Chemotalk Newsletter

Chemotalk Newsletter, Vol. 88 August 1, 2015

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News for August...

CIB1 PROTEIN MAY BE A NEW TARGET FOR TRIPLE-NEGATIVE BREAST CANCER

By Lauren Evoy Davis

Researchers at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center have identified the potential of protein called CIB1 as a new drug target for patients with an aggressive form of BREAST CANCER.

Leslie Parise, PhD, UNC Lineberger professor and chair in the UNC School of Medicine Department of Biochemistry and Biophysics, and colleagues believe the cancer cells depend on CIB1 for survival. Knowing about this dependence, they deleted the protein using genetic engineering, and discovered that they could kill certain cancerous cells and decrease tumor growth in mouse models.

³We believe that this protein could be a potentially safe therapeutic target for triple-negative breast cancer, and the future could bring drugs that specifically target this protein to kill breast cancer cells,² Dr. Parise said in a UNC news release.

This finding was first published in an issue of Breast Cancer Research and Treatment.

Study author Justin Black, calls CIB1 a ³unique target because it is not an oncogene, nor is it an enzyme, yet it appears to have a crucial role in triple-negative breast cancer tumor growth." His work as doctoral candidate in the Department of Biochemistry and Biophysics will continue as the team partners with their newly formed company, Reveris Therapeutics, along with the University of North Carolina at Chapel Hill¹s Carolina Kickstart.

Triple-negative breast cancer, which doesn't have estrogen or progesterone receptors, is particularly insidious because its tumors tend to grow and spread more quickly than other types of breast cancer, according to the American Cancer Society. Therefore, traditional hormone therapies do not work for this cancer type. Considering 1 out of 10 breast cancer patients are diagnosed with this kind of breast cancer, research teams like this one are working feverishly to discover new, effective treatments for this aggressive disease.

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PROSTATE CANCER IS 5 DIFFERENT DISEASES

Cancer Research UK scientists have for the first time identified that there are five distinct types of PROSTATE CANCER and found a way to distinguish between them, according to a landmark study published in EBioMedicine.  The findings could have important implications for how doctors treat prostate cancer in the future, by identifying tumours that are more likely to grow and spread aggressively through the body.

The researchers, from the Cancer Research UK Cambridge Institute and Addenbrooke's Hospital, studied samples of healthy and cancerous prostate tissue from more than 250 men.  By looking for abnormal chromosomes and measuring the activity of 100 different genes linked to the disease they were able to group the tumours into five distinct types, each with a characteristic genetic fingerprint.

This analysis was better at predicting which cancers were likely to be the most aggressive than the tests currently used by doctors - including the PSA test and Gleason score. But, the findings need to be confirmed in clinical trials with larger groups of men.

Study author Dr Alastair Lamb, from the Cancer Research UK Cambridge Institute, said: "Our exciting results show that prostate cancer can be classified into five genetically-different types. These findings could help doctors decide on the best course of treatment for each individual patient, based on the characteristics of their tumour.

"The next step is to confirm these results in bigger studies and drill down into the molecular 'nuts and bolts' of each specific prostate cancer type. By carrying out more research into how the different diseases behave we might be able to develop more effective ways to treat prostate cancer patients in the future, saving more lives."

Prostate cancer is the most common cancer in men in the UK, with around 41,700 cases diagnosed every year. There are around 10,800 deaths from the disease each year in the UK.

Professor Malcolm Mason, Cancer Research UK's prostate cancer expert, said: "The challenge in treating prostate cancer is that it can either behave like a pussycat - growing slowly and unlikely to cause problems in a man's lifetime - or a tiger - spreading aggressively and requiring urgent treatment. But at the moment we have no reliable way to distinguish them. This means that some men may get treatment they don't need, causing unnecessary side effects, while others might benefit from more intensive treatment.

"This research could be game-changing if the results hold up in larger clinical trials and could give us better information to guide each man's treatment - even helping us to choose between treatments for men with aggressive cancers. Ultimately this could mean more effective treatment for the men who need it, helping to save more lives and improve the quality of life for many thousands of men with prostate cancer."

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FOR CANCER PATIENTS, A LOST OPPORTUNITY

By Jane E. Brody

Few adults enter randomized studies, though the research often yields new treatments.

In 1947, children who developed ACUTE LYMPHOCYTIC LEUKEMIA DIED.  Dr. Sidney Farber, a pathologist at Boston Children's Hospital, was so distressed doing autopsies  on these children that he moved into the clinic and, against the advice of more conservative colleagues, began treating children with aminopterin, a highly toxic drug that starved their cancerous white blood cells of critical nutrients.

Miraculously, for many, the disease went into remission, only to recur months later.  But Dr. Farber's last-ditch attempt to save these children began an era of ultimately remarkable progress -- decades of clinical trials of progressively complex treatments that now cure nearly 90% of children with leukemia.

Olivia Blair of Baltimore, 3, is showing the benefits of this progress. After her T-cell acute lymhocytic leukemia was diagnosed when she was 17 months old, Olivia has weathered more than a year of treatment at Johns Hopkins Kimmel Comprehensive Cancer Center with about 15 dugs and radiation to her brain and spine.

With her disease undetectable months later, she is now in a study of an experimental drug to help maintain the remission and is back to a near-normal childhood, a thriving happy toddler who plays with other children, goes to day care and accompanies her mother grocery shopping.

Kelly Blair, Olivia's mother, said, "It was very hard for us to decide to participate in the new study, but we finally thought that even if it didn't help Olivia, it's going to help other kids."

The tortuous road to the kind of treatments now saving more than half of all cancer patients is graphically depicted in the six-hour series, "Cancer: The Emperor of All Maladies," produced by Ken Burns, which was broadcast on public television.

The series is based on a Pulitzer Prize-winning book, "The Emperor of All Maladies: A biography of Cancer," by an oncologist, Dr. Siddhartha Mukherjee, who provides telling commentary throughout.

"The outcome in children is so stunning because 80 to 90% of young patients participate in clinical trials," Dr. Mukherjee, of Columbia University, said in an interview.  "Every trial taught doctors something that led to further trials and better results."

But only about 5% of adults with cancer enter a clinical trial.  "That's not nearly enough to move cancer medicine forward," he said.  "No matter what you do in the lab or in basic science, the ultimate proof of which cancer medicines work comes from clinical trials."

Although the backbone of today's successful cancer treatments, clinical trials are poorly understood by the public.

Those who participate are randomly assigned to receive the innovative treatment being studied or the current standard of care.  Through such trials for example, highly disfiguring radical mastectomies for breast cancer have yielded to simple mastectomies or lumpectomies, typically followed by radiation and CHEMOTHERAPY, with less trauma and far better survival rates.

Even metastatic cancer that has spread now sometimes yields to treatments being tested in clinical trials.

Doug Rogers of Lexington, N.C., was 58 in 2011 when he was found to have MELANOMA that, despite the best available chemotherapy, had spread throughout his leg and adjacent lymph nodes.  He then went to the National Cancer Institute, where Dr. Steven Rosenberg and colleagues are testing an immunological remedy in which the patient's own cancer-fighting T-cells are harvested, grown in a lab to billions strong and then given back to the patient.

Mr. Rogers, who is also featured in the TV series, said that repeated scans had shown no spread of his cancer and that he was "back to doing almost everything a 62-year-old man can do." Although it was once challenging to locate and join a clinical trial, patients and families can now find studies and determine eligibility without a doctor as intermediary.  The Stand Up to Cancer website offers free information about 7,000 cancer trials in the United States and Canada.  Or you can call the American Association for Cancer Research at 1-877-769-4829.

The American Cancer Society, at cancer.org/clinicaltrials, maintains a clinical trials matching service that is also free and can help locate studies most appropriate to a patient's medical and personal circumstances. And the National Cancer Institute offers up-to-date descriptions of more than 12,000 trials accepting participants, as well as recent trial results by type of cancer, the costs involved and questions to ask about participation.  The institute also has a 10-step guide to finding a cancer trial.

The best time to explore participation in a clinical trial is often right after a cancer diagnosis and before receiving any treatment.  Some trials won't accept patients who have already been treated, and sometimes, the best chance for success lies in receiving the most effective treatment first.  However, there are also trials for patients already treated elsewhere without success.

Dr. Mukherjee recommends asking about a trial's aim.  Is it to test safety or effectiveness of a treatment?  Why is the trial being done?  What were the data that led to the trial in the first place?

"Knowing the answers to such questions allows people to manage their hopes," he said.  "If patients go into a trial with the wrong expectations, they can set themselves up for disappointment."

Dr. Wendy Schlessel Harpha of Dallas, whose non-Hodgkin's lymphoma was diagnosed in 1990, is today a highly productive author and speaker because she participated in early trials of rituximab, a monoclonal antibody. Despite intensive chemotherapy and radiation, her disease recurred and, with no other good options, she entered three successive trials that tested rituximab first for safety, then effectiveness.

She had further recurrence all treated with rituximab, which was approved in 1997.  With her last recurrence in 2007, she is now enjoying her longest remission and credits the trials with enabling her to see her three children grow up.

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ARTHRITIS DRUG SHOWS POTENTIAL FOR BLOOD CANCER TREATMENT

Scientists have discovered that a common drug given to arthritis sufferers could also help to treat patients with BLOOD CANCER.

While ruxolitinib has been developed for patients with myeloproliferative neoplasms (MPN), scientists have discovered that methotrexate can work in the same way and at one thousandth of the cost. Myeloproliferative neoplasms (MPN) cause an overproduction of blood cells. This creates a significant impact on quality of life, with symptoms such as night sweats, itching, and tiredness.

MPNs are most often diagnosed in people between the age of 50 and 70. The drug ruxolitinib has recently been developed, but it is costly. Otherwise, treatment is limited to aspirin, removal of excess blood, and mild CHEMOTHERAPY.

Methotrexate was found to work in the same way as ruxolitinib by a research team from the University of Sheffield in the United Kingdom that was led by Martin Zeidler, working together with colleagues from the Department of Haematology at the Royal Hallamshire Hospital, and funded by Cancer Research UK. The findings were published in PLOS ONE (2015; doi:10.1371/journal.pone.0130078).

"Given that a year's course of low-dose MTX costs around £30 ($46), the potential to repurpose methotrexate could provide thousands of patients with a much needed treatment option and also generate substantial savings for health care systems,² said Zeidler.  "Because methotrexate is a World Health Organization 'Essential Medicine', this also means that this well-understood drug could be used throughout the developing world."

In this study scientists used cells from the fruit fly Drosophila to screen for small molecules that suppress the signaling pathway central to the development of MPNs in humans.  Further testing confirmed this in human cells, even those carrying the mutated gene responsible for MPNs in patients.

Methotrexate is commonly used at low doses to treat inflammatory diseases that include RHEUMATOID ARTHRITIS, Crohn's disease, and psoriasis. It has few side effects. It is also used in some cancers at much higher doses where the side effects are substantial and similar to other chemotherapy agents.  Working together with clinical colleagues at the Royal Hallamshire Hospital, Zeidler is now looking to undertake clinical trials to examine the possibility of repurposing low-dose MTX to treat MPNs.

"We have the potential to revolutionize the treatment of this group of chronic diseases: a breakthrough that may ultimately represent a new treatment option able to bring relief to both patients and health funders," he added.

Nell Barrie, senior science information manager at Cancer Research UK, said: "Finding new uses for existing drugs is a great way to speed up improvements in treatment, as these drugs will have previously been through safety tests. Methotrexate is already used as a chemotherapy drug for several types of cancer, and this early research shows that at much lower doses it could have the potential to help treat certain blood disorders."

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See you in September...

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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