Drug used to prevent and treat malaria may also be effective for Zika virus

In continuation of my update on chloroquine

A new collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC San Diego School of Medicine has found that a medication used to prevent and treat malaria may also be effective for Zika virus. The drug, called chloroquine, has a long history of safe use during pregnancy, and is relatively inexpensive. The research was published today in Scientific Reports.

Zika virus remains a major global health risk. In most adults, Zika causes mild flu-like symptoms. But in pregnant women, the virus can cause serious birth defects in babies--including microcephaly--a neurological condition in which newborns have unusually small heads and fail to develop properly. There is no treatment or way to reverse the condition.

"There is still an urgent need to bolster our preparedness and capacity to respond to the next Zika outbreak," says Alexey Terskikh, Ph.D., associate professor at SBP. "Our latest research suggests the anti-malaria drug chloroquine may be an effective drug to treat and prevent Zika infections."

Terskikh is co-senior author of a new study that examined the effect of chloroquine in human brain organoids and pregnant mice infected with the virus, and found the drug markedly reduced the amount of Zika virus in maternal blood and neural progenitor cells in the fetal brain. Pregnant mice received chloroquine through drinking water in dosages equivalent to acceptable levels used in humans.

"Our research is the first to study Zika infection in a mouse model that transmits the virus in a way similar to humans," explains Alysson R. Muotri, Ph.D., professor and director of the Stem Cell Program at UC San Diego and co-senior author of the study. "Until now, researchers used a mouse strain that is deficient in interferon--a signaling protein that heightens anti-viral defenses. Those mice actually die from Zika infection, making it difficult to study the natural transmission of the virus from father and mother to fetus and to assess the effect of this transmission on the newborns.

"We believe our mouse model more accurately represents the way Zika virus infects men, women, and babies while in the womb," adds Terskikh. "Although chloroquine didn't completely clear Zika from infected mice it did reduce the viral load, suggesting it could limit the neurological damage found in newborns infected by the virus."

"In the 1950's, the Brazilian health agencies added chloroquine into cooking salt and distributed it to the population in endemic areas as an effective way of spreading the inexpensive anti-malarial drug as a prophylactic on a wide scale. This strategy was known as Pinotti's Method, named after its originator Dr. Mario Pinotti. It might be worth considering this medicated salt program one more time in Brazil", suggests Muotri.

"Chloroquine has a long history of successfully treating malaria, and there are no reports of it causing birth defects," says Terskikh. "Additional studies are certainly needed to determine the precise details of how it works. But given its low cost, availability and safety history further study in a clinical trial to test its effectiveness against Zika virus in humans is merited."

Ref : http://www.newswise.com/articles/view/685239/

Drug used to prevent and treat malaria may also be effective for Zika virus

Dr. Reddy’s Announces Approval of Impoyz (clobetasol propionate) Cream for Plaque Psoriasis

Dr. Reddy’s Laboratories Ltd. through its wholly owned subsidiary Promius Pharma, LLC, announced its fifth consecutive, first-cycle NDA approval for the Proprietary Products Group, a substantial milestone within the pharmaceutical industry.

Impoyz (clobetasol propionate) Cream, 0.025% is a high potency topical steroid approved for the treatment of moderate to severe plaque psoriasis in patients 18 years of age or older. The most common side effect of Impoyz Cream includes discoloration of the treated site. Psoriasis is a serious medical condition affecting approximately 7.5 million people in the United States. Impoyz, formerly referred to as DFD-06, had been recently licensed to Encore Dermatology Inc. for the commercialization of the product in the United States.

This approval is another example of the deep and broad capabilities within the Proprietary Products business unit at Dr. Reddy’s. The organization has achieved several milestones within drug, device, and formulation research and development for novel therapies.

“The fifth consecutive first cycle NDA approval represents Dr. Reddy’s long-term commitment to building an organization that delivers innovative medical solutions,” said Anil Namboodiripad, PhD, Senior Vice President, Proprietary Products and President, Promius Pharma. “We are looking forward to working with our partner, Encore Dermatology, to bring this novel treatment to providers and their patients.”

“Encore is excited about adding another great product to our portfolio and looking forward to the opportunity to commercialize a new product for the treatment of mild to moderate psoriasis as well as broadening our portfolio outside of atopic dermatitis and acne,” said Robert Moccia, CEO, Encore Dermatology, Inc.

Dr. Reddy’s Announces Approval of Impoyz (clobetasol propionate) Cream for Plaque Psoriasis

Trial shows apple allergen as effective treatment option for birch pollen-related apple allergy

In continuation of my update on Osimertinib

Osimertinib improves progression-free survival compared to standard first line therapy in Asian patients with EGFR-mutated non-small-cell lung cancer (NSCLC), according to the Asian subset analysis of the FLAURA trial presented at the ESMO Asia 2017 Congress, sumultaneously published in The New England Journal of Medicine.

EGFR mutations occur in 30-40% of NSCLC in Asian populations compared to 10-15% in Western populations. The phase III FLAURA trial compared osimertinib, a third generation EGFR-tyrosine kinase inhibitor (TKI), to standard of care EGFR-TKIs (erlotinib or gefitinib) as first line therapy in NSCLC patients with EGFR mutations. A total of 556 patients from Asia, Europe, and North America were randomized 1:1 to treatment with osimertinib or standard of care. Osimertinib improved progression-free survival by 54%.

This subset analysis included the 322 Asian patients in the FLAURA trial, of whom 46 were Chinese, 120 were Japanese, and 156 were from other parts of Asia.

The median progression-free survival was 16.5 months with osimertinib compared to 11.0 months for the standard therapy, with a hazard ratio of 0.54 (95% confidence interval, 0.41-0.72; p<0.0001).

The median duration of response was two-fold higher for patients treated with osimertinib (17.6 months) compared to standard of care (8.7 months). The overall response rate was 80% with osimertinib compared to 75% with standard of care treatment. Median overall survival was not reached. The incidence of grade 3 or higher toxicities was lower for osimertinib (40%) than the standard treatment (48%).

Lead author Professor Byoung Chul Cho, Yonsei Cancer Center, Seoul, Korea, said: "As in the overall trial population, osimertinib provided a significant progression-free survival benefit in Asian patients with EGFR-mutated NSCLC. Asian patients had similar toxicities with osimertinib as the overall FLAURA population. Osimertinib should be the preferred first line treatment for EGFR-mutant NSCLC in Asia."

Commenting on the findings Professor James CH Yang, Chairman, Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan, said: "The results of this subset analysis are quite compatible with the findings in the overall population presented at the ESMO 2017 Congress in Madrid. We can therefore conclude that osimertinib can be considered as the standard of care for the first line treatment of Asian advanced NSCLC patients with EGFR mutations."

"The proportion of patients having adverse events that caused them to stop taking osimertinib was similar in the overall (13%) and Asian (15%) populations," added Yang. "We tend to think osimertinib is a well tolerated drug so these discontinuation rates were surprisingly high and need further investigation."

Yang continued: "Although there was no statistical difference between the hazard ratios for progression-free survival, it was numerically lower in non-Asians (0.34) compared to Asians (0.54). There is an ongoing debate as to whether Asian and non-Asian patients with EGFR mutations have distinct responses to EGFR-TKIs. This might be due to variations in clinical practice rather than biology. A meta-analysis of all relevant studies could shed light on this issue."

"It will also be important to know whether Asian and non-Asian patients in the FLAURA trial with brain metastases had similar outcomes," said Yang.

Trial shows apple allergen as effective treatment option for birch pollen-related apple allergy

Soy foods, cruciferous vegetables may reduce breast cancer treatment’s side effects

In continuation of my update on soy milk

Consuming soy foods (such as soy milk, tofu and edamame) and cruciferous vegetables (such as cabbages, kale, collard greens, bok choy, Brussels sprouts, and broccoli) may be associated with a reduction in common side effects of breast cancer treatment in breast cancer survivors, say a team of scientists led by Georgetown Lombardi Comprehensive Cancer Center.

In the study, published in Breast Cancer Research and Treatment, higher intake of cruciferous vegetables and soy foods were associated with fewer reports of menopausal symptoms. Higher soy intake was also associated with less reported fatigue. The breast cancer survivors studied included 173 non-Hispanic white and 192 Chinese Americans including US-born Chinese and Chinese immigrants.

Researchers say breast cancer survivors often experience side effects from cancer treatments that can persist months or years after completion of treatment. For example, because many treatments designed to prevent breast cancer recurrence inhibit the body's production or use of estrogen, the hormone that can fuel breast cancer growth, breast cancer patients often experience hot flashes and night sweats, among other side effects.

The lead author on the study, Sarah Oppeneer Nomura, PhD, of Georgetown Lombardi, said that while further research is needed in larger study populations and with more detailed dietary data, this project addresses an important gap in research on the possible role of lifestyle factors, such as dietary habits, in relation to side effects of treatments.

"These symptoms can adversely impact survivors' quality of life and can lead them to stopping ongoing treatments, she says. "Understanding the role of life style factors is important because diet can serve as a modifiable target for possibly reducing symptoms among breast cancer survivors."

When study participants were evaluated separately by race/ethnicity, associations were significant among white breast cancer survivors; however; while a trend was seen in the benefit for Chinese women, results were not statically significant. Researchers explain Chinese women typically report fewer menopausal symptoms. Most of them also consume cruciferous vegetables and soy foods, making it difficult to see a significant effect in this subgroup. Indeed, in this study, Chinese breast cancer survivors ate more than twice as much soy and cruciferous vegetables.

Whether the reduction in symptoms accounts for longtime use of soy and cruciferous vegetables needs further investigation, says the study's senior author, Judy Huei-yu Wang, PhD, of Georgetown Lombardi's Cancer Prevention and Control Program.

Results obtained in preclinical studies in animals show that biologically active compounds present in both soy and cruciferous vegetables cause breast cancer cells to grow, but have opposite effects in animals that consume these compounds well before cancer is diagnosed and continue consuming them during and after cancer treatments.

Until more research is conducted, breast cancer patients should not suddenly start eating soy, if they have not consumed it before, says Leena Hilakivi-Clarke, PhD, a professor of oncology at Georgetown Lombardi and a co-author of the study.

Researchers also found suggestive associations with lower reporting of other symptoms, including joint problems, hair thinning/loss and memory less in women who consumed more soy foods, but these associations did not reach statistical significance.

Phytochemicals, or bioactive food components, such as isoflavones in soy foods and glucosinolates in cruciferous vegetables may be the source of the benefit, researchers say. Isoflavones bind to estrogen receptors and exert weak estrogenic effects, among other effects. Glucosinolates in cruciferous vegetables influence levels of metabolizing enzymes that can modulate inflammation and levels of estrogen, possibly attenuating treatment-related symptoms.

Soy foods, cruciferous vegetables may reduce breast cancer treatment’s side effects

Novel compound along with checkpoint inhibitors may enhance immune response in melanoma patients

A novel compound may restore immune response in patients with melanoma, according to a study presented at the ESMO Immuno Oncology Congress 2017.

"Checkpoint inhibitors are a standard of care immunotherapy for metastatic melanoma," said lead author Dr Sapna Patel, Assistant Professor, Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, US. "However, many patients do not respond because myeloid derived suppressor cells (MDSCs), a type of inhibitory cell, are present in the tumor microenvironment."

"In animal studies, omaveloxolone inhibited MDSCs and restored immune activity," she continued. "Myeloid-derived suppressor cells (MDSCs) produce reactive nitrogen radicals that alter the receptors on the surface of the tumor to hide it from cytotoxic lymphocytes that kill tumor cells. Omaveloxolone inhibits MDSC activity, suppresses reactive nitrogen radicals, and restores anti-tumor immune responses. Administering omaveloxolone with checkpoint inhibitors may improve the antitumor response of these immunotherapies."

This open label, multicenter, phase 1B trial investigated the safety and efficacy of omaveloxolone in combination with the checkpoint inhibitors ipilimumab or nivolumab. The study included 30 patients with unresectable or metastatic melanoma, of whom seven were naïve to checkpoint inhibitors and 23 had prior checkpoint inhibitor treatment.

The overall response rate was 57% in checkpoint inhibitor naïve patients and 17% in those with prior exposure. Median time to response was 19 weeks. There were no serious adverse events related to omaveloxolone and it was well tolerated in combination with ipilimumab or nivolumab.

Dr Patel said: "Our findings suggest that omaveloxolone may overcome resistance to checkpoint inhibitors. Omaveloxolone in combination with checkpoint blockade had activity in both naïve and checkpoint inhibitor refractory melanoma patients."

She added: "This is one of the first studies to demonstrate a meaningful response rate in the checkpoint inhibitor refractory melanoma population. Further dose escalation and dose expansion studies are underway as well as translational tissue-based experiments to clarify the impact of this treatment combination."

Commenting on the study for ESMO, Dr Olivier Michielin, head of Personalised Analytical Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland, said: "Omaveloxolone's novel mechanism of action is to block MDSCs, cells known to suppress the immune response. This study tested a new combination therapy in immuno oncology and found encouraging response rates with omaveloxolone plus ipilimumab or nivolumab in patients who were checkpoint inhibitor naïve or resistant. The combination was well tolerated and may address some of the immune escape mechanisms that limit the activity of current checkpoint blockade therapies."

Michielin added: "More data is needed before we can make a final call on whether there is a place, and where would the place be, for this combination in the current treatment portfolio. The next step should be a randomized trial to investigate whether omaveloxolone provides additional benefit when combined with the checkpoint blockade backbone, for example, comparing the efficacy of PD-1 blockade alone versus PD-1 blockade plus omaveloxolone."

Novel compound along with checkpoint inhibitors may enhance immune response in melanoma patients

Drug improves disease-free, overall survival after hematopoietic stem cell transplants

In continuation of my update on Abatacept (Orencia)

Results from a phase 2 clinical trial, presented by Seattle Children's Research Institute at the 59th American Society of Hematology (ASH) Annual Meeting, show that the drug Abatacept (Orencia) nearly eliminated life-threatening severe acute graft-versus-host disease (GvHD) in patients receiving hematopoietic stem cell transplants.

Abatacept, when added to the standard drug regimen used to prevent GvHD, reduced the occurrence of acute, grade III-IV GvHD from 32 to 3 percent in pediatric and adult patients who underwent mismatched unrelated donor stem cell transplants to treat advanced cancer and other blood disorders. As a result, patients receiving the post-transplant regimen with abatacept experienced improved disease-free and overall survival compared to those who did not.

Acute GvHD is the most deadly complication that can arise after stem cell transplantation. Graft-versus-host disease occurs when the donated T cells, white blood cells in the immune system that fight infection, launch a vigorous attack on a patient's organs, including the skin, liver, kidneys, lung, and the gastrointestinal tract. For patients receiving cells from an unrelated donor, the rate of mild-to-severe forms of acute GvHD can reach as high as 80 percent, with up to half of patients dying from the most severe forms.

"Given the serious threat of graft-versus-host disease, new approaches to make stem cell transplants safer for patients remain a critical unmet need," said Dr. Leslie Kean, the trial's principal investigator and associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children's. "To see such striking results in patients at extremely high risk for graft-versus-disease is incredibly encouraging."

Kean first became interested in using abatacept to prevent GvHD based on the immunotherapy drug's success in treating patients with rheumatoid arthritis. In rheumatoid arthritis, abatacept inhibits T-cell activation and prevents the chain of events that lead to debilitating joint inflammation.

Similarly, feasibility studies conducted by Kean found that abatacept blocks the activation of certain T cells after transplant. In their models, abatacept reduced the proliferation and activation of effector T cells. Effector T cells incite GvHD when they become overactive as the patient's immune system starts to rebuild itself from the donor stem cells.

"Preventing graft-versus-host disease and relapse after transplant requires a difficult balance of eliminating the bad, overactive effector T cells, without suppressing the good, regulatory T cells," said Kean, who is also an associate professor of pediatrics at the University of Washington School of Medicine and a member of the Fred Hutchinson Cancer Research Center. "As we make improvements to our toolbox of agents capable of achieving this Holy Grail of stem cell transplant, it's essential to include targeted approaches like abatacept."

The multicenter data presented included two patients cohorts who were enrolled across 18 sites. In the cohort of patients who received transplants from mismatched unrelated donors, all 43 patients received four doses of abatacept with a calcineurin inhibitor and methotrexate. To serve as the control, researchers looked at data from a national database of matched patients receiving two commonly used regimens to prevent GvHD - a calcineurin inhibitor and methotrexate (CNI/MTX) or a calcineurin inhibitor and methotrexate plus anti-thymocyte globulin (+ATG).

At 100 days post-transplant, the cumulative incidence of grade III-IV acute GvHD occurred in 3 percent of patients receiving abatacept compared to 32 percent receiving CNI/MTX and 22 percent receiving +ATG. Patients receiving abatacept had intact immune reconstitution, significant improvement in transplantation-related mortality, no major uncontrolled infection and no increase in disease relapse. Significant survival advantages for the abatacept group were demonstrated at one year post-transplant. Overall survival improved to 85 percent (vs. 57 percent in CNI/MTX and 68 percent in +ATG controls); 79 percent of patients experienced disease-free survival (vs. 50 percent in CNI/MTX and 63 percent in +ATG controls).

The second cohort of 140 patients with human leukocyte antigen-matched unrelated donor transplants completed enrollment in November 2017, with data expected from this randomized double-blind arm of the study in the next six months.

"As a transplant physician, it's beyond heartbreaking to witness a patient develop severe acute graft-versus-host disease after having their leukemia cured through bone marrow transplant," said Kean. "To have a therapy at our disposal that safely targets just the T cells causing graft-versus-host disease would represent a major step forward in stem cell transplantation. It not only offers new hope that we can prevent graft-versus-host disease upfront, but that we can also significantly improve outcomes for patients requiring high-risk transplants."

Drug improves disease-free, overall survival after hematopoietic stem cell transplants

Ortho Dermatologics Announces U.S. FDA Filing Acceptance For IDP-118, Novel Plaque Psoriasis Treatment

Ortho Dermatologics, a division of Valeant Pharmaceuticals International, Inc. (NYSE: VRX and TSX: VRX), today announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for IDP-118 (halobetasol propionate and tazarotene) lotion, an investigational topical treatment for plaque psoriasis. The PDUFA action date is June 18, 2018.

tazarotene 

If approved, IDP-118 will be the first and only topical lotion that contains a unique combination of halobetasol propionate and tazarotene in one formulation for the treatment of plaque psoriasis in adult patients, allowing for a potentially expanded duration of use.

The most common adverse events were contact dermatitis (7.4%) and application site pain (2.6%)...

Ortho Dermatologics Announces U.S. FDA Filing Acceptance For IDP-118, Novel Plaque Psoriasis Treatment

New small-molecule drug restores brain function, memory in mouse model of Alzheimer's disease

In continuation of my update  on canola oil

An international team of researchers has shown that a new small-molecule drug can restore brain function and memory in a mouse model of Alzheimer's disease. The drug works by stopping toxic ion flow in the brain that is known to trigger nerve cell death. Scientists envision that this drug could be used to treat Alzheimer's and other neurodegenerative diseases such as Parkinson's and ALS.

"This is the first drug molecule that can regulate memory loss by directly blocking ions from leaking through nerve cell membranes," said Ratnesh Lal, a professor of bioengineering at the University of California San Diego and co-senior author of the study.

Various studies have linked Alzheimer's disease to the accumulation of two particular proteins in the brain called amyloid-beta and tau. One theory is that these protein clusters create pores in nerve cell membranes that allow ions to travel in and out uncontrollably. This would alter ion levels inside the cells and in turn trigger neuronal dysfunction and cell death.

The new drug, a small molecule called anle138b, blocks these pores from moving ions in and out of nerve cells. Anle138b attaches to both amyloid-beta and tau protein clusters and deactivates the pores created by these clusters.

Researchers administered anle138b to mice with a genetic predisposition for developing an Alzheimer's-like condition. The mice had symptoms such as abnormal brain function, impaired memory and high levels of either amyloid-beta or tau proteins in the brain. Treatment with anle138b normalized brain activity and improved learning ability in mice.

The study was led by the German Center for Neurodegenerative Diseases, the University Medical Center Göttingen, the Braunschweig University of Technology, the Max Planck Institute for Biophysical Chemistry, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain in Göttingen, Germany, and the University of California San Diego. Researchers published their findings on Dec. 5 in EMBO Molecular Medicine.

Christian Griesinger, a professor at the Max Planck Institute for Biophysical Chemistry and co-senior author of the study, noted, "The drug is able to reach the brain when taken orally. Therefore, it is easy to administer, and we are currently performing toxicology studies to eventually be able to apply anle138b to humans."

The team cautions that since the drug has so far only been tested in mice, it is unclear how well it would perform in humans. "I would like to emphasize that none of the current animal models fully recapitulate the symptoms seen in Alzheimer's patients. Thus, care has to be taken when interpreting such data. However, our study offers evidence that anle138b has potential for neuroprotection," said André Fischer, a senior researcher at the German Center for Neurodegenerative Diseases and the University Medical Center Göttingen, who is also a co-senior author of the study.

While collaborators in Germany will be pursuing clinical studies in human patients with neurodegenerative diseases, Lal and his research group at the UC San Diego Jacobs School of Engineering are particularly interested in testing anle138b on a variety of other diseases that are linked to toxic ion flow caused by amyloid proteins, including diabetes, tuberculosis and certain types of cancer. Lal's group has performed extensive research on amyloid ion channels and their roles in these diseases. "Blocking the ion leakiness of amyloid channels using anle138b could be an effective therapy for various diseases," Lal said.

Lal serves as co-director for the Center of Excellence for Nanomedicine and Engineering, a subcenter of the Institute of Engineering in Medicine at UC San Diego. His research group will also work on targeted delivery of the drug using their patent pending "nanobowls," which are magnetically guided nanoparticles that can be packed with drugs and diagnostic molecules, deliver them to particular sites in the body and release them on demand. Future studies will focus on using these nanobowls to deliver anle138b to the brain, as well as other diseased tissues and organs affected by toxic amyloid-beta ion channels.

http://ucsdnews.ucsd.edu/pressrelease/experimental_drug_block_toxic_ion_flow_linked_to_alzheimers_disease

New small-molecule drug restores brain function, memory in mouse model of Alzheimer's disease

Avion Pharmaceuticals Announces FDA Approval of Balcoltra (levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets) Oral Contraceptive

 

Avion Pharmaceuticals, LLC, the makers of the Prenate® line of prescription prenatal vitamins, received approval of its new drug application (NDA) for the oral contraceptive Balcoltra (levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets), the company's first internally developed NDA. Avion expects to commercially launch this new oral contraceptive to the prescribing community in Spring 2018.

The approval of Balcoltra, the only branded oral contraceptive combining 0.1 mg levonorgestrel, 20 mcg ethinyl estradiol tablets and ferrous bisglycinate tablets 36.5 mg, marks a milestone for Avion Pharmaceuticals and a win for the women's health category by allowing women to have access to a clinically effective form of oral contraception for pregnancy prevention.

"Avion is excited to offer our women's health community this oral contraceptive formulation that fills a gap in the current branded options available to women," stated Art Deas, CEO of Avion. "The validity of data related to safety and efficacy for Balcoltra also provides another viable prescribing option for our prescribing community," added Deas.

"Avion has always focused on creating a meaningful and long-term supporting role for our women's healthcare prescribers," added Avion President Mike Sullivan. "The Balcoltra™ approval and forthcoming launch is a monumental event for Avion, allowing us to solidify our commitment to the women's healthcare community."

Ref :





Avion Pharmaceuticals Announces FDA Approval of Balcoltra (levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets) Oral Contraceptive

New molecule demonstrates ability to block lymphoma growth

The prestigious scientific journal Clinical Cancer Research has published a study conducted by the research group led by Dr. Francesco Bertoni of the Institute of Oncology Research (IOR, affiliated to USI Università della Svizzera italiana), that have tested a new molecule that demonstrates its ability to inhibit lymphoma growth.

Lymphomas are tumors that originate from blood cells, more specifically from lymphatic tissue. There are numerous types of lymphomas and each have different characteristics, aggressiveness, evolution and prognosis. In most cases, the standard treatments include irradiation and chemotherapy, two therapies that can have important side effects. Innovative biological approaches and the discovery of new biological molecules are changing the therapeutic approach and increasing the chances of healing.

Cancer cells are able to elude physiological control and grow in uncontrolled manner. In fact, groups of "pro-tumor" proteins can get activated and no longer respond to the normal intracellular "anti-tumor" control mechanisms. Among the "pro-tumor" proteins, the network including the signal molecules "PI3K/AKT/mTOR" is well known to sustain the survival and proliferation of cancer cells. Importantly, the PI3K/AKT/mTOR signaling axis is active in lymphomas and blocking could represent a good strategy to fight lymphoma cells.

The IOR research group led by Dr. Francesco Bertoni (who is also Vice-president of the SSAK Swiss Group for Clinical Cancer Research Project Group Lymphoma) with in particular Chiara Tarantelli and Eugenio Gaudio, has focused on the possibility to inhibit the PI3K/AKT/mTOR signaling with PQR309 (bimiralisib) in the lymphoma cells. PQR309 is a new molecule produced by a Swiss company that directly blocks multiple proteins driving the PI3K/AKT/mTOR signaling and has shown the ability to block the growth of lymphoma cells.

A drug (idelalisib) that acts by blocking only one specific type of protein in the "PI3K" family (PI3K delta) is already approved for clinical use, but many patients do not respond to this treatment. However, in the laboratory, PQR309 shows that it has anti-tumor activity even in lymphoma models that do not respond to idelalisib. PQR309 seems to act even better when combined with other novel anti-tumoral drugs. Furthermore, the mechanism of action of the drug PQR309 has been investigated and compared to that of other signaling inhibitors, obtaining results with implications in the design of novel treatment schemes for patients with lymphoma.

The results of this study, together with the ongoing clinical studies with PQR309, can lead to better treatments for people affected with lymphoma and to better understanding of the mechanisms of action of anti-lymphoma agents. Lymphomas are among the 10 most common cancers in adults and the third most frequent neoplasia in children and adolescents. Despite the great advancements made in their treatment, European statistics show that around 5 people per 100.000 still succumb to lymphoma every year.

Ref: https://www.usi.ch/en/feeds/6604

New molecule demonstrates ability to block lymphoma growth

New cancer drug begins clinical trial in human patients with rare brain tumor

A drug that spurs cancer cells to self-destruct has been cleared for use in a clinical trial of patients with anaplastic astrocytoma, a rare malignant brain tumor, and glioblastoma multiforme, an aggressive late-stage cancer of the brain. This phase Ib trial will determine if the experimental drug PAC-1 can be used safely in combination with a standard brain-cancer chemotherapy drug, temozolomide.

The trial is approved for patients who have seen their cancer progress after first-line therapy. This is an extension of an ongoing human phase I clinical trial of PAC-1 alone in patients with various late-stage cancers. Phase I trials are designed to test the safety of new drugs in human patients.

PAC-1 is unusual in that it is able to cross the blood-brain barrier, a formidable obstacle to most anti-cancer drugs. The drug targets procaspase-3, an enzyme that is overexpressed in many cancer cells, said University of Illinois chemistry professor Paul Hergenrother, who discovered PAC-1's anti-cancer effects more than a decade ago. After tests in human cell lines and rodents proved promising, Hergenrother and veterinary oncologist Dr. Timothy Fan, a professor of veterinary clinical medicine at Illinois, tested PAC-1 in pet dogs with a variety of naturally occurring cancers.

"Most cancers have elevated levels of procaspase-3," Hergenrother said. "When it is turned on, procaspase-3 kills cells."

Cancer cells override this normal cell-recycling pathway, however, he said.

"PAC-1 restores the activation of procaspase-3 and, because this enzyme is elevated in cancer cells, targets cancer cells over noncancerous cells," he said.

PAC-1 has been evaluated in pet dogs with naturally occurring osteosarcoma, lymphoma and, most recently, glioma - a brain cancer similar to glioblastoma in humans. One 2016 study found that the combination of PAC-1 with doxorubicin, a chemotherapeutic agent that also is used in humans, saw tumor reductions in four of four dogs with lymphoma and in three of six dogs with osteosarcoma. The trials in dogs continue and, so far, have found PAC-1 to be safe, with few observable side effects apart from occasional gastrointestinal distress. The researchers report their latest findings in rodents and in dogs with brain cancer in the journal Oncotarget.

Dogs with certain naturally occurring cancers may be better than other animal models of human cancers because mice and rats used in many cancer drug-testing models must be implanted with human cancer cells to mimic specific types of tumors, Fan said.

"This requires that the rodents be immunocompromised to mitigate rejection of human cells," he said. "As such, most rodent tumor models do not faithfully recapitulate the tumor microenvironment - in particular, the body's immune surveillance of the tumor.

"Rodent models are limited, but they are still useful," Fan said.

Certain cancers in dogs are genetically similar to those in humans and respond to the same medications. Dogs also are more similar in size to humans, and so can be better models to evaluate how well drug agents perform on larger tumor masses.

"I look at pets with spontaneous tumors as being complementary to rodent models and recognize that not all discoveries in pet dogs will necessarily translate similarly to people," Fan said.

The ongoing clinical trial of PAC-1 in human patients with late-stage solid tumors and lymphoma has shown that the drug is well-tolerated at tested doses up to 450 milligrams per day, said medical oncologist Dr. Arkadiusz Dudek, who chairs an advisory board for Vanquish Oncology, which is funding the clinical trials.

The extension of the phase I trial to brain-cancer patients will begin with a PAC-1 dose of 375 mg per day and will increase the dose incrementally to test its safety in combination with the standard brain-cancer chemotherapy agent, temozolomide, he said.

So far, the clinical trials of PAC-1 alone have seen no significant side effects in humans. None of the human patients in the first five dose levels of the single-agent trial has dropped out as a result of side effects, the researchers report. The team cannot report on clinical outcomes in a phase I clinical trial, since such trials are designed to measure safety, not efficacy.

Surgery is a first-line therapy for anaplastic astrocytoma, followed by treatment with temozolomide, a chemotherapy drug that is one of the few effective treatments for brain cancer, Dudek said. Humans with glioblastoma multiforme usually undergo surgery to remove as much of the cancerous tissue as possible, followed by radiation and oral treatment with temozolomide.

It is almost impossible to find and remove all glioblastoma cancer cells in surgery, however, Dudek said.

"Glioblastoma multiforme has this feature of spreading silently along the blood vessels inside the brain," he said. "That's a reason why most patients will unfortunately have disease coming back later on after surgery and radiation."

The median survival time for human patients with glioblastoma undergoing the standard treatment is about 15 months.

The three dogs in the glioma trial received daily oral doses of PAC-1 in combination with temozolomide and "curative-intent" radiation.

Temozolomide is normally too expensive to use in canine patients, Fan said. The dogs tolerated the combination treatment very well and responded well to the therapy, he said.

"All three dogs had, at the very least, what we call a partial response, which means more than a 30 percent reduction in the tumor," he said. "And one of the dogs had a complete response, as identified with serial MRI scans, with a 100 percent reduction in the tumor mass 84 days after combination therapy."

Fan said a much larger study in dogs would be needed to determine whether the therapeutic effects were consistent and reproducible, and to quantify how much PAC-1 contributed to the positive results.

Vanquish Oncology, a drug-development startup company Hergenrother helped found in 2011, has licensed the technology from the University of Illinois and is focused on moving PAC-1 into the clinic. As with any investigational agent, determining the true safety and efficacy profile of PAC-1 will take several years of human clinical trials.

https://news.illinois.edu/blog/view/6367/583399

New cancer drug begins clinical trial in human patients with rare brain tumor

Garlic compound can combat robust bacteria in patients with chronic infections

An active sulphurous compound found in garlic can be used to fight robust bacteria in patients with chronic infections, a new study from the University of Copenhagen indicates. Here the researchers show that the garlic compound is able to destroy important components in the bacteria's communication systems, which involve regulatory RNA molecules.

'We really believe this method can lead to treatment of patients, who otherwise have poor prospects. Because chronic infections like cystic fibrosis can be very robust. But now we, together with a private company, have enough knowledge to further develop the garlic drug and test it on patients', says Assistant Professor Tim Holm Jakobsen from the Costerton Biofilm Center at the Department of Immunology and Microbiology.

The study is the latest addition from a research group headed by Professor Michael Givskov, which since 2005 has focussed on garlic's effect on bacteria. At the time they learned that garlic extract is able to inhibit bacteria, and in 2012 they showed that the sulphurous compound ajoene found in garlic is responsible for the effect. The new study, which has been published in the scientific journal Scientific Reports, takes an even closer look and documents ajoene's ability to inhibit small regulatory RNA molecules in two types of bacteria.

'The two types of bacteria we have studied are very important. They are called Staphylococcus aureus and Pseudomonas aeruginosa. They actually belong to two very different bacteria families and are normally fought using different methods. But the garlic compound is able to fight both at once and therefore may prove an effective drug when used together with antibiotics', says Tim Holm Jakobsen.

Previous studies have shown that garlic appears to offer the most powerful, naturally occurring resistance to bacteria. In addition to inhibiting the bacteria's RNA molecules, the active garlic compound also damages the protective slimy matrix surrounding the bacteria, the so-called biofilm. When the biofilm is destroyed or weakened, both antibiotics and the body's own immune system are able to attack the bacteria more directly and thus remove the infection.

In 2012 the researchers took out a patent on the use of ajoene to fight bacterial infections. Now the company Neem Biotech has bought the licence to use the patent. Their medical product, NX-AS-401, which aims to treat patients with cystic fibrosis, has now obtained a so-called 'orphan drug designation'. This means that clinical trials on patients will be conducted soon.

If the clinical trials show good results, the drug can be marketed as the first in a series of antimicrobial connections with brand new modes of action developed by Givskov's research team.

Ref : http://healthsciences.ku.dk/news/2017/11/garlic/

Garlic compound can combat robust bacteria in patients with chronic infections

Vanillin could prevent or reduce psoriatic skin inflammation

Small amounts of artificial vanilla extract, also known as vanillin, are in a wide range of products, from baked goods to perfumes. But vanillin's versatility doesn't stop there. In a recent mouse study reported in ACS' Journal of Agricultural and Food Chemistry, researchers report that this compound could also prevent or reduce psoriatic skin inflammation.

Psoriasis is an inflammatory skin disorder that affects about 125 million people worldwide, resulting in scaly red plaques that typically show up on the elbows, knees or scalp. Immune system proteins called interleukins (IL) 17 and 23 are known to be key players in the development of the condition. Interestingly, vanillin can have effects on different interleukins that are involved in other inflammatory conditions and diseases. So, Chien-Yun Hsiang and Tin-Yun Ho wanted to see if treatment with vanillin could prevent psoriatic symptoms.

The researchers induced psoriatic skin inflammation on groups of mice by putting a compound called imiquimod on their skin. In addition, the mice were orally given daily doses (0, 1, 5, 10, 50 or 100 milligrams/kilograms of body weight) of vanillin for seven days. Mice treated with 50- or 100-milligram/kilograms of body weight doses had reduced psoriatic symptoms compared to those receiving smaller or no doses of vanillin. In all mice treated with vanillin, IL-17 and IL-23 protein levels were decreased. The researchers say that vanillin was an effective compound against psoriatic skin inflammation in this animal model.

Vanillin could prevent or reduce psoriatic skin inflammation

Immune-boosting drug combination may hold promise for treating ovarian cancer

Johns Hopkins Kimmel Cancer Center researchers demonstrated that mice with ovarian cancer that received drugs to reactivate dormant genes along with other drugs that activate the immune system had a greater reduction of tumor burden and significantly longer survival than those that received any of the drugs alone.

The study already spurred a clinical trial in ovarian cancer patients. The investigators, led by graduate student Meredith Stone, Ph.D.; postdoctoral fellow Kate Chiappinelli, Ph.D.; and senior author Cynthia Zahnow, Ph.D., believe it could lead to a new way to attack ovarian cancer by strengthening the body's natural immune response against these tumors. It was published in the Dec. 4, 2017, issue of the Proceedings of the National Academy of Sciences.

Ovarian cancer is currently the leading cause of death from gynecological malignancies in the U.S. "We've taken two types of therapies that aren't very effective in ovarian cancer and put them together to make them better at revving up the immune system and attacking the tumor," says Zahnow, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Zahnow says that a class of immunotherapy drugs known as checkpoint inhibitors, currently being studied at the Bloomberg~Kimmel Institute for Cancer Immunotherapy, helps the immune system recognize cancers and fight them off. The drugs have shown success in treating melanoma, nonsmall cell lung cancer and renal cell cancers, but they have had only modest effects on ovarian cancer.

Similarly, another class of drugs known as epigenetic therapies has been used to treat some types of cancer by turning on genes that have been silenced-- either by the presence of chemical tags, known as methyl groups, or by being wound too tightly around protein spools, known as histones--but these drugs haven't been effective against ovarian cancer either.

Zahnow and her colleagues became inspired to investigate a new way to treat ovarian cancer by two recent publications from their group that showed epigenetic drugs turn on immune signaling in ovarian, breast and colon cancer cells (Li et al., Oncotarget 2014). These immune genes are activated when epigenetic therapy turns on segments of ancient retroviruses that activate type 1 interferon signaling in the cells (Chiappinelli et al., Cell 2015). Stone, Chiappinelli and Zahnow wanted to know if this increase in immune signaling could lead to the recruitment of tumor killing immune cells to the cancer.

Zahnow and her colleagues worked with a mouse model of the disease in which mouse ovarian cancer cells are injected into the animals' abdomens to mimic human disease. These cells eventually develop into hundreds of small tumors, which cause fluid to collect within the abdomen, a condition known as ascites. Floating in this fluid is a milieu of both cancer and immune cells, offering a convenient way to keep tabs on both the tumor and the animals' immune response.

The researchers started by pretreating the ovarian cancer cells outside of the animal in a culture dish with a DNA methyltransferase inhibitor (a drug that knocks methyl groups from DNA) called 5-azacytidine (AZA). After injecting these cells into mice, the researchers found that animals receiving the pretreated cells had significantly decreased ascites or tumor burden and significantly more cancer-fighting immune cells in the ascites fluid compared to those injected with untreated cells. These cells also had increased activity in a variety of genes related to immune response. Pretreating these cells with histone deacetylase inhibitors (HDACis), which help DNA uncoil from histones, didn't affect the animals' ascites or boost their immune response.

These early findings suggested that changes in gene activity induced by AZA cause the tumor cells themselves to summon immune cells to their location. In addition, when the researchers transplanted untreated cells into mice and treated the animals with both AZA and an HDACi, significantly more immune cells were in the ascites fluid, suggesting that the HDACi was acting on the animals' immune systems. These mice also had decreased ascites, lower tumor burden and longer survival than mice that received just AZA.

When the researchers treated the mice with both AZA and an HDACi, along with an immune checkpoint inhibitor, they got the greatest response--the highest decreases in ascites and tumor burden, and the longest survival. Further experiments using immunocompromised mice showed that the immune system is pivotal to the action of these drugs, rather than the drugs themselves acting directly to kill tumor cells.

"We think that AZA and the HDACis are bringing the soldiers, or immune cells, to the battle. But the checkpoint inhibitor is giving them the weapons to fight," says Zahnow, who also collaborated with epigenetics scientist Stephen Baylin, M.D., on this project.

The preclinical data generated through this study is already being used to help patients with ovarian cancer through an ongoing clinical trial to test the effectiveness of combining AZA and a checkpoint inhibitor. Future trials may add an HDACi to determine if it affects outcomes.

"Combining epigenetic therapy and a checkpoint blocker leads to the greatest reduction in tumor burden and increase in survival in our mouse model and may hold the greatest promise for our patients," says Zahnow.

Ref : https://www.hopkinsmedicine.org/news/media/releases/combination_strategy_could_hold_promise_for_ovarian_cancer

Immune-boosting drug combination may hold promise for treating ovarian cancer

FDA Approves Kaléo’s Auvi-Q (Epinephrine Injection, USP) 0.1 mg Auto-Injector for Life-Threatening Allergic Reactions in Infants and Small Children

In continuation of my update on epinephrine

Kaléo, a privately-held pharmaceutical company,  announced that the U.S. Food and Drug Administration (FDA) has approved its supplemental New Drug Application (sNDA) for Auvi-Q (epinephrine injection, USP) 0.1 mg, the first and only epinephrine auto-injector (EAI) specifically designed for the treatment of life-threatening allergic reactions, including anaphylaxis, in infants and small children weighing 16.5 to 33 pounds (7.5 to 15 kilograms) who are at risk for or have a history of serious allergic reactions.

The sNDA for the Auvi-Q 0.1 mg Auto-injector was granted Priority Review by the FDA, an expedited regulatory pathway reserved for products that may provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to available therapies.

Auvi-Q is a compact epinephrine auto-injector with industry-first features, including a voice prompt system that guides a user with step-by-step instructions through the delivery process, and a needle that automatically retracts following administration. The new 0.1 mg-dose epinephrine auto-injector has a shorter needle length and lower dose of epinephrine than current FDA approved 0.15 mg and 0.3 mg epinephrine auto-injectors.

Children are increasingly being treated for anaphylaxis. There was a 129.8 percent increase in emergency room visits for anaphylaxis among children four years old and younger between 2005 and 2014.[i] According to a study published in Allergy, Asthma & Clinical Immunology, 43 percent of children weighing 16.5 pounds (7.5 kilograms) to 33 pounds (15 kilograms) treated with a 0.15 mg EAI having a standard 12.7 mm needle length are at risk of having the needle strike the bone, therefore potentially impacting the administration of epinephrine during a life-threatening emergency.[ii] The needle length in Auvi-Q 0.1 mg was specifically designed for use with infants and small children to help mitigate this safety concern.

“Today’s decision by the FDA to approve the Auvi-Q 0.1 mg Auto-injector is exciting for all of us in the life-threatening allergy community who have been working for many years to fulfill this unmet medical need,” said Spencer Williamson, President and CEO of kaléo. “As a company that focuses on patients first, and providing potentially life-saving treatments, we are particularly glad we will be able to help caregivers by providing an EAI that was specifically designed with an appropriate dose and needle length for infants and children (16.5 to 33 pounds) in order to maximize the potential for a safe administration of epinephrine.”

“The approval of Auvi-Q 0.1 mg will help achieve our goal of working to fulfill unmet medical needs,” said Eric S. Edwards, MD, PhD, Vice President of Innovation and Research & Development at kaléo. “We developed the Auvi-Q 0.1 mg EAI to deliver a dose of epinephrine appropriate to infants and small children weighing 16.5 – 33 pounds, with a shorter needle length to help mitigate the risk of striking bone which could potentially cause injury or interfere with the delivery of epinephrine.”

Only Auvi-Q 0.1 mg has a dose and needle length designed specifically for treating anaphylaxis in infants and small children weighing 16.5 – 33 pounds. Auvi-Q 0.1 mg includes the innovative AUVI-Q electronic voice instruction system as well as visual cues to help guide users step-by-step through the administration.

“The approval of an epinephrine auto-injector specifically designed for infants and small children is timely, especially given the recent changes to guidelines recommending that certain high-risk infants, as young as four to six months old, be introduced to peanut-containing foods,” said Eleanor Garrow-Holding[1], President and CEO of the Food Allergy & Anaphylaxis Connection Team (FAACT). “We are pleased that the pediatric allergy healthcare community and parents of infants and small children with life-threatening allergies will have the ability to obtain an FDA-approved epinephrine auto-injector in the event of an allergic emergency. We look forward to the availability of Auvi-Q 0.1 mg.”

“Until now, healthcare practitioners and caregivers to infants and small children have not had an epinephrine auto-injector with an appropriate dose of epinephrine available to them, potentially causing some delay in the administration of epinephrine in a life-threatening allergic emergency,” said Dr. Vivian Hernandez-Trujillo[1], a pediatric allergist, and fellow of the American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; and American Academy of Pediatrics specializing in the management of life-threatening allergies and anaphylaxis. “Having an epinephrine auto-injector with a needle length and dose specifically designed for infants and small children should help alleviate concerns around hitting the bone or injecting too much epinephrine.”

Identical twin brothers, Evan and Eric Edwards, the inventors of Auvi-Q, know what it is like to live with life-threatening allergies, both as patients and parents of food-allergic children. Their goal was to develop an epinephrine auto-injector that contained innovative features, such as a voice instruction system that helps guide patients and caregivers step-by-step through the injection process. Evan and Eric Edwards believe and trust in Auvi-Q, not only for themselves, but also for their children and other families who may have to depend on it to administer epinephrine during an allergic emergency.

FDA Approves Kaléo’s Auvi-Q (Epinephrine Injection, USP) 0.1 mg Auto-Injector for Life-Threatening Allergic Reactions in Infants and Small Children