cancer, and done extensive studies on her immune system.  And it had found what researchers had long hoped for: a mutation in the cancer that was unique to it and not found in normal cells, and a type of T-cell that would attack the mutation. Tests revealed that only 25% of the T-cells that had been given to Ms. Bachini were of this specialized type.

Again, the team cultured Ms. Bachini's T-cells, but this time it used only the ones that would go after the mutation.  In October she received more than 120 billion T-cells, 95% of which were the highly specific ones.

Her tumors quickly began shrinking, and have continued to do so for the past six months, Dr. Rosenberg said.

Ms. Bachini said she was grateful for every day.  She walks her dog, a 140-pound Labrador, two miles a day, and said she was constantlly on the run with three teenage daughters still at home.  "I pretty much can do anything I want," she said.

Dr. Rosenberg said that his team would check up on her every two months, and that if the tumors started growing again, it might be possible to treat her again.  As for her long-term outlook, he said, "We'll just have to wait and see."

In the meantime, he said, the team has identified unique mutations and T-cells ready to attach them in two of three other patients with cancer in the gastrointestinal tract. Treatment plans are underway.

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From the "Duh Department":


A new study has found that patients are more likely to have magnetic resonance imaging scans that indicate nothing is wrong if they are referred by a doctor who owns the machine.  The scientists conclude that doctors with a financial interest in the machines may be more likely to order M.R.I.'s even when clinical findings do not require it.

The researchers reviewed referrals for knee M.R.I. examinations made by two physician groups, one with a financial interest in a scanner the other without.  There were 350 referrals in each group, and none of the patients had had a previous M.R.I. or knee surgery.  The study was published in Radiology.

Of the 700 examinations, 205 had negative results, indicating no abnormalities.  But the rate of negatives was 33% in patients referred by doctors who owned the machine, compared with 25% of patients referred by those without a financial stake.

"There is a potential for bias in certain settings," said Dr. Matthew P. Lungren, the study's lead author.  "The doctor should be transparent and acknowledge his interest."

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Scientists at Dana-Farber Cancer Institute, the Massachusetts Institute of Technology, and other institutions have discovered a sign of the early development of PANCREATIC CANCER ­ an upsurge in certain amino acids that occurs before the disease is diagnosed and symptoms appear. The research is published by the journal Nature Medicine.

Although the increase isn't large enough to be the basis of a new test for early detection of the disease, the findings 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.

"Most people with pancreatic ductal adenocarcinoma (PDAC) [by far the most common form of cancreatic cancer] are diagnosed after the disease has reached an advanced stage, and many die within a year of diagnosis," said Brian Wolpin, MD, MPH, of Dana-Farber, co-senior author of the new study with Matthew Vander Heiden, MD, PhD, of MIT and Dana-Farber. "Detecting the disease earlier in its development may improve our ability to treat it successfully. In this study, we asked whether PDAC produces metabolic changes ­ changes in the way the body uses energy and nutrients ­ that can be detected before the disease is diagnosed."

The researchers utilized blood samples collected years earlier from 1,500 people participating in large health-tracking studies. They analyzed the samples for more than 100 different metabolites ­ substances produced by the metabolic process ­ and compared the results from participants who had gone on to develop pancreatic cancer and those who had not.

"We found that higher levels of branched chain amino acids were present in people who went on to develop pancreatic cancer compared to those who did not develop the disease," Wolpin said. (Branched chain amino acids are one family of amino acids, the building blocks of proteins.) The amount of time that would elapse before those individuals were diagnosed with pancreatic cancer ranged from two to 25 years, although the highest risk was in the several years before diagnosis, the researchers found.

"These findings led us to hypothesize that the increase in branched chain amino acids is due to the presence of an early pancreatic tumor," Wolpin remarked. This theory was confirmed in laboratory experiments performed by Vander Heiden's group at the Koch Institute for Integrative Cancer Research at MIT. Their experiments showed that mice with newly formed pancreatic tumors had above-normal blood levels of these amino acids.

The researchers found the increase was due to a breakdown of muscle tissue, which caused branched amino acids to be released into the bloodstream. This process is similar to what occurs in patients with cancer cachexia. "What was surprising about our results was that it appears the breakdown of muscle protein begins much earlier in the disease process than previously appreciated," noted Vander Heiden.

The findings provide an important lead to scientists studying how pancreatic tumors interact with patients' normal tissues, the authors say. According to Vander Heiden, this work provides a glimpse into how pancreatic cancer changes the way the rest of the body handles nutrients. "This work has the potential to spur progress in detecting pancreatic tumors earlier and identifying new treatment strategies for those with the disease," he remarks.

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Two recently published studies by a research team at University Hospitals (UH) Case Medical Center Seidman Cancer Center have the potential to advance treatments for SMALL CELL LUNG CELL CANCER (SCLC). This aggressive form of lung cancer has seen no treatment advances in 30 years and "is a disease in urgent need of new drug therapies," write the study's authors.

"In small cell lung cancer, which impacts about 30-40,000 people each year in the United States, there has been no therapeutic progress and very little research," says Afshin Dowlati, MD, lead author and Director of the Center for Cancer Drug Development at UH Seidman Cancer Center. "Additionally, there are no approved targeted therapies for the disease. These studies lay the foundation for future research aimed at finding important new treatments for this highly malignant cancer."

A study titled, RET Mutation and Expression in Small Cell Lung Cancer, was published in the September issue of Journal of Thoracic Oncology and found a new mutation in SCLC which may play a role in the disease's development. The researchers found that the genetic mutation, called RET (rearranged during transfection), was linked to rapid cell growth.

The research team examined specimens in its database of metastatic SCLC tumors, one of the largest databases of its kind in the country. They found that the RET mutant protein was potentially linked to faster-growing cells that were sensitive to ponatinib and vandetanib, two new targeted drug therapies. Future clinical trials for patients with the RET mutation are planned to further validate the data.

"We were encouraged to find that these two cancer-fighting therapies are potentially effective at stopping cancer cell growth in certain small cell lung cancers," says Dr. Dowlati, who is Professor of Medicine ­ Hematology/Oncology, Case Western Reserve University School of Medicine and a member of the Case Comprehensive Cancer Center. "These findings have the potential to give cancer physicians a new tool to more effectively tailor treatments for patients."

The other study, published in PLOS One, outlines a novel approach to identify new drug therapies for SCLC based on tumors' genomic profiles. The research team discovered new molecular targets for treating the disease by extracting data from SCLC tumors to examine drug sensitivity. Through this analysis, they outlined a promising new approach to predict which cancer-fighting drugs would be the most broadly effective at slowing tumor growth.

"This study enabled us to identify which drugs may be the most useful in which types of tumors," says Dr. Dowlati. "Small cell lung cancer is one of the fastest growing cancers and these studies have yielded small but important therapeutic insights into this disease." Dr. Dowlati is additionally the Rosalie and Morton A. Cohen Chair in Oncology and the Lucile and Robert H. Gries Endowed Director, Center for Cancer Drug Development at UH Seidman Cancer Center.

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Happy Halloween!

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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