Tag Archives: #drug

New Benefits from Anti-Diabetic Drug Metformin (Medicine)

Metformin inhibits disease progression in non-diabetic chronic kidney disease (ND-CKD)

Researchers from Kumamoto University (Japan) have found that the anti-diabetic drug metformin significantly prolongs the survival of mice in a model that simulates the pathology of non-diabetic chronic kidney disease (ND-CKD) by ameliorating pathological conditions like reduced kidney function, glomerular damage, inflammation and fibrosis. Metformin’s mechanism is different from existing therapeutics which only treat symptoms, such as the blood pressure drug losartan, so the researchers believe that a combination of these medications at low dose will be highly beneficial.

CKD (chronic kidney disease) is a general term for kidney damage that results from persistent decline in kidney function due to proteinuria, kidney inflammation, or fibrosis. As CKD progresses, patients are forced to undergo dialysis, and diabetes is one of its biggest risk factors. CKD can also occur in association with lifestyle-related conditions such as hypertension, insufficient exercise, smoking, hyperuricemia, and mutations in kidney-related genes. This type of CKD is classified as non-diabetic chronic kidney disease (ND-CKD) and has limited treatment options.

Alport syndrome is an inherited kidney disease that falls under the ND-CKD umbrella. In Alport syndrome, abnormalities in type 4 collagen, a constituent of the membrane responsible for urine filtration in the kidney, cause abnormal glomerular filtration which results in chronic loss of kidney function. It is a serious disease that eventually progresses to end-stage renal failure, requiring dialysis or kidney transplant. As with diabetic kidney disease and ND-CKD, Alport syndrome is currently treated by maintaining kidney function using blood pressure-lowering drugs but patients eventually transition to end-stage renal failure. Therefore, a new therapeutic agent that is effective and safe enough to be administered to patients for a long period of time is needed.

Metformin, unlike losartan, also targets amelioration of metabolic abnormalities. © Professor Hirofumi Kai

Metformin is used as a treatment for type 2 diabetes because it improves insulin sensitivity. It is an inexpensive and safe drug that has been used by diabetics for many years. Interestingly, because of its mechanism of action, metformin was also known to be protective against many diseases involving inflammation and fibrosis, and was known to improve the renal pathology of diabetic kidney disease. However, it was unclear whether metformin also had a protective effect on ND-CKD, which is not caused by diabetes.

Researchers selected an Alport syndrome mouse model for their ND-CKD experiments and worked to identify novel therapeutic targets based on pathogenic mechanisms. They focused on drugs traditionally used for CKD patients, metformin and losartan—which works by lowering blood pressure and inhibiting proteinuria caused by increased glomerular filtration.

Administration of metformin or losartan to ND-CKD model mice significantly suppressed proteinuria and serum creatinine, which are indicators of CKD. Inflammation and fibrosis, which also reduce kidney function, significantly improved. Furthermore, metformin was found to have a nephroprotective effect similar to losartan.

Left: Administration of metformin or losartan to model mice significantly prolonged survival.
Right: Combined administration of low dose metformin and losartan significantly prolonged the survival of mice at doses where metformin alone does not show any effect. © Professor Hirofumi Kai

The results of a detailed gene expression analysis found that the renal pathology of the ND-CKD mouse model was caused by abnormal expression of genes related to glomerular epithelial cell podocytes (cells responsible for kidney filtering) and genes involved in intracellular metabolism. Interestingly, the improvement caused by losartan was limited to genes involved in podocyte abnormalities. Metformin, on the other hand, improved the expression of genes related to podocyte abnormalities and those related to intracellular metabolism. In other words, metformin clearly has a different target of action (also improved targeting of metabolic abnormalities) from that of losartan.

Finally, they found that administration of low-dose metformin and losartan to model mice significantly prolonged their survival. Researchers also found that in studies using doses at which metformin alone was not effective, the combination of metformin and losartan significantly prolonged mice survival. Put plainly, this study showed that an appropriate combination of the two therapeutic drugs could effectively treat the ND-CKD (Alport syndrome) mouse model.

This study raises the possibility that metformin, a proven and inexpensive diabetic drug, may delay the progression of kidney pathology in ND-CKD, including Alport syndrome. Metformin is currently available for use in patients with diabetes in clinical practice, but not in non-diabetic patients.

“This study appears to show that metformin has therapeutic effects for both diabetic and non-diabetic kidney disease,” said Professor Hirofumi Kai, who led the research project. “However, metformin is contraindicated in patients with severe renal dysfunction (eGFR < 30) due to the development of lactic acidosis as a side effect and should be administered with caution to patients with mild to moderate renal dysfunction.”

This research found that the appropriate combination of metformin and losartan significantly improved renal pathology and prolonged survival in a ND-CKD mouse model. This suggests that the old inexpensive drug metformin could become a new inexpensive drug for patients with chronic kidney disease.

This research was posted online in “Scientific Reports” on 29 March 2021.


Source:
Omachi, K., Kaseda, S., Yokota, T., Kamura, M., Teramoto, K., Kuwazuru, J., … Kai, H. (2021). Metformin ameliorates the severity of experimental Alport syndrome. Scientific Reports, 11(1). doi:10.1038/s41598-021-86109-1

[Publication URL]
https://www.nature.com/articles/s41598-021-86109-1

[Funds]
1) KAKENHI Grants from MEXT Japan, 2) The Alport Syndrome Research Funding Program of the
Alport Syndrome Foundation, 3) the Pedersen family, Kidney Foundation of Canada, 4) a grant from
the National Institutes of Health

Featured image: Low dose metformin was found to have a nephroprotective effect similar to losartan. © Professor Hirofumi Kai


Provided by Kumamoto University

A Drug That Can Stop Tumors From Growing (Medicine)

CU Cancer Center research shows inhibiting NLRP3 can reduce inflammation in melanoma cells.

Cancer doctors may soon have a new tool for treating melanoma and other types of cancer, thanks to work being done by researchers at the University of Colorado Cancer Center.

In a paper published in the journal PNAS last month, CU Cancer Center members Mayumi Fujita, MD, PhD, Angelo D’Alessandro, PhD, Morkos Henen, PhD, MS, Beat Vogeli, PhD, Eric Pietras, PhD, James DeGregori, PhD, Charles Dinarello, MD, and Carlo Marchetti, PhD, along with Isak Tengesdal, MS, a graduate student in the Division of Infectious Diseases at the University of Colorado School of Medicine, detail their work on NLRP3, an intracellular complex that has been found to participate in melanoma-mediated inflammation, leading to tumor growth and progression. By inhibiting NLRP3, the researchers found, they can reduce inflammation and the resultant tumor expansion.

Carlo Marchetti
Carlo Marchetti, PhD © Anschutz

Specifically, NLRP3 promotes inflammation by inducing the maturation and release of interleukin-1-beta, a cytokine that causes inflammation as part of the normal immune response to infection. In cancer, however, inflammation can cause tumors to grow and spread.

“NLRP3 is a member of a larger family that is involved in sensing danger signals,” Marchetti says. “It is a receptor that surveils the intercellular compartment of a cell, looking for danger molecules or pathogens. When NLRP3 recognizes these signals, it leads to the activation of caspase-1, a protein involved in the processing and maturation of interleukin-1-beta into its biological active form, causing an intense inflammatory response. We found that in melanoma, this process is dysregulated, resulting in tumor growth.”

Making checkpoint inhibitors more effective

The oral NLRP3 inhibitor used in their study (Dapansutrile) has already shown to be effective in clinical trials to treat gout and heart disease, and it is currently being tested in COVID-19 as well. The CU cancer researchers are now trying to find out if this NLRP3 inhibitor can be successfully used in melanoma patients who are resistant to checkpoint inhibitors.

“Checkpoint inhibitors increase the efficacy of the immune system to kill tumors, but sometimes tumors become resistant to this treatment,” Marchetti says. “A big part of cancer research now is to find therapies that can be combined with checkpoint inhibitors to improve their efficacy.”

The importance of inflammation

With the hypothesis that an NLRP3 inhibitor is one of those therapies, CU Cancer Center researchers are studying the drug’s effects on melanoma, as well as breast cancer and pancreatic cancer. In addition to improving the immune response, the NLRP3 inhibitor can also help reduce the side effects of checkpoint inhibitors. Marchetti says this research can make a big difference for melanoma patients who don’t respond to checkpoint inhibitors alone.

“This was a very collaborative project that involved a lot of members of the university, and we are very excited about it,” he says. This project is important because it further shows that NLRP3-mediated inflammation plays a critical role in the progression of melanoma, and it opens new strategies to improve patient care.”


Reference: Isak W. Tengesdal, Dinoop R. Menon, Douglas G. Osborne, Charles P. Neff, Nicholas E. Powers, Fabia Gamboni, Adolfo G. Mauro, Angelo D’Alessandro, Davide Stefanoni, Morkos A. Henen, Taylor S. Mills, Dennis M. De Graaf, Tania Azam, Beat Vogeli, Brent E. Palmer, Eric M. Pietras, James DeGregori, Aik-Choon Tan, Leo A. B. Joosten, Mayumi Fujita, Charles A. Dinarello, Carlo Marchetti, “Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion”, Proceedings of the National Academy of Sciences Mar 2021, 118 (10) e2000915118; DOI: 10.1073/pnas.2000915118


Provided by Anschutz

Protein Based Biomarker Identifies the Chemo Drug Sensitivity (Medicine)

Cancer is the world’s second deadliest disease which contributes towards the fatality of over 10 million people per year. Oncologists adopt a variety of treatment procedures to treat cancer cells. Among the different methods used to fight cancer, chemotherapeutic treatment is a prominent and well-adopted technique. It is a drug based method, wherein powerful chemical compounds are injected into the body to annihilate the malignant cells. Although these chemicals support the destruction of the cancerous cells, optimizing their dosage has always been a challenge to the medical specialists.

Cisplatin is a chemotherapy medication which is used to treat a number of cancers such as lung cancer, brain tumor, breast cancer, liver cancer etc. This platinum-metal based chemotherapy drug is highly powerful and is instituted by the intravenous route into the body. Although it is renowned for effective destruction of cancerous cells for the past 4 decades, its alarming side effects is of serious concern to the medical community. Researchers have reported that administration of high dosage of the chemical is not only ineffective on the tumor cells but is also responsible for adverse side effects which may even lead to the sudden demise of the patient. control on the level of the cisplatin drug has been a matter of persisting concern for medical practitioners.  A recent study on monitoring the cisplatin level in liver cancer cells reported by researchers from the Graduate School of Medical and Dental Sciences at Niigata University and their collaborators from Niigata Medical Center, Uonuma Institute of Community Medicine Niigata University Hospital, Niigata City General Hospital, Saiseikai Niigata Hospital and, Kashiwazaki General Hospital and Medical Center provides a ray of hope to the health professionals. The findings were published recently in the prestigious Scientific Reports journal from Nature publishing house. The multi-disciplinary research team has identified adipose most abundant 2 protein (APM2) as a potential marker to indicate the permissible level of the drug. They have experimentally investigated the liver and gastro cancer cells and have compared the variation in the protein concentration in the presence and absence of the chemo drug.

Over expression of APM2 induce resistance to cisplatin © Nigata University

“Our results demonstrate a significant relationship between the high level of APM2 expression in serum, cancerous cells in the liver, the surrounding liver tissue and cisplatin resistance. The study reveals that APM2 expression is related to cisplatin sensitivity” explains Professor Kenya Kamimura of the Division of Gastroenterology and Hepatology, the Graduate School of Medical and Dental Sciences, Niigata University. The research study paves way for effective monitoring of chemotherapeutic drug level and their safe administration. Professor Kenya Kamimura states with confidence that, “The serum APM2 can be an effective biomarker of the liver and gastric cancer cells for determining the sensitivity to cisplatin.  The results of the study would provide an advantage for the technicians, allowing easy adaption in small local clinics.”

The research group has noticed that APM2 concentration favours the development of ERCC6L gene card. This is manifested by the growth of the cancerous cells and marks the resistance to the chemo drug.  The valuable findings offers the potential to control the cisplatin dosage level and avoid cytotoxicity. Such a study is essential in today’s context as research groups across the globe strive to develop new methodologies to optimize the dosage and control the severe side-effects induced by the concentration of chemo drugs. The research team has also utilized bioinformatics based tools to complement the experimentally obtained results.

Serum APM2 concentration could estimate the cisplatin sensitivity of the liver cancer © Nigata University

“To the best of our knowledge, this is the first report to demonstrate that the serum level of APM2 can be the predictor of the CDDP chemosensitivity. This study thus represents a milestone for detecting CDDP sensitivity, and further studies will help modify APM2 expression, which could contribute to the chemosensitization of the tumor” describes Professor Kenya Kamimura.

The interesting results of the research study has laid a foundation to track the chemo drug level. Future studies will explore the mechanism and relation between APM2 and ERCC6L. Such studies are on the cutting edge research areas of oncological sciences and hold immense potential in further extending the results to other types of cancers.

The research in the authors’ laboratories has been supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Sciences 20390205, 25670370, and 23659395 to Takeshi Suda and Yutaka Aoyagi; 17K09408 to Kenya Kamimura; and grant provided from the Ichiro Kanehara Foundation.

Featured image: APM2 overexpression increases ERCC6L expression © Nigata University


Publication Details

Journal: Scientific Reports
Title: Adipose Most Abundant 2 Protein is a Predictive Marker for Cisplatin Sensitivity in Cancers
Authors: Kenya Kamimura, Takeshi Suda, Yasuo Fukuhara, Shujiro Okuda, Yu Watanabe, Takeshi Yokoo, Akihiko Osaki, Nobuo Waguri, Toru Ishikawa, Toshihiro Sato, Yutaka Aoyagi, Masaaki Takamura, Toshifumi Wakai & Shuji Terai
DOI: 10.1038/s41598-021-85498-7


Provided by Nigata University

Researchers Take Early Step Toward Leukemia Drug Therapy (Medicine)

Focus on adult AML has revealed encouraging results

A McMaster stem cell research team has made an important early step in developing a new class of therapeutics for patients with a deadly blood cancer.

The team has discovered that for acute myeloid leukemia (AML) patients, there is a dopamine receptor pathway that becomes abnormally activated in the cancer stem cells. This inspired the clinical investigation of a dopamine receptor-inhibiting drug thioridazine as a new therapy for patients, and their focus on adult AML has revealed encouraging results.

AML is a particularly deadly cancer that starts with a DNA mutation in the blood stem cells of the bone marrow that produce too many infection-fighting white blood cells. According to the Canadian Cancer Society about 21% of people diagnosed with AML will survive at least five years.

“We have successfully understood the mechanism by which the drug benefited patients, and we are using this information to develop a new, more tolerable formulation of the drug that is likely to work in some of the patients,” said senior author of the paper Mick Bhatia, a professor of biochemistry and biomedical sciences at McMaster. He also holds the Canada Research Chair in Human Stem Cell Biology.

The phase one study of 13 patients is being featured on the cover of the journal Cell Reports Medicine published today.

Bhatia said the team has continued to carefully analyze and further refine their therapeutic approach and results of the initial trial.

“Together, these achievements highlight the importance of the new paradigm of that issues impacting patients can be taken to the lab bench and solutions back to patients. These “bed to bench, and back to bed” approaches and partnerships to advance novel therapeutics Canadians suffering from cancer,” he added.

The study was supported, in part, by the Canadian Cancer Society.

The paper is available at https://bit.ly/3jS4Xtr

Featured image: Mick Bhatia, a professor of biochemistry and biomedical sciences at McMaster © McMaster University


Reference: Lili Aslostovar, Allison L. Boyd et al., “Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients”, Cell Reports Medicine, 2(2), 2021. https://doi.org/10.1016/j.xcrm.2021.100202


Provided by McMaster University

Drug Developed by Georgia State Researcher Is Promising Against Pancreatic and Breast Cancers (Medicine)

ProAgio, a drug developed by Georgia State University biology professor Zhi-Ren Liu and his team, is effective at treating pancreatic cancer and prolonging survival in mice, according to a study published in the journal Cellular and Molecular Gastroenterology and Hepatology.

A second study, published in the Journal of Experimental Medicine, shows the drug is also effective against triple-negative breast cancer, a fast-growing and hard-to-treat type of breast cancer that carries a poor prognosis.

ProAgio, created from a human protein, targets the cell surface receptor integrin αVβ₃, which is expressed on cancer-associated fibroblasts. Fibroblasts are cells that generate collagen and other fibrous molecules and can be mobilized into service by a tumor, creating a thick, physical barrier known as the stroma, which protects the cancer and helps it grow. The drug works by inducing apoptosis, or programmed cell death, in cancer-associated fibroblasts that express integrin αVβ₃.

The dense fibrotic stroma is what makes pancreatic cancer, which has a five-year survival rate of just eight percent, so lethal and difficult to treat. Among triple-negative breast cancer patients, research shows denser stroma is associated with poorer survival and high recurrence rates.

“All solid tumors use cancer-associated fibroblasts, but in pancreatic cancer and triple-negative breast cancer, the stroma is so dense there’s often no way for conventional drugs to penetrate it and effectively treat the cancer,” said Liu.

The stroma also helps the tumor hide from your body’s immune system. Immunotherapy, a type of treatment that uses your immune system to fight cancer, is less effective against tumors protected by a dense stroma that is rich in cancer-associated fibroblasts.

Zhi-Ren Liu, Professor of Biology. Liu works to understand the molecular mechanism of cell abnormality, with the goal of developing new diagnostic and therapeutic strategies. © GSU

Cancer-associated fibroblasts promote angiogenesis, or the development of new blood vessels. Angiogenesis plays an important role in the spread of cancer because solid tumors need a blood supply to grow. In both studies, Liu and his team show roAgio has a profound effect on tumor vasculature. In the case of pancreatic cancer, it reopened blood vessels that had collapsed due to high extravascular stress caused by the dense stroma. In the case of triple-negative breast cancer, the drug’s anti-angiogenic activity reduced irregular, leaky angiogenic tumor vessels. In both cases, ProAgio allowed drugs to effectively reach the cancer.

Liu’s drug is unique in that it targets only cancer-associated fibroblasts — a subclass of the cells that is actively engaged in supporting cancer — rather than inactive fibroblasts. This reduces side effects of the drug and increases its effectiveness.

“When you have a wound, for example, normal fibroblasts will secrete fibers to limit the damage and promote healing,” said Liu. “The tumor region is basically a wound that won’t heal. Quiescent fibroblasts may play a role in preventing cancer from spreading. You don’t want to kill the good guys, only the bad guys.”

ProAgio is licensed to ProDa BioTech, a pharmaceutical research company founded by Liu. In 2018, ProDa BioTech received $2 million from the National Cancer Institute to fund toxicology and pharmacokinetic studies that are required before moving the drug to early-stage clinical trials. Those studies have been completed and the company has submitted an Investigational New Drug (IND) Application, a request for authorization from the Food and Drug Administration to administer ProAgio to human subjects.

Once the IND is granted, Liu says the immediate next step is to begin clinical trials. The first trial, to determine patient tolerability and recommended phase II dose, will begin in early 2021 at the National Institute of Health Clinical Center in Bethesda, Md., and will be led by Christine Alewine, M.D., an oncologist at the National Cancer Institute. In late 2021, Emory University is set to begin a multi-site trial among breast cancer and pancreatic cancer patients.


Reference: Ravi Chakra Turaga, Malvika Sharma… Zhi-Ren Liu, “Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment”, CMGH, 11(1), pp. 161-179, 2021. DOI: https://doi.org/10.1016/j.jcmgh.2020.08.004


Provided by Georgia State University

Single-cell Test Can Reveal Precisely How Drugs Kill Cancer Cells (Medicine)

Cancer cells are smart when it comes to anti-cancer drugs, evolving and becoming resistant to even the strongest chemotherapies over time. To combat this evasive behavior, researchers have developed a method named D2O-probed CANcer Susceptibility Test Ramanometry (D2O-CANST-R) to see, at single-cell/organelle level, how pharmaceuticals induce cancer cell death and how cancer cells adapt.

D2O-probed CANcer Susceptibility Test Ramanometry (D2O-CANST-R) (Image by LIU Yang)

The research, conducted by the Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT) of the Chinese Academy of Sciences (CAS), was published on Jan. 12 in Analytical Chemistry, a journal of the American Chemical Society.  

“Understanding the mechanism of cellular response to drugs and pharmaceutical therapies is crucial to improving cancer treatment,” said paper author XU Jian, director of the Single-Cell Center at QIBEBT. He explained that cancer cells can resist chemotherapy by changing metabolic activity for adaptation to drug stress, but exactly how this happens is poorly understood. “Approaches are needed to rapidly illuminate the particular effects of a drug on metabolic activity of cancer cells. This is clinically important as precise and personal administration of cancer chemotherapy is crucial for saving cancer patients’ lives.” 

Maryam Hekmatara, a PhD student of XU, and her workmates paired a powerful algorithm with Raman spectroscopy, which involves using a laser to excite photons in a sample to reveal structural information, including interactions. They examined how rapamycin, an anti-cancer drug, changed the metabolic activity in a human cancer cell line and in yeast.  

Their method revealed the changes small organelles inside the cells made in energy use and consumption. With a resolution capability of less than one micrometer – the width of a human hair is typically 80 to 100 micrometers, for comparison – the approach has the potential to reveal the metabolism in a cancer cell with very fine details.  

“The method is able to rapidly and precisely track and distinguish changes in lipid and protein metabolic-inhibitory effect of rapamycin,” Hekmatara said, noting the method takes just days compared to traditional tests that can take much longer to see if an individual patient’s cells will respond favorably to a drug. “It is also very precise, as it can distinguish cancer cell responses to drugs at the single cell and single organelle resolution, which is crucial for understanding why the drug is – or is not – effective.” 

The researchers plan to further study how cells become resistant, as well as further develop their method as a personalized approach to determine the most effective anti-cancer drug for a patient.  

Paper co-authors also include Mohammadhadi Heidari Baladehi and JI Yuetong, all of whom are affiliated with the Single-Cell Center at QIBEBT and the University of CAS. 

Reference: Maryam Hekmatara, Mohammadhadi Heidari Baladehi, Yuetong Ji, and Jian Xu, “D2O-Probed Raman Microspectroscopy Distinguishes the Metabolic Dynamics of Macromolecules in Organellar Anticancer Drug Response”, Anal. Chem. 2021. https://pubs.acs.org/doi/10.1021/acs.analchem.0c03925
https://doi.org/10.1021/acs.analchem.0c03925

Provided by Chinese Academy of Sciences

Living Macrophages-based Drug Promotes Antitumor Immunotherapy (Medicine)

Immunotherapy is one of the most promising approaches to inhibit tumor growth and metastasis by activating host immune functions. However, so far, immunotherapy still exhibits limitations of efficacy and safety, such as huge individual differences in treatment responses, difficulty to work on solid tumors, systemic immune storm and other immunotoxicity.

Schematic depiction of PLP NPs loaded on BMDM surface (MPLP) (Image by SIAT) 

Therefore, the development of advanced strategies to activate in situ tumor-specific immune response for the anticancer immunotherapy is highly desirable. 

A research team led by Prof. CAI Lintao at the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences developed a “cytopharmaceutical” based on living macrophages.  

The study was published in Biomaterials, Jan. 7. 

As important immune cells, macrophages can not only directly kill tumor cells, but also present antigens to effector cells as antigen-presenting cells. What’s more, they can also form antigen-specific immune memory, allowing the body to trigger a stronger immune response when specific antigen appear again.  

In previous studies, macrophages were usually used as drug carriers and did not effectively exert their anti-tumor immunity after entering the tumor microenvironment. Therefore, it will be a promising tumor treatment strategy of using natural living macrophages as drug carriers and maintaining the anti-tumor immunity of macrophages. 

In this study, CAI’s group constructed Poly I: C-encapsulated poly (lactic-co-glycolic acid) nanoparticles (PLP NPs) with a slow release profile. They synthesized a biomimetic system (MPLP), which loaded PLP NPs on the surface of bone marrow-derived macrophage (BMDM) via the maleimide-thiol conjugation. This system could effectively deliver PLP, control drug release and activate the tumor-specific immune response in situ

“PLP NPs loading does not affect the activity and function of BMDM. BMDM acts as a living cell drug vehicle and promotes the accumulation of PLP NPs in tumors, where Poly I: C is released from PLP NPsand reprograms BMDM into tumoricidal M1 macrophage,” said Prof. CAI. “MPLP triggers potent antitumor immune responses in vivo and effectively inhibits local and metastatic tumors without causing adverse pathological immune reactions.” 

The study offers an inspiration to facilitate clinical translation through the delivery of drugs by living immune cells for future anticancer therapy. 

Reference: Haimei Zhou, Huamei He, Ruijing Liang, Hong Pan, Ze Chen, Guanjun Deng, Shengping Zhang, Yifan Ma, Lanlan Liu, Lintao Cai, In situ Poly I:C released from living cell drug nanocarriers for macrophage-mediated antitumor immunotherapy, Biomaterials, 2021, 120670, ISSN 0142-9612, https://doi.org/10.1016/j.biomaterials.2021.120670. (http://www.sciencedirect.com/science/article/pii/S0142961221000211)

Provided by Chinese Academy of Sciences

LSU Health New Orleans Discovers Potential New Rx Strategy for Stroke (Medicine)

Research conducted at LSU Health New Orleans Neuroscience Center of Excellence reports that a combination of an LSU Health-patented drug and selected DHA derivatives is more effective in protecting brain cells and increasing recovery after stroke than a single drug. The findings are published in Brain Circulation, available here.

Αmyloid β peptide–mediated damage © LSU health

Nicolas Bazan, MD, PhD, Boyd Professor, Professor of Neurology and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, and Ludmila Belayev, MD, LSU Health New Orleans Professor of Neuroscience, Neurology, and Neurosurgery, discovered this novel therapeutic strategy for ischemic stroke using an experimental model.

During an ischemic stroke, signals are produced from arriving blood white cells and primary brain immune cells called microglia that cause neuroinflammation leading to a buildup of chemicals that harm the brain. Platelet-activating factor (PAF) accumulates, and inhibition of this process plays a critical role in neuronal survival. Dr. Bazan’s earlier studies also showed that in addition to its anti-inflammatory properties, DHA, an essential omega-3 fatty acid, stimulates the production of Neuroprotectin D1 (NPD1), a molecule that protects brain cells and promotes their survival. One complicating factor in developing neuroprotective strategies for stroke are the multiple routes and events that occur in the brain during a stroke, which has been approached mainly by monotherapeutic agents that were mostly unsuccessful.

Because no single therapy has proven effective in treating the complexity of stroke, the team aimed at two different events – blocking pro-inflammatory platelet-activating factor receptors (PAF-R) and activating cell-survival pathways. They found that treatment with LAU-0901, a synthetic molecule discovered in the Bazan lab that blocks pro-inflammatory platelet-activating factor, plus aspirin-triggered NPD1 (AT-NPD1) reduced the size of the damaged area in the brain, initiated repair mechanisms, and remarkably improved behavioral recovery.

Total lesion volumes were reduced with LAU‑0901 plus NPD1 by 62% and LAU‑0901 plus AT‑NPD1 by 90%. Combinatory treatment with LAU‑0901 plus AT‑NPD1 improved the behavioral score up to 54% on day three. LAU‑0901 and LAU‑0901 plus DHA decreased the production of 12‑hydroxyeicosatetraenoic acid, a pro‑inflammatory mediator.

“The biological activity of LAU-0901 and AT-NPD1 is due to specific activation or modulation of signaling pathways associated with the immune system, inflammation, cell survival, and cell-cell interactions,” notes Dr. Bazan. “These findings provide a major conceptual advance of broad therapeutic relevance for cell survival, brain function and, particularly, stroke and neurodegenerative diseases.”

“We discovered that these novel molecules promote neuronal cell survival with important anti-inflammatory activity,” explains Dr. Belayev. “This combinatorial therapy may hold promise for future therapeutic development against ischemic stroke.”

According to the Centers for Disease Control and Prevention, someone in the United States has a stroke every 40 seconds. Every 4 minutes, someone dies of stroke. Every year, more than 795,000 people in the United States have a stroke. About 87% of all strokes are ischemic strokes, in which blood flow to the brain is blocked. Stroke-related costs in the United States came to nearly $46 billion between 2014 and 2015. This total includes the cost of health care services, medicines to treat stroke, and missed days of work. Stroke is a leading cause of serious long-term disability. Stroke reduces mobility in more than half of stroke survivors age 65 and over.

Other LSU Health authors include Drs. Pranab K. Mukherjee, Eric J. Knott and Reinaldo B. Oria, along with Larissa Khoutorova and graduate students Madigan M. Reid and Cassia R. Roque. Dr. Andre Obenaus, Lawrence Nguyen, and Jeong Bin Lee from the University of California Irvine School of Medicine, and Dr. Nicos A. Petasis of the University of Southern California, are also co-authors.

This research was supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and Brazilian CAPES.

Reference: Belayev L, Obenaus A, Mukherjee PK, Knott EJ, Khoutorova L, Reid MM, Roque CR, Nguyen L, Lee JB, Petasis NA, Oria RB, Bazan NG. Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke. Brain Circ [serial online] 2020 [cited 2020 Dec 30];6:260-8. Available from: http://www.braincirculation.org/text.asp?2020/6/4/260/305408

Provided by LSU Health

LSU Health Sciences Center New Orleans (LSU Health New Orleans) educates Louisiana’s health care professionals. The state’s health sciences university leader, LSU Health New Orleans includes a School of Medicine with branch campuses in Baton Rouge and Lafayette, the state’s only School of Dentistry, Louisiana’s only public School of Public Health, and Schools of Allied Health Professions, Nursing, and Graduate Studies. LSU Health New Orleans faculty take care of patients in public and private hospitals and clinics throughout the region. In the vanguard of biosciences research, the LSU Health New Orleans research enterprise generates jobs and enormous annual economic impact. LSU Health New Orleans faculty have made lifesaving discoveries and continue to work to prevent, advance treatment or cure disease. To learn more, visit http://www.lsuhsc.edu, http://www.twitter.com/LSUHealthNO, or http://www.facebook.com/LSUHSC.

Triple Chemo Combo Improves Metastatic Colorectal Cancer Outcomes (Oncology / Medicine)

Researchers from SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI), part of the National Institutes of Health, have shown that a triple drug combination – of irinotecan, cetuximab, and vemurafenib – is a more powerful tumor fighter and keeps people with metastatic colon cancer disease free for a significantly longer period of time compared with patients treated with irinotecan and cetuximab.

Scott Kopetz, MD, of SWOG Cancer Research Network © SWOG Cancer Research Network

Results of the SWOG study, led by Scott Kopetz, MD, PhD, of M.D. Anderson Cancer Center, are published in the Journal of Clinical Oncology. The findings are expected to change the standard of care for patients with colorectal cancer that is metastatic – when tumors spread to other parts of the body – and includes a mutation in the BRAF gene called V600E. This mutation is found in about 10 percent of metastatic colorectal cancers and tumors with the mutation rarely responds to treatment, resulting in a poor prognosis for patients.

Kopetz is an expert in the science of BRAF-mutated colorectal cancer and has tested a variety of combination therapies to treat it, including leading the BEACON trial. This phase III trial found that two targeted drugs – cetuximab and encorafenib – significantly shrank tumors and helped patients live longer compared with those who received standard treatment. These results made a splash last year when simultaneously published in the New England Journal of Medicine and presented at the European Society of Medical Oncology annual meeting.

In his SWOG study, S1406, Kopetz and his team also pursued combination therapies to see what might work best. In this trial, they tested 106 patients whose metastatic colorectal cancer includes the deadly V600E mutation. All the patients had been previously treated with chemotherapy, and their cancer didn’t respond. The team randomly assigned study participants to one of two treatment groups – those who received irinotecan and cetuximab and those who received that combination with a third drug, vemurafenib.

The SWOG team found that patients who received the triple combination had better tumor response rates to the drugs – 17 percent compared to 4 percent – and stayed cancer-free longer. On a molecular level, Kopetz said, here’s how the triplet works: Irinotecan, a traditional chemotherapy drug, kills cancer cells. Cetuximab, a monoclonal antibody, is a targeted drug that blocks cancer growth by blocking the action of a protein called epidermal growth factor receptor, or EGFR. Kopetz says vemurafenib, a BRAF inhibitor and another targeted therapy, attacks the BRAF protein directly, further slowing tumor growth.

“That 1-2-3 action, that triple threat, shuts off a powerful growth pathway in these cancers,” Kopetz said. “In this trial, unlike in BEACON, we added chemo and found that it makes for a more effective way to treat this aggressive form of colorectal cancer.”

Another intriguing finding: An 87 percent decline in circulating tumor DNA (ctDNA) of the BRAFV600E variant allele frequency in patients receiving all three drugs, compared with no ctDNA drop in patients receiving the two-drug combination. Kopetz said this is strong evidence that measuring the presence of ctDNA can be an effective way to measure short-term response to treatment. And it could be as easy as drawing blood, using a test known as a liquid biopsy.

The SWOG study results will be accompanied by an editorial in JCO in January 2021.

Reference: Scott Kopetz, Shannon L McDonough, Heinz-Josef Lenz, Anthony Martin Magliocco, Chloe Evelyn Atreya, Luis A. Diaz, “Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406)”, Journal of Clinical Oncology, Vol. 35, Issue 15, 2020. https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.3505

Provided by SWOG