Vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers.
Certain genetic changes are known to reduce the ability of an enzyme called tet methylcytosine dioxygenase 2, or TET2, to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, say the authors. The new study found that vitamin C activated TET2 function in mice engineered to be deficient in the enzyme.
“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” says corresponding study author Benjamin G. Neel, MD, PhD, professor in the Department of Medicine and director of Perlmutter Cancer Center.
Changes in the genetic code, or mutations, that reduce TET2 function are found in 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of preleukemia called myelodysplastic syndrome, and in nearly 50 percent of patients with chronic myelomonocytic leukemia. Such cancers cause anemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages.
Along with these diseases, new tests suggest that about 2.5 percent of all United States cancer patients—or about 42,500 new patients each year—may develop TET2 mutations, including some with lymphomas and solid tumours, say the authors.
The study results revolve around the relationship between TET2 and cytosine, one of the four nucleic acid “letters” that comprise the DNA code in genes. Every cell type has the same genes, but each gets different instructions to turn on only those needed in a given cellular context. These “epigenetic” regulatory mechanisms include DNA methylation, the attachment of a small molecule termed a methyl group to cytosine bases that shuts down the action of a gene containing them.
The back-and-forth attachment and removal of methyl groups also fine tunes gene expression in stem cells, which can mature, specialize, and multiply to become muscle, bone, nerve, or other cell types. This happens as the body first forms, but the bone marrow also keeps pools of stem cells on hand into adulthood, ready to become replacement cells as needed. In leukemia, signals that normally tell a blood stem cell to mature malfunction, leaving it to endlessly multiply and “self-renew” instead of producing normal white blood cells needed to fight infection.
The enzyme studied in this report TET2, enables a change in the molecular structure, or oxidation, of methyl groups that is needed for them to be removed from cytosines. This “demethylation” turns on genes that direct stem cells to mature, and to start a countdown toward self-destruction as part of normal turnover. This serves as an anti-cancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, says Dr. Neel.
To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the research team genetically engineered mice such that the scientists could switch the TET2 gene on or off.
Similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behaviour. Remarkably, these changes were reversed when TET2 expression was restored by a genetic trick. Previous work had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Because only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the authors hypothesized that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.
Indeed, they found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells from human patients implanted in mice.
NYU Langone Healthhttp://tinyurl.com/y8pvrxso

A new diagnostic developed by Alberta scientists will allow men to bypass painful biopsies to test for aggressive prostate cancer. The test incorporates a unique nanotechnology platform to make the diagnostic using only a single drop of blood, and is significantly more accurate than current screening methods.
The Extracellular Vesicle Fingerprint Predictive Score (EV-FPS) test uses machine learning to combine information from millions of cancer cell nanoparticles in the blood to recognize the unique fingerprint of aggressive prostate cancer. The diagnostic, developed by members of the Alberta Prostate Cancer Research Initiative (APCaRI), was evaluated in a group of 377 Albertan men who were referred to their urologist with suspected prostate cancer. It was found that EV-FPS correctly identified men with aggressive prostate cancer 40 percent more accurately than the most common test—Prostate-Specific Antigen (PSA) blood test—in wide use today.
"Higher sensitivity means that our test will miss fewer aggressive cancers," said John Lewis, the Alberta Cancer Foundation’s Frank and Carla Sojonky Chair of Prostate Cancer Research at the University of Alberta. "For this kind of test you want the sensitivity to be as high as possible because you don’t want to miss a single cancer that should be treated."
According to the team, current tests such as the PSA and digital rectal exam (DRE) often lead to unneeded biopsies. Lewis says more than 50 per cent of men who undergo biopsy do not have prostate cancer, yet suffer the pain and side effects of the procedure such as infection or sepsis. Less than 20 per cent of men who receive a prostate biopsy are diagnosed with the aggressive form of prostate cancer that could most benefit from treatment.
It’s estimated that successful implementation of the EV-FPS test could eventually eliminate up to 600-thousand unnecessary biopsies, 24-thousand hospitalizations and up to 50 per cent of unnecessary treatments for prostate cancer each year in North America alone. Beyond cost savings to the health care system, the researchers say the diagnostic test will have a dramatic impact on the health care experience and quality of life for men and their families.

Medicalexpress
medicalxpress.com/news/2017-06-blood-nanotechnology-aggressive-prostate-cancer.html

Breast cancer cells that spread to other parts of the body break off and leave the primary tumour at late stages of disease development, scientists from the Wellcome Trust Sanger Institute and their collaborators have found.
The results show that catching and treating breast cancer before it spreads is a realistic goal. It also opens the door to predicting which drugs will work against breast cancer that has already spread.
It is estimated that 35,000 people in the UK have metastatic breast cancer. The survival rates are poor: around 15 out of 100 women will survive advanced breast cancer for five years or more after diagnosis. The prognosis has not improved in the past 20-30 years.
Most of the research into breast cancer has focused on primary breast cancer, and there is little understanding of the biology underpinning breast cancer that has spread to other parts of the body, known as metastatic cancer. This is in part due to the difficulty in acquiring samples of tumours that have spread to other tissues.
In this study, scientists investigated how breast cancer evolves from the original tumour in the breast to tumours that have spread, or metastasised. It has been controversial whether the breast cancer cells that spread to other parts of the body break off and leave the primary tumour in the breast at early or at late stages of cancer development. The team found that most of the genetic changes in the original breast tumour were also present in the metastatic tumours, showing that the cancer cells spread late in disease development.
This shows promise for breast cancer patients as diagnosing and treating the breast cancer at early stages means there is a greater chance of preventing cancer cells spreading to other tissues, such as the lungs, brain and bone.
“As the cells that cause the spread of breast cancer leave relatively late, it means they are still quite similar to the cells in the primary tumour. Therefore by studying the genome of the primary breast cancer tumour, in the future we may be able to predict what cells that might have spread ‘look’ like, and potentially which treatments they will respond to.”
Dr Lucy Yates, first author from the Wellcome Trust Sanger Institute and Guys and St Thomas’ NHS Trust
In the retrospective study, the team sequenced the DNA of 299 tumours from 170 patients with breast cancer that either returned in the remaining breast – local relapse – or had spread – metastatic breast cancer.
Researchers found that in the time between breast cancer patients being diagnosed with primary cancer and the diagnosis of metastasis, the breast cancer cells had gained genetic changes, or mutations, that increased the aggressiveness of the tumour. This may explain why metastatic breast cancer is currently difficult to treat.
“Most women who have metastatic breast cancer do not have another biopsy of the cancer, and rarely have it analysed using genetic sequencing. In this study we found that in some cases, the metastatic tumours had particular genetic changes that could be targeted with treatments. We would not have seen these mutations by sequencing the primary tumour alone. Our results suggest that it should be more routine to biopsy the metastasis and have it genetically analysed in order to open up clinical trials of treatment options for metastatic breast cancer.”
Studies are now open to recruit patients with metastatic breast cancer across Europe – these studies will first extend the analysis performed here to many more patients, but the ultimate goal is to build a platform for identifying an appropriate clinical trial of new treatments for each patient with metastatic breast cancer.

Sanger Institute
www.sanger.ac.uk/news/view/new-genetic-analysis-reveals-late-spread-breast-cancer-and-backs-key-role-early-diagnosis

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Method to more accurately test anti-cancer drugs have now been developed at the Sahlgrenska Academy, University of Gothenburg. The method paves the way to much earlier assessment of who benefits from a specific drug and who does not.
“It is common for cancer patients to be prescribed drugs that fail to help them, often with side effects. But, we have shown that this method can be used as early as in the drug development phase to determine which patient groups will benefit from the drug,” says Berglind Osk Einarsdottir, a researcher at Sahlgrenska Cancer Center.
The method for identifying whether cancer patients will benefit from a specific treatment is based on taking biopsies of the tumours during surgery – small tissue samples that are processed and implanted under the skin of a number of mice.
In her research, Berglind Osk Einarsdottir follows the tumours growth in the animal models, and tests how they respond to different cancer drugs. The experiments take anywhere from a few weeks to few months, depending on the growth rate of the tumours.
 “This is not a method that is currently used in Swedish healthcare, but we chose to perform experiments to show that it works and can be used in the future if needed,” says Berglind Osk Einarsdottir.
She feels the potential really lies in the reverse application, where the same drug is tested on mice implanted with tumour tissue from many different patients. One of her substudies involves this very notion, namely how 33 patients responded to the anticancer agent Karonudib, which was recently developed at Karolinska Institutet.
The experiments showed that two-thirds of the patient samples responded to the treatment. The question was, what did they have in common – similar DNA, metabolism, protein expression or something else? Such knowledge would make it possible to better predict in which patients a drug will really inhibit tumour growth and help kill cancer cells.
 “It turned out that it didn’t matter what mutations were found in the tissues. What we did see was a possible way that the tumours could become resistant to the treatment. Some samples had a high expression of a protein that helps the cells repel the drug, and that was what we found – a potential mechanism for resistance.”
“You can use the method in patient oriented way, where the aim is to identify which anti-cancer drug will benefit a specific patient the best. Or in a drug development oriented way, where the aim is to identify which subgroup of patients will benefit the most from a specific anti-cancer drug. It is here that we think the greatest opportunities exist,” she says.

University of Gothenburg
www.gu.se/english/about_the_university/news-calendar/News_detail//improved-accuracy-when-testing-cancer-drugs.cid1472499