Tag: Medicine

Adolescents and young adults with familial adenomatous polyposis bear a high risk of developing cancer

Engineered cells may be harnessed in new immunotherapy for cancer patients, Tel Aviv University researchers say

Lipid metabolism found to affect cancer cells’ visibility to the immune system, say TAU, Sheba Medical Center researchers

Tel Aviv University and Sheba Medical Center researchers say they have discovered why more than half of patients with metastatic melanoma do not respond to immunotherapy cancer treatments.

Wielding proteomics, an innovative “protein mapping” approach, a team of researchers led by Prof. Tami Geiger, Prof. Gal Markel, and Dr. Michal Harel of TAU’s Sackler School of Medicine and Sheba’s Ella Lemelbaum Institute for Immuno-Oncology have answered the burning question: Why do immunotherapy treatments greatly help some patients with melanoma but not affect 60 percent of metastatic melanoma patients?

The researchers, whose findings were published on September 5 in Cell, compared the responses of 116 melanoma patients to immunotherapy — one group in which immunotherapy was successful and a second in which immunotherapy was not successful. Harnessing proteomics, a powerful protein mapping technology, they discovered differences in the metabolism, or energy production process, of the cancer cells of the two groups.

“In recent years, a variety of cancer immunotherapy therapies have been used, therapies that strengthen the anti-cancer activity of the immune system,” explains Prof. Markel, a senior oncologist and scientific director of the Ella Lemelbaum Institute. “These treatments have been shown to be highly effective for some patients and have revolutionized oncology. However, many patients do not respond to immunotherapy, and it is critical to understand why.

“Can we predict who will respond? Can we alter treatment in order to increase responses? In our research, we focused on metastatic melanoma, a devastating disease that until recently had no efficient treatments. It was clear to us that pre-treatment samples from responders and non-responders would be key.”

To better understand treatment resistance mechanisms, the scientists examined tumors taken from 116 patients using proteomics.

“In the proteomic lab, we use an instrument called a mass-spectrometer, which enables global mapping of thousands of proteins,” explains Prof. Geiger, head of TAU’s Proteomics Lab. “We then followed up with extensive computational analysis to identify the proteins that differentiated between the response groups.”

The proteomic comparison identified major differences between responders and non-responders to immunotherapy. “In the responders, we found higher levels of proteins associated with lipid metabolism, which led to better recognition by the immune system,” says Prof. Geiger.

In collaboration with the Salk Institute in San Diego and Yale School of Medicine, researchers then examined their findings in melanoma tissue cultures and a mouse model of metastatic melanoma.

Using genetic engineering, they were able to silence the mechanism responsible for fatty acid metabolism.

“We found that upon silencing this metabolic pathway, the cancer cells manage to ‘hide’ from T-cells that are supposed to detect and destroy them,” says Prof. Geiger. “As a result, cancer in these mice developed at a faster rate compared to the control group.

“In our study, we identified a significant difference between melanoma patients who live for years thanks to immunotherapy, and patients who are not at all affected by the treatment.”

“These findings can also be relevant to many other malignancies,” adds Prof. Markel. “Now, in subsequent studies, we are looking for ways to improve the response to immunotherapy and expand the circle of patients who benefit from it. In addition, we are looking for a method that will allow clinicians to anticipate which patients will respond to treatments.”

TAU researchers say injection of synthetic DNA material found to activate brain’s immune cells and kill invading tumor cells

Brain metastases are the final, lethal consequence of many aggressive cancers, and researchers are racing to discover ways of preventing these intractable growths from developing.

A new Tel Aviv University study finds a known adjuvant — an ingredient used in some vaccines that helps create a stronger immune response — that contains synthetic DNA material may be an effective means of preventing brain metastases in patients whose primary tumors have been excised.

Research for this study was led jointly by Dr. Amit Benbenishty of TAU’s Sagol School of Neuroscience, Dr. Pablo Blinder of TAU’s George S. Wise Faculty of Life Sciences, and Prof. Shamgar Ben-Eliyahu of TAU’s School of Psychological Sciences, in collaboration with Dr. Lior Mayo of TAU’s Sagol School of Neuroscience, Prof. Neta Erez of TAU’s Sackler School of Medicine, and Prof. Dritan Agalliu of Columbia University Medical Center. It was published on March 28 in PLoS Biology.

“Some 20 to 40% of lung, breast and melanoma cancer patients develop brain metastases, and current treatments for brain metastases are ineffective,” Dr. Blinder says. “Surgery for removing primary tumors is usually essential, but the period immediately before and after surgery requires that all chemotherapy and radiotherapy be stopped. This creates a high potential for the initiation and rapid progression of deadly metastases.

“Our study showed that an intravenous injection of CpG-C, an adjuvant of synthetic DNA material, during this specific time frame reduces the development of brain metastases,” Dr. Blinder continues. “When the drug is administered systemically, it crosses the blood-brain barrier and works by activating microglia, the brain’s primary immune cells, to kill invading tumor cells.”

The scientists harnessed different mouse models to test the efficacy of the CpG-C drug in reducing brain metastases resulting from different cancers of both mouse and human origin. The research team used a combination of cutting-edge imaging techniques to discover the specific immune cells involved in mediating a protective effect against brain metastases and examine tumor progression in the animal models.

“Currently, patients with small-cell lung carcinoma are given preventative whole-brain radiotherapy to reduce brain metastases, but that has many negative side effects,” Dr. Blinder explains. “Our approach gets the immune troops ‘ready for combat,’ in both the brain and the rest of the body. It’s not tumor specific, and it has a promising safety profile in humans. Prof. Ben-Eliyahu’s group at TAU and others have previously shown that this drug is beneficial in fighting primary tumors and metastases in other organs.

“We hope that this drug can be implemented as a preventative treatment for various types of metastasizing tumors with the goal of preventing or reducing brain metastases.”

The new treatment could be administered to cancer patients undergoing surgery to excise a primary tumor several days before the operation and continuing a few weeks after surgery. The group is currently conducting several studies to verify that the systemic CpG-C treatment does not risk the patients’ health nor the success of surgery to remove a primary tumor.

“We were able to verify that this treatment does not disrupt tissue healing, which is important in the post-operative period,” Prof. Ben-Eliyahu says. “The treatment does not seem to increase the risk of other common surgery-related complications, such as an exaggerated post-operative inflammatory response.

“We are now testing the potential simultaneous use of anti-stress-inflammatory drugs, which we also found effective in reducing perioperative risks of metastases and may mitigate the deleterious stress-inflammatory responses to surgery and potentially to CpG-C treatment. If these tests are successful, we plan to conduct initial studies in cancer patients.”

Injection of nanoparticle has proven effective in mouse models, researchers say

Researchers at Tel Aviv University have developed a novel nano-vaccine for melanoma, the most aggressive type of skin cancer. Their innovative approach has so far proven effective in preventing the development of melanoma in mouse models and in treating primary tumors and metastases that result from melanoma.

The focus of the research is on a nanoparticle that serves as the basis for the new vaccine. The study was led by Prof. Ronit Satchi-Fainaro, chair of the Department of Physiology and Pharmacology and head of the Laboratory for Cancer Research and Nanomedicine at TAU’s Sackler Faculty of Medicine, and Prof. Helena Florindo of the University of Lisbon while on sabbatical at the Satchi-Fainaro lab at TAU. The results were published recently in Nature Nanotechnology.

Creating a nano-vaccine

Melanoma develops in the skin cells that produce melanin or skin pigment. “The war against cancer in general, and melanoma in particular, has advanced over the years through a variety of treatment modalities, such as chemotherapy, radiation therapy and immunotherapy; but the vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” says Prof. Satchi-Fainaro. “In our study, we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma and to sensitize the immune system to immunotherapies.”

The researchers harnessed tiny particles, about 170 nanometers in size, made of a biodegradable polymer. Within each particle, they “packed” two peptides — short chains of amino acids, which are expressed in melanoma cells. They then injected the nanoparticles (or “nano-vaccines”) into a mouse model bearing melanoma.

“The nanoparticles acted just like known vaccines for viral-borne diseases,” Prof. Satchi-Fainaro explains. “They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides — that is, the melanoma cells. This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

A vaccine against cancer

The researchers then examined the effectiveness of the vaccine under three different conditions. First, the vaccine proved to have prophylactic effects. The vaccine was injected into healthy mice, and an injection of melanoma cells followed. “The result was that the mice did not get sick, meaning that the vaccine prevented the disease,” says Prof. Satchi-Fainaro.

Second, the nanoparticle was used to treat a primary tumor: A combination of the innovative vaccine and immunotherapy treatments was tested on melanoma model mice. The synergistic treatment significantly delayed the progression of the disease and greatly extended the lives of all treated mice.

Finally, the researchers validated their approach on tissues taken from patients with melanoma brain metastases. This suggested that the nano-vaccine can be used to treat brain metastases as well. Mouse models with late-stage melanoma brain metastases had already been established following excision of the primary melanoma lesion, mimicking the clinical setting. Research on image-guided surgery of primary melanoma using smart probes was published last year by Prof. Satchi-Fainaro’s lab.

“Our research opens the door to a completely new approach — the vaccine approach — for effective treatment of melanoma, even in the most advanced stages of the disease,” concludes Prof. Satchi-Fainaro. “We believe that our platform may also be suitable for other types of cancer and that our work is a solid foundation for the development of other cancer nano-vaccines.”

Genes found to safeguard against infection as well as resuscitate infected cells, TAU researchers say

The Zika virus has affected over 60 million people, mostly in South America. It has potentially devastating consequences for pregnant women and their unborn children, many of whom are born with severe microcephaly and other developmental and neurological abnormalities. There is currently no vaccine or specific treatment for the virus.

A new Tel Aviv University study uses a genetic screen to identify genes that protect cells from Zika viral infection. The research, led by Dr. Ella H. Sklan of TAU’s Sackler School of Medicine, was published in the Journal of Virology on May 29. It may one day lead to the development of a treatment for the Zika virus and other infections.

The study was based on a modification of the CRISPR-Cas9 gene-editing technique. CRISPR-Cas9 is a naturally occurring bacterial genome editing system that has been adapted to gene editing in mammalian cells. The system is based on the bacterial enzyme Cas9, which can locate and modify specific locations along the human genome. A modification of this system, known as CRISPR activation, is accomplished by genetically changing Cas9 in a way that enables the expression of specific genes in their original DNA locations.

“CRISPR activation can be used to identify genes protecting against viral infection,” Dr. Sklan says. “We used this adapted system to activate every gene in the genome in cultured cells. We then infected the cells with the Zika virus. While most cells die following the infection, some survived due to the over-expression of some protective genes. We then used next-generation sequencing and bioinformatic analysis to identify a number of genes that enabled survival, focusing on one of these genes called IFI6. A previous screen conducted by another research group had identified this gene with respect to its role vis-à-vis other viruses.

“IFI6 showed high levels of protection against the Zika virus both by protecting cells from infection and by preventing cell death,” Dr. Sklan continues. “If its yet unknown mode of action can be mimicked, it may one day serve as the basis for the development of a novel antiviral therapy to fight the Zika virus or related infections.”

Together with Dr. Nabila Jabrane-Ferrat of The French National Center for Scientific Research, Dr. Sklan moved the study of the identified genes into Zika-infected human placenta tissues, which serve as a gateway for viral transmission to the fetus. These genes were induced following infection, indicating they might play a protective role in this tissue as well.

“Our results provide a better understanding of key host factors that protect cells from ZIKV infection and might assist in identifying novel antiviral targets,” concludes Dr. Sklan. Moving forward, the researchers hope to discover the mechanism by which the IFI6 gene inhibits infection.

Research for the study was conducted by Dr. Anna Dukhovny of TAU’s Sackler School of Medicine, and bioinformatics analysis conducted by Kevin Lamkiewicz of Friedrich Schiller University. Part of the study was conducted during Dr. Sklan’s sabbatical in Prof. Jae Jung’s lab at the University of Southern California.

Fat cells allow melanoma cells to penetrate the dermis, from which they spread, causing fatal metastases in vital organs, TAU researchers say

New material may prevent one of the costliest and most prevalent bacterial diseases in the world

Tooth decay is among the costliest and most widespread bacterial diseases. Virulent bacteria cause the acidification of tooth enamel and dentin, which, in turn, causes secondary tooth decay.

A new study by Tel Aviv University researchers finds potent antibacterial capabilities in novel dental restoratives, or filling materials. According to the research, the resin-based composites, with the addition of antibacterial nano-assemblies, can hinder bacterial growth and viability on dental restorations, the main cause of recurrent cavities, which can eventually lead to root canal treatment and tooth extractions.

Research for the study was led by Dr. Lihi Adler-Abramovich and TAU doctoral student Lee Schnaider in collaboration with Prof. Ehud Gazit, Prof. Rafi Pilo, Prof. Tamar Brosh, Dr. Rachel Sarig and colleagues from TAU’s Maurice and Gabriela Goldschleger School of Dental Medicine and George S. Wise Faculty of Life Sciences. It was published in ACS Applied Materials & Interfaces on May 28.

Can your fillings fight germ?

“Antibiotic resistance is now one of the most pressing healthcare problems facing society, and the development of novel antimicrobial therapeutics and biomedical materials represents an urgent unmet need,” says Dr. Adler-Abramovich. “When bacteria accumulate on the tooth surface, they ultimately dissolve the hard tissues of the teeth. Recurrent cavities — also known as secondary tooth decay — at the margins of dental restorations results from acid production by cavity-causing bacteria that reside in the restoration-tooth interface.”

This disease is a major causative factor for dental restorative material failure and affects an estimated 100 million patients a year, at an estimated cost of over $30 billion.

Historically, amalgam fillings composed of metal alloys were used for dental restorations and had some antibacterial effect. But due to the alloys’ bold color, the potential toxicity of mercury and the lack of adhesion to the tooth, new restorative materials based on composite resins became the preferable choice of treatment. Unfortunately, the lack of an antimicrobial property remained a major drawback to their use.

“We’ve developed an enhanced material that is not only aesthetically pleasing and mechanically rigid but is also intrinsically antibacterial due to the incorporation of antibacterial nano-assemblies,” Schnaider says. “Resin composite fillings that display bacterial inhibitory activity have the potential to substantially hinder the development of this widespread oral disease.”

From nano materials to major breakthroughs

The scientists are the first to discover the potent antibacterial activity of the self-assembling building block Fmoc-pentafluoro-L-phenylalanine, which comprises both functional and structural subparts. Once the researchers established the antibacterial capabilities of this building block, they developed methods for incorporating the nano-assemblies within dental composite restoratives. Finally, they evaluated the antibacterial capabilities of composite restoratives incorporated with nanostructures as well as their biocompatibility, mechanical strength and optical properties.

“This work is a good example of the ways in which biophysical nanoscale characteristics affect the development of an enhanced biomedical material on a much larger scale,” Schnaider says.

“The minimal nature of the antibacterial building block, along with its high purity, low cost, ease of embedment within resin-based materials and biocompatibility, allows for the easy scale-up of this approach toward the development of clinically available enhanced antibacterial resin composite restoratives,” Dr. Adler-Abramovich says.

 
The researchers are now evaluating the antibacterial capabilities of additional minimal self-assembling building blocks and developing methods for their incorporation into various biomedical materials, such as wound dressings and tissue scaffolds.