Another reason to continue Metformin for your type II diabetes !!

Fragile X syndrome is a genetic disease caused by defects in the Fragile X Mental Retardation 1 gene (FMR1), which triggers excess production of protein in the brain, as well as dysregulated connections between neurons and changes in behavior. The condition leads to impairments in speech and language, behavior and social interaction. It affects about 1 in 5,000 boys and 1 in 6,000 girls and is often co-diagnosed with autism, anxiety disorders and seizures. I have never personally worked on the Fragile X syndrome but I have indirectly been associated with ongoing research efforts about this disease through a close friend of mine and an accomplished neuroscientist Dr. Udai Bhan Pandey, currently an associate professor of Human Genetics at University of Pittsburgh. Earlier in his career, Dr. Pandey worked on Fragile X syndrome for his Ph.D. dissertation in the same lab in which I was working on a GI cancer model.  I vividly remember how passionately he used to talk about this disease and as to how there is no cure for fragile X syndrome back in 2003. Even today after 14 years, there is no cure yet.

A new study led by researchers at McGill University, the University of Edinburgh and Université de Montréal has found that Metformin improves social, behavioral and morphological defects in mice model of Fragile X syndrome. For those who are not aware about Metformin, it is a common drug used in individuals with high risk for diabetes type 2, obesity or impaired glucose tolerance. It has had a strong safety profile in children and adults with type 2 diabetes and obesity. 

Ilse Gantois, Arkady Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Erika Freemantle, Ruifeng Cao, Vijendra Sharma, Tine Pooters, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong, Shane Wiebe, Isabelle A Groves, Seyed Mehdi Jafarnejad, Clément Chapat, Elizabeth A McCullagh, Karine Gamache, Karim Nader, Jean-Claude Lacaille, Christos G Gkogkas, Nahum Sonenberg. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nature Medicine, 2017; DOI: 10.1038/nm.4335

In this study, Gantois et al. beautifully demonstrate that metformin, a type II diabetes drug that crosses the blood-brain barrier, corrects various neurological and behavioral phenotypes of fragile x syndrome in a mouse model known as Fmr1−/y.  These mice have increased abundance of an kinase (a type of cellular enzyme) known as RAF and enhanced activity of its related kinases and gene targets. These investigators found that a chronic (10-day) treatment with metformin reduced the abundance of RAF and suppressed the activation of enzymes such as MEK, ERK, mTOR, and translation initiation factor eIF4E in the prefrontal cortex and hippocampus of Fmr1−/y mice which are important molecules in the pathogenesis of fragile X disease. Decreased mTOR activity correlates with decreased expression of the gene encoding MMP9, a protease (another type of enzyme) that regulates synaptic function. Metformin suppressed repetitive behavior, the incidence of macroorchidism, and defects in dendritic spine development and synaptic activity in Fmr1−/y mice, phenotypes that are common in fragile x syndrome patients.

Please note that this study is conducted in mice model, and in spite of lot of similarities between mice and human, further tests will be needed to assess whether metformin can specifically improve cognitive function in mammals and assess the extent of its benefits versus its side effects which are many. Yet scientific community is very optimistic about these findings suggesting that metformin might be repurposed for use in fragile x patients.

Dr. Nahum Sonenberg, a pioneering scientist of our times, best known for his seminal contributions to our understanding of translation of proteins from RNAs, and notable for the discovery of the mRNA 5' cap-binding protein, eIF4E, the rate-limiting component of the eukaryotic translation apparatus and also a senior author of this research work says about Metformin:  "Basically, it's something like a wonder drug,"

https://en.wikipedia.org/wiki/Nahum_Sonenberg

'Wonder drug' in the past few years, metformin has generated extensive interest for its potential in treating numerous health problems such as cancer, cardiovascular diseases, neurological diseases and aging. Numerous preclinical, epidemiological and clinical studies in the past have suggested that metformin use is associated with inhibition of cancer cell growth and reduction in all-cancer incidents in comparison with users of other hypoglycemic drugs. So if you are type 2 diabetes patient and your doctor has advised you to take metformin, you have another good reason to keep taking this drug regularly without fail.

http://www.healthline.com/health/metformin-oral-tablet#about3

Dual Targeting of NEDD9/AURKA and ROCK pathways could be a viable therapeutic strategy to treat triple negative breast cancer.

Despite major discoveries in cancer biology in recent years, metastases (spread of primary tumor cells) are the cause of 90% of human cancer deaths. Very little is known about the genetic and biochemical determinants of metastasis. Metastasis is a multistage process involving abnormal tumor cell migration and invasion, transit in the blood or lymph, extravasation and colonization in the normal tissues at secondary sites. Acquisition of invasive behavior involves activation of signaling pathways controlling cytoskeletal dynamics, as well as turnover of cell–matrix and cell–cell adhesions. Cancer invasion is a heterogeneous and adaptive process involving changes in cell morphology and generation of cell polarity. Cancer cells display exceptional ability to adapt to different environmental conditions engaging in different migration strategies. Cancer cells can migrate either individually in the absence of cell–cell junctions, or collectively upon retention of cell–cell adhesions. In turn, cancer cells can use a number of strategies when migrating individually such as they could change their shape between elongated-mesenchymal, rounded- amoeboid, spike-mediated or while migrating collectively they would behave as if in a multicellular streaming or tumor budding to accomplish collective invasion into normal tissues at a different site.

Scaffolding protein known as NEDD9 is a critical regulator of cancer cell migration especially for individual mesenchymal type of migration for many types of tumor cells and its elevated expression has been reported in many tumor types including breast, lung, and melanoma. Mesenchymal migration is characterized by an elongated cell morphology, multiple focal/3D adhesions, and the ability to degrade ECM by matrix metalloproteinases (MMPs) creating a path through the basement membrane/tissue. A major regulator of mesenchymal migration, Rac1 GTPase, is activated by a number of guanine nucleotide exchange factors (GEFs), including melanoma-specific DOCK3, which in turn is recruited/activated by NEDD9.

In a recent study conducted by a former colleague and friend Dr. Elena Pugacheva, an Associate Professor at University of West Virginia, amoeboid movement of triple negative breast cancer (TNBC) cells was found to be defective in some respects such as decreased cell contractility. It is important to note that a triple negative breast cancer diagnosis means that the tumor is estrogen receptor-negative, progesterone receptor-negative and HER2-negative, thus giving rise to the name “triple negative breast cancer.” While this type of breast cancer is typically responsive to chemotherapy, the bad news is when TNBC tumor recurs then it becomes hard to treat as they do not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors, such as Herceptin (chemical name: trastuzumab) which is commonly used to treat other types of breast cancer in case of tumor recurrence. For doctors and researchers, there is intense interest in finding new medications that can treat this kind of breast cancer.

Dr. Pugacheva and her team at West Virginia University School of Medicine provides a mechanistic explanation as to how NEDD9 drives invasion processes in TNBC cells which paves roads to develop new therapeutic strategies so as to use a combination of anti-NEDD9/AURKA and anti-ROCK–targeting compounds to inhibit these movement signaling cascades relevant in TNBCs. In this study, investigators report that deficiency in NEDD9 signaling itself leads to inhibition of key aspects of both mesenchymal and amoeboid migration in TNBC cells, resulting in substantial hindrance on cell invasion and metastasis. NEDD9 deficiency in TNBC cells results in rounded/amoeboid morphology along with a decrease in the total number of mature (pFAK/pPaxillin positive) adhesions and an increase in the number of recently formed adhesion structures. Together, these findings suggest that NEDD9 is also required for the disassembly of fibrillar adhesions similar to vinculin, which regulates the recruitment and release of focal adhesion proteins in a force-dependent manner. Overall this work strongly suggests that a dual targeting strategy (using both anti-NEDD9/AURKA and anti-ROCK–targeting compounds) could be an efficient therapeutic approach to hinder the metastasis of triple negative breast cancers, indicating towards an important need for further clinical evaluation of this therapeutic regimen to impede the spread of disease and improve patient survival in patients setting.

For details, please refer to the original work:

http://mcr.aacrjournals.org/content/15/6/670

http://directory.hsc.wvu.edu/Individual/Index/31447

For further reading about NEDD9 signaling pathway please refer to:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758619/

http://cancerres.aacrjournals.org/content/early/2010/10/07/0008-5472.CAN-10-0353

Eating less and periodic fasting is good for health

Almost all cultures in the world have been insisting on eating less and observing periodic fasting for religious regions but now a group of scientists have confirmed in the laboratory that it is good practice with health benefits:

Scientists at University of Southern California observed that the fasting mimicking diet promotes the growth of new beta cells in the pancreas that are responsible for producing insulin which leads to reduction in the symptoms of type 1 and type 2 diabetes in mice. Some of this phenomenon was observed in human beta cells growing in petri-dish as well.

"Cycles of a fasting-mimicking diet and a normal diet essentially reprogrammed non-insulin-producing cells into insulin-producing cells," said Dr. Valter Longo, who is director of the Longevity Institute at the USC Leonard Davis School of Gerontology. Dr. Longo, further said - "By activating the regeneration of pancreatic cells, we were able to rescue mice from late-stage type 1 and type 2 diabetes. We also reactivated insulin production in human pancreatic cells from type 1 diabetes patients."

"These findings warrant a larger FDA trial on the use of the fasting-mimicking diet to treat human diabetes patients to help them produce normal levels of insulin while improving insulin function," Dr. Longo said. "Hopefully, people with diabetes could one day be treated with an FDA-approved fasting-mimicking diet for a few days each month and gain control over their insulin production and blood sugar."

However, this study does not mean that patients with diabetes should start trying fasting mimicking diet without any clinical supervision. This study is still in early stages and your doctor will tell you whether or not FDA, and if yes, when will start any clinical trial. Dr. Logo warned the patients: "In regard to our recent studies on diabetes, DO NOT try to apply any type of fasting mimicking diet (FMD) to treat either type 1 or type 2 diabetes either on your own or with the help of a doctor. The combination of the FMD and insulin or other drugs could increase the risk of severe complications, including the possibility of death. Although the use of the FMD to treat either type 1 or 2 diabetes is promising, it must be tested and proven safe and effective for human use in FDA-approved clinical trials."

http://www.cell.com/cell/fulltext/S0092-8674(17)30130-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867417301307%3Fshowall%3Dtrue

A perspective on "Critics assail India's attempt to ‘validate’ folk remedy"

Following is a letter written by me in response to a report published in reputed journal Science which appeared online just last week:

In my opinion, brouhaha against scientific validation efforts by the government of India for the potential medicinal use of panchagavya, a mixture made of cow urine, dung, milk, yogurt, and clarified butter, based on the ancient Indian medical literature, is unfounded (1). It’s not unwise to explore the therapeutic potential of folk remedies using the modern scientific methodologies given most synthetic drugs used in the modern medicine have associated severe side effects and often times do not provide any significant health benefit at all. There are many instances when properly designed scientific studies to explore an active ingredient derived from a natural source used in the folk medicine have resulted in wonder drugs that saved millions of lives worldwide. Most recent such example is story of Artemisinin which was extracted from Chinese herb Artemisia annua, also known as sweet wormwood, which was further studied elaborately using tools of modern science by Dr. Youyou Tu who later was awarded with Nobel Prize just a couple years ago. The results obtained after decades long research program initiated at the behest of China Academy of Chinese Medical Sciences in Beijing was a paradigm shift in the medical field that allowed for Artemisinin to be both clinically studied and produced on industrial scale.

Author of this letter himself is involved in a collaborative project in which a big team of researchers is studying anti-cancer effects of a small molecule namely 'Minnelide' which is a water soluble derivative of triptolide, a diterpene triepoxide extracted from the Chinese plant Trypterygium wilfordii (2). Minnelide has shown a lot of promise as a potential chemotherapeutic options in multiple tumor cell lines (3) and currently being tested in clinics in a phase II, international open label trial in patients with refractory pancreatic cancer (4).

However, forcing a group of scientists some of whom may not have faith in drug discovery program originating from traditional medicine may not be fruitful in long run. There ought to be a balance between political and pure scientific influence in making decisions about science policy. An overall strategy for making decisions regarding government funded research need to be formulated with the consensus of government funding agencies as well as scientists likely to work on the projects of increased and decreased areas of emphasis as decided by government. Utmost importance should be given to allocate the budget adequate enough so as to serve both national interests and to foster a world-class scientific and technical enterprise. To this end, political and scientific administration need to establish a dialogue process that could help engage scientists who naturally have academic interests in pursuing folk medicine based drug discovery research.

References:

(1) S. Kumar, Critics assail India’s attempt to “validate” folk remedy. Science 355, 898–898 (2017)

(2) R. Chugh, V. Sangwan, S. P. Patil, V. Dudeja, R. K. Dawra, S. Banerjee, R. J. Schumacher, B. R. Blazar, G. I. Georg, S. M. Vickers, A. K. Saluja, A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer. Sci. Transl. Med. 4, 156ra139 (2012)

(3) Giri B, Banerjee B, George J, Modi S, Gupta VK, Singh MK, Dudeja V, Saluja AK. Triptolide pro-drug decreases tumor burden and halts tumor progression in a murine model of acute myeloid leukemia. Cancer Res, 76 (Supplement), 3499 (2016)

(4) https://clinicaltrials.gov/ct2/show/NCT03117920Show Less

Competing Interests: None declared.

Weblink to my letter: 

http://science.sciencemag.org/content/355/6328/898/tab-e-letters

Omics! Omics!: NGS Saves A Young Life

Omics! Omics!: NGS Saves A Young Life: One of the most electrifying talks at AGBT this year was given by Joe DeRisi of UCSF, who gave a brief intro on the difficulty of diagnosin...

Particle beam cancer therapy: The promise and challenges

http://www.sciencedaily.com/releases/2014/03/140303143251.htm

For some patients with advanced breast cancer, chemo may be enough and they can be spared from the ordeal of going through surgery and radiation

It’s not been much time when Angelina Jolie initiated a “to go for or not to go for mastectomy” debate after being found with mutation in one of those ‘breast cancer risk prone gene BRCA1’. Well before you decide to go under a knife of surgeon, this could be a worth considering study that just came up from a very experienced physician based in India, which you want to discuss with your team of doctors.  

In a very prestigious AACR meeting currently ongoing in San Antonio, namely “2013 San Antonio Breast Cancer Symposium, held Dec. 10–14” Dr. Rajendra Badwe from Tata Memorial Hospital, Mumbai, India raised many eyebrows when he presented his findings in which he and his team led a study of 350 women with widely spread breast cancers that had shrunk after initial chemotherapy. Almost 50% of these patients went through mastectomy (surgery to remove the breast or the lump plus any cancerous lymph nodes). Rest of them did not have surgery. After about two years, 40 % of both groups were alive, suggesting that just chemotherapy could be enough. Women diagnosed with advanced breast cancer who respond well to chemotherapy get no additional benefit from having surgery and radiation afterwards. However, Dr. Rajendra Badwe, went on saying that options for surgery and radiation can be reserved for patients who need it for palliative reasons.

http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=3236&utm_source=twitter&utm_medium=tweet&utm_content=newsrelease&utm_campaign=2013sabcs

Targeting a specific area of the body for surgery or radiation is called loco-regional treatment, or LRT. Conventional wisdom has been that women with advanced (Stage 4) breast cancer, in which the disease has metastasized (spread to other organs), are treated only with chemotherapy unless other health issues (among them the relief of pain or other symptoms; the prevention of bone fractures; the tumor causing an open wound) dictate otherwise. In last decade, however, research community divided on into two school of thought on whether or not to use other supplementary treatment modalities such as surgery and radiation so they realized severe need of trials to confirm their theories. To find which of the two treatment methods resulted in the best survival outcomes for patients, Badwe and his colleagues in India, conducted a prospective, randomized, controlled trial funded by Badwe's hospital and the Department of Atomic Energy Clinical Trial Center in India.

Between 2005 and 2013 the researchers enrolled 350 women with metastatic breast cancer whose tumor responded positively to six cycles of chemotherapy. One group of patients received LRT, while the other group did not receive LRT. Both groups were matched for age, tumor size and extent of the metastases, and hormone receptor and HER2 receptor status.

Patients in the LRT group had either a lumpectomy or mastectomy and surgical removal of lymph nodes, followed by radiation treatment. All patients whose breast cancers were hormone-related received standard hormone therapy, regardless of the group to which they had been assigned.While the cancer was well-controlled in women who underwent surgery, that didn't translate into a survival advantage over the women who did not have surgery, Badwe said.The researchers also found a 7 percent excess death rate in patients who received LRT. The finding was not statistically significant, they said, but it aligned with the previous such findings that suggest surgical removal of the primary tumor in patients with advanced breast cancer might trigger the metastases.

“From a clinical practice point of view, as a surgeon I might know when to operate,” Dr. Badwe said. “But most importantly, when not to operate is equally important. “We need to know what the tumor is sensitive to,” Badwe said. “That is of greater value than loco-regional treatment.”

The extra expense of surgery and radiation, and the impact of those treatments on a patient’s quality of life also contribute to the researchers’ position that LRT should be done only within the tenets of clinical trials, he said.

While given the genetic differences between various populations, findings from this study have to be analyzed in that perspective, however, these findings open the door for more research on this aspect and warrant for more efforts towards new targeted therapies.