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2015/02/05

A New Weapon to Fight Breast Cancer

Congratulations to Pfizer for receiving accelerated approval for its investigational new drug, IBRANCE to treat advanced breast cancer from the U.S. FDA on February 3.  IBRANCE is an inhibitor of cyclin-dependent kinase 4/6 (CDK4/6) involved in promoting the growth of cancer cells. IBRANCE is the first CDK4/6 inhibitor approved by the FDA to treat cancer. Breast cancer in women is the second most common type of cancer in the US.  According to the American Cancer Society, about 231,840 new cases of invasive breast cancer will be diagnosed in women and about 40,290 women will die from breast cancer in 2015 in the US.  Worldwide, breast is one of the 5 most common sites diagnosed with cancer. IBRANCE is intended to treat postmenopausal women with estrogen receptor-positive and epidermal growth receptor 2-negative (ER+/HER2-) metastatic breast cancer.  This group of patients represents the largest proportion of breast caner cases, and “This approval represents the first treatment advance for this group of women in more than 10 years,” said Mace Rothenberg, the head of oncology for Pfizer. IBRANCE was reviewed and approved under the FDA’s Breakthrough Therapy designation and Priority Review programs. “IBRANCE is the first CDK4/6 inhibitor approved by the FDA to treat cancer,” commented Qunsheng Ji, Vice President of Oncology at WuXi.  “This represents a significant advance in bridging basic biology with patient benefit, and exemplifies the importance of understanding of the disease in developing innovative medicine for cancer treatment.  The success of IBRANCE also represents the outcomes of collective and persistent efforts on scientific researches and drug discovery in cell cycle fried over the last two decades.”

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2015/02/01

BCX4161, a Promising New Orally Administered Drug for the Rare and Genetic Disorder Hereditary Angioedema, Received Fast Track Status from the FDA

BioCryst Pharmaceuticals, Inc., a small pharmaceutical company headquartered in Durham, North Carolina announced on January 26 that one of the drugs in the company’s pipeline, BCX4161 has been granted fast track status by the FDA. BCX4161 is a novel and selective inhibitor of plasma kallikrein discovered by BioCryst and is in development for the treatment of hereditary angioedema (HAE). HAE is a rare and hereditary disease affecting approximately 1 in 10,000 to 1 in 50,000 people.  The gene responsible for HAE is called C1-inhibitor (C1NH).  HAE patients suffer episodic attacks of edema in various parts of the body including hands, feet, face and airway.  In addition, patients often have bouts of excruciating abdominal pain and other GI track symptoms due to intestinal edema.  Severe airway edema can lead to death by asphyxiation.  BCX4161 inhibits plasma kallikrein and consequently suppresses bradykinin production. Bradykinin is the mediator of acute swelling attacks in HAE patients. Current treatment options include purified C1 inhibitor concentrate (Cinryze, Berinert, or Ruconest), Ecallantide (a kallibrein inhibitor) and Icatibant (a bradykinin B2 receptor antagonist).  These drugs are in either intravenous or subcutaneous injection form with various adverse effects.  BCX4161 is being developed as an orally administered drug and has the potential to significantly improve HAE patient treatment and their quality of life.   Related Links: http://www.haea.org/patients/what-is-hae/ http://www.omim.org/entry/106100

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2015/01/22

First Crystal Structure of Human GLUT1 Solved

An article published in the prestigious Nature magazine this summer by a group led by one of a 2012 recipient of WuXi Life Science and Chemistry Awards, Dr. Nieng Yan of Tsinghua University, made a great contribution toward the understanding of GLUT1 functions and implications in disease intervention by solving the first crystal structure of human GLUT1.  The article is titled “Crystal structure of the human glucose transporter GLUT1” (Nature 510, 121-125, PMID: 24847886). Glucose is the essential energy source for human cell metabolism.  To transport glucose across the plasma membrane, cells reply on a family of membrane proteins called glucose transporters (GLUTs), encoded by solute carrier 2A gene family (SLC2A).  These transporters allow glucose uptake across the plasma membrane through facilitative diffusion.  Fourteen members have been identified in this family of glucose transporters and they are responsible for glucose uptake in different cell types and tissues in humans.  Glucose homeostasis is vital for metabolism supplying energy source for essential cellular functions via respiration, and providing building blocks and reducing power required for cellular growth and proliferation via several well-characterized biochemical pathways.  Perturbation of glucose uptake causes many diseases. GLUT1 (glucose transporter 1) is one of the members of GLUT family.  It is mainly expressed in erythrocytes and in the endothelial cells of blood-tissue barrier, such as blood-brain barrier and placenta.  Mutations in GLUT1 cause several rare hereditary diseases including GLUT1 deficiency syndrome 1 and 2, Dystonia 9, and idiopathic generalized epilepsy-12.  Disregulation, mainly over-expression of GLUT1 is associated with a number of cancers, cancer progression and poor prognosis.  Therefore, characterizing the structure of GLUT1 and deciphering the mechanisms involved in regulation of glucose transport would provide structural basis for understanding the physiology and pathophysiology of glucose uptake-associated functions and diseases. Although structures of homologous GLUT1 from bacteria have been solved, these GLUT1 transporters are proton-driven symporters.  Human GLUT1 is a proton-independent uniporter that transport glucose down its concentration-gradient through facilitative diffusion.  This paper provided the first crystal structure for a uniporter GLUT1.  According to the paper, “Structure resolution of the human GLUT1 serves as a framework for understanding its functional mechanism.”  By comparison to the structures reported for bacterial GLUT1, insights regarding the differences between proton-driven active versus facilitative diffusion could be gained and be applicable to similar uniporters. There are practical implications from this work as well.  For instance, by mapping variants observed in GLUT1 on to the crystal structure, functional consequence could be deduced providing support to classification of genetic variants and diagnosis of rare diseases associated with GLUT1 mutations.  GLUT1 is one of the members of glucose transporters whose expression is frequently upregulated in malignant cancers to increase glucose uptake to support malignant growth and proliferation.  Crystal structure of GLUT1 will provide clues for therapeutic development aiming at either blocking the transporter or utilizing the transporter to deliver chemotherapeutic drugs.  As the authors stated, “the structure also serves as a guiding principle for the development of potential therapeutic agents that target GLUT1 and other physiologically important MSF (major facilitator superfamily) sugar transporters.”  In addition, GLUT1 has been shown to interact with the receptor-binding domains of the human T-cell leukemia virus (HTLV)-1 and -2 envelope glycoproteins.  The crystal structure resolution of GLUT1 could also result in novel therapeutic interventions for HTLV infections.

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2015/01/22

Antibodies Designed to Combat Ebola May Provide Protection from the Rare but Deadly Infection

New insights about experimental monoclonal antibody cocktails that recognize Ebola virus may soon help provide an effective treatment option.  Ebola virus disease (EVD) is a highly lethal illness in humans that is sometimes associated with bleeding. It is caused by a family of viruses (Filoviridae, genus Ebolvirus) linked to hemorrhagic fever. No approved medications exist to prevent or treat EVD. Investigators from The Scripps Research Institute (TSRI) and Mapp Biopharmaceuticals are developing 3 different monoclonal antibody (mAb) cocktails (or mixtures) that bind to Ebola virus and limit its spread to healthy cells. In past outbreaks—affecting mainly small, isolated human populations in African countries—the mortality rates ranged from 30 to 90%1,2. Currently, the 2014 outbreak in Western Africa is the largest on record, with more than 15,000 confirmed infections and 5,400 deaths as of November 20143. The experimental Ebola antibody cocktails, MB-003 and ZMAb have shown success in treating non-human primates. A small supply of ZMapp—the most effective of the 3 experimental therapies — was exhausted after treating 6 medical and religious workers (some of whom died) that contracted EVD1, 4. New information about the rationale for how the cocktails work may aid in developing a much needed treatment option; however, well-designed clinical trials must ultimately determine ZMapp efficacy. Dr. Charles Murin of TSRI and co-authors reported their findings in the October 2014 issue of the Proceedings of the National Academy of Sciences. 1 The researchers used electron microscopy and other methods to compare structural features and Ebola-specific binding capabilities of the antibody cocktails MB-003, ZMAb, and ZMapp.1 The results showed the antibodies fall into 3 groups based on the vulnerable viral region they bind (specifically, the mucin-like domain, the glycan cap, or the core glycoprotein). Analyses also revealed that while each of the cocktails contain some unique components, redundancies exist, and in some cases, the cocktails contain antibodies that compete for overlapping regions of the virus. It is hopeful that the new study will help identify the components of the cocktails that most effectively target distinct regions of the virus and aid in developing enhanced drug formulations. Fortunately, ebolavirus mutations thus far detected in Guinea and Sierra Leone have not altered the sites of the Ebola virus that are recognized by the ZMapp antibodies1—indicating that new supplies of ZMapp “would likely have efficacy against viral strains circulating in the ongoing 2014 outbreak.” The authors note, “This work provides clear next steps to determine if ZMapp can be honed for even greater potency, efficacy, or production.” This work by Murrin and colleagues provides direction for strategically selecting next-generation antibody cocktails that may be effective against existing ebolaviruses and mutated viral variants.1   References:   1Murin, C.D., Fusco, M.L., Bornholdt, Z.A., et al. 2014. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proceedings of the National Academy of Sciences doi:10.1073/pnas.1414164111. 2World Health Organization. http://www.who.int/mediacentre/factsheets/fs103/en/. Accessed November 20, 2014. 32014 Ebola Outbreak in West Africa. http://www.cdc.gov/vhf/Ebola/outbreaks/2014-west-africa/index.html. Accessed November 20, 2014. 4Judging An Ebola Drug In The Middle Of A Crisis. http://www.kpbs.org/news/2014/aug/21/evaluating-san-diego-companys-ebola-drug-amidst-cr/. Accessed November 20, 2014. 5Detailed Picture Of ZMapp Shows Room For Improvement. http://www.kpbs.org/news/2014/nov/18/detailed-picture-zmapp-shows-room-improvement/. Accessed November 20, 2014.    

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2014/12/03

Existing Medications for Erectile Dysfunction May Alleviate Symptoms of Duchene Muscular Dystrophy

Duchene muscular dystrophy (DMD) is a rare genetic disorder and is caused by a defect in the dystophin gene.  Insufficient levels of dystophin inhibit the function of nitric oxide, a chemical required for proper blood flow into muscles during exercise. The condition affects 1 in 3,600 male children globally and rarely affects females.  The disease causes devastating symptoms, including, progressive inability to walk or raise arms, weakened heart muscles and respiratory system, cognitive impairment and shortened lifespan[1]. Presently, glucocorticoids may be used to treat some symptoms associated with DMD; however, greater than 25% of patients treated with these medications experience significant side effects. A new study recently published in the journal Neurology indicates that medications historically prescribed for treating erectile dysfunction may help people diagnosed with DMD. Ronald Victor, M.D. with Ceders-Siani Medical Center in Los Angeles, CA, and colleagues reported their findings in the June 10, 2014 issue of Neurology[2]. The team investigated the effectiveness of sildenafil (Viagra) and tadalafil (Cialis) for treating DMD in boys between 8 to 13 years who were taking corticosteroids. One trial compared blood flow in 10 boys with DMD to healthy boys of the same age. The results confirmed that taking corticosteroids did not restore normal blood flow in boys with DMD. In a follow up study, boys with DMD received one alternating daily dose of both sildenafil and tadalafil two weeks apart. Following a handgrip exercise and a resting period, blood flow measurements were assessed. The results indicated that after taking sildenafil and tadalafil, blood flow in boys with DMD was similar to blood flow in healthy boys, even after exercise. The researchers also reported that higher doses of the drugs produced greater benefits in boys with DMD. Although these results are encouraging, additional studies are required to confirm the safety and efficacy of sildenafil and tadalafil for treating boys with DMD. The authors note, “this proof-of-concept study does not address the crucial issue question of whether restoring normal blood flow regulation will preserve dystrophic skeletal muscle and slow disease progression.” The investigators add that promising preclinical studies and results recently reported in the journal Neurology support moving forward with a larger clinical trial designed to determine if daily tadalafil preserves muscle function in boys with DMD. [1] http://mda.org/disease/duchenne-muscular-dystrophy/signs-and-symptoms [2] Nelson, M., Rader, F., Tang, X., et al. Neurology. 2014;82:2085-2091.

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