Medical experts launch crowd funding project to investigate effect of malaria drug on colorectal cancer

In continuation of my update on Artesunate

Medical experts investigating whether a common malaria drug could have a significant impact on colorectal cancer have launched a crowd funding project to fund their work.

Scientists at St George's, University of London, and St George's Hospital, are in the second phase of research into whether the malaria drug artesunate, can have a positive effect on colorectal cancer patients by reducing the multiplication of tumour cells and decreasing the risk of cancer spreading or recurring after surgery. If it does the drug could be used to provide a cheap adjunct to current expensive chemotherapy.

Artesunate is derived from the plant Artemisia Annua also known as Sweet Wormwood. The Chinese scientist Tu Youyou whose research in the 1960s led to the development of artesunate from a plant used in Chinese traditional medicine, was recently awarded the Nobel Prize 2015.

Over one million patients are diagnosed with colorectal cancer globally each year. Colorectal cancer is the third most common cancer in men and the second most common cancer in women and is a leading cause of mortality. In the UK,110 new cases are diagnosed daily, with older patients particularly at risk of death (Ferlay et al 2014). Current treatments involve complex combinations of surgery, chemotherapy and radiotherapy.

Unfortunately all these measures have not increased overall survival rates beyond 60% at the 5 year stage after patients receive a diagnosis. New treatments are urgently needed to improve survival rates. Developing new, effective drugs however can take many years and sometimes even decades. Repurposing safe and established existing drugs for cancer treatment is therefore gaining interest amongst the scientific community.

Medical experts launch crowd funding project to investigate effect of malaria drug on colorectal cancer

Research: Epigenetic factor reduces sensitivity of breast cancer cells to common cancer drug

, 

In continuation of my update on lapatinib

A surprising, paradoxical relationship between a tumor suppressor molecule and an oncogene may be the key to explaining and working around how breast cancer tumor cells become desensitized to a common cancer drug, found researchers at the Perelman School of Medicine at the University of Pennsylvania. The drug, lapatinib, activates the suppressor called FOXO, in HER2+ breast cancer cells, but then FOXO becomes a turncoat molecule, working with an epigenetic regulator that controls gene expression. This drug-triggered relationship induces the expression of the oncogene c-Myc, leading to reduced sensitivity to the cancer drug and eventually relapse. They published their cover article today in Cancer Cell.

"We found that an epigenetic pathway is crucial for growth of HER2+ cells and this epigenetic factor reduces sensitivity of the cancer cells to lapatinib, a HER2 inhibitor," said senior author Xianxin Hua, MD, PhD, a professor of Cancer Biology. "We need to understand how the body initially responds to these drugs and why there is a relapse and devise a new tool to fix that."

Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. The HER2 pathway is mutated in many cancers, which drives tumors, but inhibitors of this pathway, such as lapatinib, have only limited success because cancer cells quickly adapt.

FOXO was normally thought of as the "good guy" molecule that controls cancerous cell growth, while c-Myc, the cancer-promoting molecule, the "bad guy." However, FOXO becomes the agent that desensitizes cells to cancer drugs, so this "good guy" molecule is converted to a "bad guy," during the treatment of the cancer cells with the anti-cancer drug.

"Now that we know about this triangle among FOXO, c-Myc, and the epigenetic pathway, we can stop c-Myc with an epigenetic inhibitor," Hua said. "Multiple epigenetic regulators participate in the drug-desensitizing pathway, so they could serve as new targets to improve therapy for this type of cancer."

Research: Epigenetic factor reduces sensitivity of breast cancer cells to common cancer drug

Investigational antiviral drug effectively treats Lassa virus infection in guinea pigs

We know that, Favipiravir, also known as T-705 or Avigan, is an experimental antiviral drug being developed by Toyama Chemical of Japan with activity against many RNA viruses. Like some other experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative. Favipiravir is active against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses.[1Activity against enteroviruses and Rift Valley fever virus has also been demonstrated.

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[4] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.[1]

In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics

Favipiravir, an investigational antiviral drug currently being tested in West Africa as a treatment for Ebola virus disease, effectively treated Lassa virus infection in guinea pigs, according to a new study from National Institutes of Health (NIH) scientists and colleagues. Lassa fever is endemic to West Africa and affects about 300,000 people annually, killing roughly 5,000. In some parts of Sierra Leone and Liberia, it is believed nearly 15 percent of people admitted to hospitals have Lassa fever, according to the Centers for Disease Control and Prevention. No vaccine or licensed treatment exists for Lassa fever, although ribavirin, licensed for hepatitis C treatment, has been used with limited success. In the new study, published Oct. 12, 2015, in Scientific Reports, favipiravir not only effectively treated guinea pigs infected with Lassa virus, it also worked better than ribavirin.

Two days after infecting groups of guinea pigs with a lethal dose of Lassa virus, the scientists treated the rodents daily for two weeks with either ribavirin, low doses of favipiravir, or high doses of favipiravir. They also evaluated the effect of high-dose favipiravir in the rodents that began treatment five, seven or nine days after infection. All of the animals that received high-dose favipiravir were completely protected from lethal infection; animals treated seven or nine days after infection had begun showing signs of disease, but their conditions quickly improved when treatment began. Those animals in the low-dose favipiravir group showed mild to moderate signs of disease, but those symptoms resolved after about one week of treatment. The animals treated with ribavirin appeared normal during the treatment phase but developed severe disease shortly after treatment ended.

Investigational antiviral drug effectively treats Lassa virus infection in guinea pigs

CU Cancer Center study reports 'robust antitumor activity' of TAK-733 drug in mouse models of colorectal cancer

In continuation of my update on TAK-733

A University of Colorado Cancer Center study recently published online ahead of print in the journal Oncotarget reports "robust antitumor activity" of the drug TAK-733 in cells and mouse models of colorectal cancer. In all, 42 of 54 tested cell lines were sensitive to the drug, as were 15 of 20 tumors grown on mice from patient samples. Nine of these patient-derived tumors showed regression, meaning that tumor tumors shrank in response to the drug.

"This was a large preclinical study that showed good activity for the drug and gave preliminary evidence for a potential biomarker that could predict which tumors would respond best to the drug," says Christopher Lieu, MD, investigator at the CU Cancer Center and assistant professor of medical oncology at the University of Colorado School of Medicine.

Specifically, the drug intercedes in the MAPK signaling pathway, a cascade of cellular communication that controls cell growth and survival and is frequently altered in many cancers (especially including melanoma, non-small cell lung cancer, and colorectal cancer). The drug does this by silencing an essential link in this signaling chain, namely the molecule MEK. Without activity of the MEK kinase, MAPK signaling cannot occur and instead of surviving and proliferating, cancer cells dependent on this pathway die.

A handful of successful MEK kinase inhibitors exist, including trametinib and selumetinib.

"The preclinical results for TAK-733 were fairly impressive. We had high hopes that TAK-733 could be a next-generation MEK inhibitor that might support or replace the use of current drugs," Lieu says.

The study seemed a perfect precursor to a human clinical trial of TAK-733 in colorectal cancer.

CU Cancer Center study reports 'robust antitumor activity' of TAK-733 drug in mouse models of colorectal cancer

Sense oligonucleotide antidote reverses actions of antisense antithrombotic drug, prevents bleeding

Researchers from Isis Pharmaceuticals (Carlsbad, CA) and Prysis Biotechnologies (Pudong, Shanghai, China) have demonstrated proof-of-concept for using a sense oligonucleotide to undo the effects of an antisense drug, an antithrombotic agent in this novel study. The sense oligonucleotide antidote reversed the actions of the antisense antithrombotic drug in the mouse model and prevented the bleeding that commonly occurs with anti-coagulation therapy, as described in an article in Nucleic Acid Therapeutics, a peer-reviewed journal from Mary Ann Liebert, Inc. publishers. The article is available free on the Nucleic Acid Therapeutics website until November 13, 2015.

Jeff Crosby, Chenguang Zhao, Hong Zhang, A. Robert MacLeod, Shuling Guo, and Brett Monia treated mice with an antisense oligonucleotide drug designed to suppress the ability of liver and blood cells to produce prothrombin, a protein required for blood to coagulate. Subsequent treatment with a prothrombin sense oligonucleotide antidote led to a dose-dependent reversal of the antisense drug activity and the return of prothrombin to normal levels. The authors describe the study design and the implications of their findings in the article "Reversing Antisense Oligonucleotide Activity with a Sense Oligonucleotide Antidote: Proof of Concept Targeting Prothrombin."

"An elegant demonstration of the feasibility of reversing the effects of an antisense oligonucleotide in vivo by administering an antidote oligonucleotide," says Executive Editor Graham C. Parker, PhD, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI. "It will be fascinating to now see how the chemistry can be optimized to achieve translation to clinical efficacy."

Sense oligonucleotide antidote reverses actions of antisense antithrombotic drug,
prevents bleeding

Sense oligonucleotide antidote reverses actions of antisense antithrombotic drug, prevents bleeding

Tamoxifen drug clears MRSA, reduces mortality

In continuation of my update on Tamoxifen

Researchers at University of California, San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences have found that the breast cancer drug tamoxifen gives white blood cells a boost, better enabling them to respond to, ensnare and kill bacteria in laboratory experiments. Tamoxifen treatment in mice also enhances clearance of the antibiotic-resistant bacterial pathogen MRSA and reduces mortality.

The study is published October 13 by Nature Communications.

"The threat of multidrug-resistant bacterial pathogens is growing, yet the pipeline of new antibiotics is drying up. We need to open the medicine cabinet and take a closer look at the potential infection-fighting properties of other drugs that we already know are safe for patients," said senior author Victor Nizet, MD, professor of pediatrics and pharmacy. "Through this approach, we discovered that tamoxifen has pharmacological properties that could aid the immune system in cases where a patient is immunocompromised or where traditional antibiotics have otherwise failed."

Tamoxifen targets the estrogen receptor, making it particularly effective against breast cancers that display the molecule abundantly. But some evidence suggests that tamoxifen has other cellular effects that contribute to its effectiveness, too. For example, tamoxifen influences the way cells produce fatty molecules, known as sphingolipids, independent of the estrogen receptor. Sphingolipids, and especially one in particular, ceramide, play a role in regulating the activities of white blood cells known as neutrophils.

"Tamoxifen's effect on ceramides led us to wonder if, when it is administered in patients, the drug would also affect neutrophil behavior," said first author Ross Corriden, PhD, project scientist in the UC San Diego School of Medicine Department of Pharmacology.

To test their theory, the researchers incubated human neutrophils with tamoxifen. Compared to untreated neutrophils, they found that tamoxifen-treated neutrophils were better at moving toward and phagocytosing, or engulfing, bacteria. Tamoxifen-treated neutrophils also produced approximately three-fold more neutrophil extracellular traps (NETs), a mesh of DNA, antimicrobial peptides, enzymes and other proteins that neutrophils spew out to ensnare and kill pathogens. Treating neutrophils with other molecules that target the estrogen receptor had no effect, suggesting that tamoxifen enhances NET production in a way unrelated to the estrogen receptor. Further studies linked the tamoxifen effect to its ability to influence neutrophil ceramide levels.

Ref : http://www.nature.com/ncomms/2015/151013/ncomms9369/full/ncomms9369.html

Tamoxifen drug clears MRSA, reduces mortality

FDA approves Endo’s BELBUCA (buprenorphine) buccal film for use in patients with chronic pain

New treatment option combines proven efficacy and established safety profile of buprenorphine with a novel delivery system that adds convenience and flexibility.

Endo Pharmaceuticals Inc., a subsidiary of Endo International plc (NASDAQ: ENDP) (TSX: ENL), and BioDelivery Sciences International, Inc. (NASDAQ: BDSI), announced today that the U.S. Food and Drug Administration (FDA) has approved BELBUCA™ (buprenorphine) buccal film for use in patients with chronic pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.  BELBUCA™, which is the first and only buprenorphine developed with a dissolving film that is absorbed through the inner lining of the cheek for chronic pain management, is expected to be commercially available in the U.S. during the first quarter of 2016 in seven dosage strengths, allowing for flexible dosing ranging from 75 μg to 900 μg every 12 hours. This enables physicians to individualize titration and treatment based on the optimally effective and tolerable dose for each patient.

“The availability of new, convenient and flexible treatment options is important for patients whose lives are burdened by chronic pain, a debilitating condition that affects more Americans than diabetes, heart disease and cancer combined,” said Richard L. Rauck, M.D., Director of Carolinas Pain Institute, Winston Salem, NC. “BELBUCA™ provides a unique approach for chronic pain management, combining the proven efficacy and established safety of buprenorphine with a novel buccal film delivery system that adds convenience and flexibility. For both opioid-naïve and opioid-experienced patients who require around-the-clock treatment and for whom alternative treatment options are inadequate, BELBUCA™ offers appropriate, consistent pain relief and a low incidence of typical opioid-like side effects.”

BELBUCA™ is a mu-opioid receptor partial agonist and a potent analgesic with a long duration of action that utilizes BDSI’s patented BioErodible MucoAdhesive (BEMA®) drug delivery technology. Through this unique delivery system, buprenorphine is efficiently and conveniently delivered across the buccal mucosa (inside lining of the cheek). Buprenorphine is a Schedule III controlled substance, meaning that it has been defined as having lower abuse potential than Schedule II drugs, a category that includes most opioid analgesics. Among chronic pain patients taking opioids, the vast majority are on daily doses of 160 mg of oral morphine sulfate equivalent (MSE) or less. With seven dosage strengths up to 160 mg MSE, BELBUCA™ offers a treatment choice for a wide range of opioid needs in chronic pain sufferers.

FDA approves Endo’s BELBUCA (buprenorphine) buccal film for use in patients with chronic pain

Last resort antibiotics may no longer work

Last resort antibiotics may no longer work

Antiviral agent protects rhesus monkeys from deadly Ebola virus

Rhesus monkeys were completely protected from the deadly Ebola virus when treated three days after infection with a compound that blocks the virus's ability to replicate. These encouraging preclinical results suggest the compound, known as GS-5734, should be further developed as a potential treatment, according to research findings to be presented tomorrow at the IDWeek conference.

Travis Warren, Ph.D., a principal investigator at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), said the work is a result of the continuing collaboration between USAMRIID and Gilead Sciences of Foster City, Calif. Scientists at the Centers for Disease Control and Prevention (CDC) also contributed by performing initial screening of the Gilead Sciences compound library to find molecules with promising antiviral activity.

The initial work identified the precursor to GS-5734, a small-molecule antiviral agent, which led to the effort by Gilead and USAMRIID to further refine, develop and evaluate the compound. Led by USAMRIID Science Director Sina Bavari, Ph.D., the research team used cell culture and animal models to assess the compound's efficacy against several pathogens, including Ebola virus.

In animal studies, treatment initiated on day 3 post-infection with Ebola virus resulted in 100 percent survival of the monkeys. They also exhibited a substantial reduction in viral load and a marked decrease in the physical signs of disease, including internal bleeding and tissue damage.

"The compound, which is a novel nucleotide analog prodrug, works by blocking the viral RNA replication process," said Warren. "If the virus can't make copies of itself, the body's immune system has time to take over and fight off the infection."

In cell culture studies, GS-5734 was active against a broad spectrum of viral pathogens. These included Lassa virus, Middle East Respiratory Syndrome (MERS) virus, Marburg virus, and multiple variants of Ebola virus, including the Makona strain causing the most recent outbreak in West Africa.

Ref : https://idsa.confex.com/idsa/2015/webprogram/Paper54208.html

Antiviral agent protects rhesus monkeys from deadly Ebola virus

YK-4-279 compound works against some forms of leukemia: Study

A compound discovered and developed by a team of Georgetown Lombardi Comprehensive Cancer Center researchers that halts cancer in animals with Ewing sarcoma and prostate cancer appears to work against some forms of leukemia, too. That finding and the team's latest work was published online Oct. 8 in Oncotarget. 

The compound is YK-4-279, the first drug targeted at similar chromosomal translocations found in Ewing sarcoma, prostate cancer and in some forms of leukemia. Translocations occur when two normal genes break off from a chromosome and fuse together in a new location. This fusion produces new genes that manufacture proteins, which then push cancer cells to become more aggressive and spread. One of those proteins is EWS-FLI1. YK-4-279 appears effective in controlling the cancer promoting functions of EWS-FLI1.

"EWS-FLI1 is already known to drive a rare but deadly bone cancer called Ewing sarcoma, which occurs predominantly in children, teens and young adults," says Aykut Üren, MD, professor of molecular oncology at Georgetown Lombardi. "It also appears to drive cancer cell growth in some prostate cancers."

In this new study led by Üren, mice with EWS-FLI1-driven leukemia were given injections of YK-4-279 five days per week for two weeks and compared with untreated mice. By the end of the first week the mice receiving YK-4-279 had much lower numbers of leukemia cells. At the end of two weeks the treated mice were nearly normal by many measures, while the untreated mice had overwhelming numbers of cancer cells and died on average after three weeks, the researchers say. By contrast, mice receiving only two weeks of YK-4-279 lived nearly three times as long.

"The fact that treated mice did not get sick from the YK-4-279 gives us an early indication that it might be safe to use in humans, but that is a question that can't be answered until we conduct clinical trials," Üren explains. "We are looking for ways that would allow us to administer more of it, or even to formulate a pill."

Üren says much more work remains for the team in order to translate this drug from a laboratory application into clinical trials.

Support for this work came from the Children's Cancer Foundation, St. Baldrick's Foundation, Go4theGoal, the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, the Austrian Science Fund (FWF), the Children´s Cancer Research Institute and from grants from the National Institutes of Health (RC4CA156509, R01CA133662, R01CA138212).

YK-4-279 compound works against some forms of leukemia: Study