BreakThrough Digest Medical News |
- Mouse studies reveal promising vitamin D-based treatment for MS
- Repurposed antidepressants have potential to treat small-cell lung cancer
- Prostate Cancer Foundation announces new urine test for prostate cancer available
| Mouse studies reveal promising vitamin D-based treatment for MS Posted: 26 Sep 2013 09:00 PM PDT A diagnosis of multiple sclerosis (MS) is a hard lot. Patients typically get the diagnosis around age 30 after experiencing a series of neurological problems such as blurry vision, wobbly gait or a numb foot. From there, this neurodegenerative disease follows an unforgiving course.
Many people with MS start using some kind of mobility aid — cane, walker, scooter or wheelchair — by 45 or 50, and those with the most severe cases are typically bed-bound by 60. The medications that are currently available don’t do much to slow the relentless march of the disease. In search of a better option for MS patients, a team of University of Wisconsin-Madison biochemists has discovered a promising vitamin D-based treatment that can halt — and even reverse — the course of the disease in a mouse model of MS. The treatment involves giving mice that exhibit MS symptoms a single dose of calcitriol, the active hormone form of vitamin D, followed by ongoing vitamin D supplements through the diet. The protocol is described in a scientific article that was published online in August in the Journal of Neuroimmunology. “All of the animals just got better and better, and the longer we watched them, the more neurological function they regained,” says biochemistry professor Colleen Hayes, who led the study. MS afflicts around 400,000 people nationwide, with 200 new cases diagnosed each week. Early on, this debilitating autoimmune disease, in which the immune system attacks the myelin coating that protects the brain’s nerve cells, causes symptoms including weakness, loss of dexterity and balance, disturbances to vision, and difficulty thinking and remembering. As it progresses, people can lose the ability to walk, sit, see, eat, speak and think clearly. Current FDA-approved treatments only work for some MS patients and, even among them, the benefits are modest. “And in the long term they don’t halt the disease process that relentlessly eats away at the neurons,” Hayes adds. “So there’s an unmet need for better treatments.” While scientists don’t fully understand what triggers MS, some studies have linked low levels of vitamin D with a higher risk of developing the disease. Hayes has been studying this “vitamin D hypothesis” for the past 25 years with the long-term goal of uncovering novel preventive measures and treatments. Over the years, she and her researchers have revealed some of the molecular mechanisms involved in vitamin D’s protective actions, and also explained how vitamin D interactions with estrogen may influence MS disease risk and progression in women. In the current study, which was funded by the National Multiple Sclerosis Society, Hayes’ team compared various vitamin D-based treatments to standard MS drugs. In each case, vitamin D-based treatments won out. Mice that received them showed fewer physical symptoms and cellular signs of disease. First, Hayes’ team compared the effectiveness of a single dose of calcitriol to that of a comparable dose of a glucocorticoid, a drug now administered to MS patients who experience a bad neurological episode. Calcitriol came out ahead, inducing a nine-day remission in 92 percent of mice on average, versus a six-day remission in 58 percent for mice that received glucocorticoid. “So, at least in the animal model, calcitriol is more effective than what’s being used in the clinic right now,” says Hayes. Next, Hayes’ team tried a weekly dose of calcitriol. They found that a weekly dose reversed the disease and sustained remission indefinitely. But calcitriol can carry some strong side effects — it’s a “biological sledgehammer” that can raise blood calcium levels in people, Hayes says — so she tried a third regimen: a single dose of calcitriol, followed by ongoing vitamin D supplements in the diet. This one-two punch “was a runaway success,” she says. “One hundred percent of mice responded.” Hayes believes that the calcitriol may cause the autoimmune cells attacking the nerve cells’ myelin coating to die, while the vitamin D prevents new autoimmune cells from taking their place. While she is excited about the prospect of her research helping MS patients someday, Hayes is quick to point out that it’s based on a mouse model of disease, not the real thing. Also, while rodents are genetically homogeneous, people are genetically diverse. “So it’s not certain we’ll be able to translate (this discovery to humans),” says Hayes. “But I think the chances are good because we have such a broad foundation of data showing protective effects of vitamin D in humans.” The next step is human clinical trials, a step that must be taken by a medical doctor, a neurologist. If the treatment works in people, patients with early symptoms of MS may never need to receive an official diagnosis. “It’s my hope that one day doctors will be able to say, ‘We’re going to give you an oral calcitriol dose and ramp up the vitamin D in your diet, and then we’re going to follow you closely over the next few months. You’re just going to have this one neurological episode and that will be the end of it,’” says Hayes. “That’s my dream.” ### Contact: Colleen Hayes |
| Repurposed antidepressants have potential to treat small-cell lung cancer Posted: 26 Sep 2013 09:00 PM PDT A bioinformatics approach to repurposing drugs resulted in identification of a class of antidepressants as a potential new treatment for small-cell lung cancer (SCLC), according to a study published in Cancer Discovery, a journal of the American Association for Cancer Research.
Based on data generated using bioinformatics, two drugs approved by the U.S. Food and Drug Administration (FDA) to treat symptoms of depression were tested on SCLC cells and animal models. Both antidepressants were found to induce SCLC cell death. They were also effective in mice bearing human SCLCs that had become resistant to the chemotherapy drug cisplatin. The antidepressants tested were imipramine, which modulates the activity of certain hormones causing mood disorders; and promethazine, a sedative, antiemetic, and antipsychotic drug. Bioinformatics is a combination of mathematics and computer science used to sort, classify, and analyze large databases of biological and biochemical information. “We implemented a bioinformatics-based drug repositioning approach toward accelerated evaluation of FDA-approved drugs for cancer treatment. From the day we started this project, it took less than 20 months to initiate a clinical trial,” said Julien Sage, associate professor of pediatrics and genetics at Stanford University School of Medicine in California. “This is a good example of how we can combine ‘big data’ and the mature field of preclinical animal models to rapidly find new uses for old drugs. “Unlike most targeted therapies, which are often specific for a single molecule or pathway, the drugs we identified target multiple receptors at the surface of neuroendocrine cancer cells, which may make it difficult for cancer cells to develop resistance,” he added. “We are in the process of identifying the optimal treatment regimen for patients with SCLC and modifying these drugs to prevent them from entering the brain, in order to minimize side effects.” SCLC is a deadly subtype of lung cancer of neuroendocrine origin, and patients diagnosed with SCLC have a dismal prognosis. There is currently no approved targeted therapy for this disease and no new drugs have been identified in the last few decades. Sage and colleagues focused their search on drugs targeting the two top pathways identified using a bioinformatics approach: the neuroactive ligand receptor interaction pathway and the calcium signaling pathway. Of the six antidepressants initially shortlisted, imipramine and promethazine emerged as successful candidates for further study based on the results of experiments using SCLC cell lines and mice bearing human SCLC tumors. The researchers then generated mutant mice bearing cisplatin-resistant SCLC tumors and found that the growth of chemotherapy-resistant tumors were inhibited by imipramine, suggesting that the identified antidepressants will be effective against SCLCs in patients who developed resistance to standard chemotherapy. They conducted further experiments and found these two drugs acted on SCLCs primarily by inducing cell death mechanisms within the cancer cells. They also found that SCLC cells express certain receptors called GPCRs, and imipramine and promethazine caused cell death by engaging these receptors and their downstream signaling mechanisms. Because imipramine was also effective in an animal model of pancreatic neuroendocrine tumors, the researchers are hoping their observations with SCLC can be extended to a number of other neuroendocrine cancers. Based on their preclinical results, the researchers have initiated a phase 2a clinical trial to test desipramine, a drug similar to imipramine, in SCLC and other high-grade neuroendocrine tumors. ### This study was funded by the Lucile Packard Foundation for Children’s Health, the United States Department of Army, the NLM Biomedical Informatics Training Grant to Stanford University, the National Cancer Institute, the Stanford Dean’s Fellowship, NRSA T32 Academic Research Training in Pulmonary Medicine, a California TRDRP post-doctoral fellowship, and a Stanford Cancer Institute Developmental Cancer Research Award. The intellectual property from this work has been licensed to NuMedii, a company further developing these drugs. Contact: Jeremy Moore |
| Prostate Cancer Foundation announces new urine test for prostate cancer available Posted: 25 Sep 2013 09:00 PM PDT A new urine test for prostate cancer that measures minute fragments of RNA is now commercially available to men nationwide through the University of Michigan MLabs. The new test?Mi-Prostate Score (MiPS)?improves the utility of the PSA blood test, increases physicians’ ability to pick out high-risk prostate tumors from low-risk tumors in patients, and may help tens of thousands of men avoid unnecessary biopsies.
The MiPS test incorporates blood PSA levels and two molecular RNA markers specific for prostate cancer in one final score that provides men and their doctors with a personalized prostate-cancer risk assessment. Drawbacks of stand-alone PSA testing for prostate cancer
Improving upon the PSA test
An ultra-specific test for prostate cancer
A commercial urine test (PROGENSA PCA3) for PCA3, developed and marketed by the California-based biotech company Gen-Probe, gained FDA approval in 2012 for use in men who are considering repeat biopsy after an initially negative result. While a welcome development, research shows that the new urine test offered by MLabs that measures both PCA3 and TMPRSS2:ERG should improve a doctor’s ability to stratify men suspected of having prostate cancer. In a study published in Science Translational Medicine, Tomlins and colleagues found the highest rates of cancer in men with the highest levels of TMPRSS2:ERG and PCA3 in their urine. The men in the study were stratified into three groups based upon the levels of TMPRSS2:ERG and PCA3 in their urine: low, intermediate and high levels, or scores. Cancer was diagnosed in each of the groups respectively: 21%, 43%, and 69%. High-grade prostate cancer, defined in the study as a Gleason score greater than 6, also occurred at different frequencies in the three groups with 7%, 20%, and 40% diagnosed in each group respectively. Other research has shown that the two-marker urine test is more effective than the PSA test alone, or PSA testing that’s incorporated into a commonly used online tool (the Prostate Cancer Risk Calculator), at predicting the presence of prostate cancer. ### Contact: Rebecca Levine |
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