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Cancer-Killing Virus Therapy Shows Promise Against Inoperable Advanced Melanoma

Early results show that a new combination drug therapy is safe and effective against advanced melanoma in patients who were not able to have their tumors surgically removed. The drug combination is among the first, researchers say, to demonstrate the potential value of a live common cold virus, a coxsackievirus, to infect and kill cancer cells. The Phase I study, led by a researcher at New York University (NYU) Langone Health and its Perlmutter Cancer Center, is also among the first to show how such oncolytic viruses can safely boost the action of widely used cancer therapies that help the body's immune defense system detect and kill cancer cells. Currently, such immunotherapies are only effective in shrinking melanoma tumors in just over a third of patients who receive them. The new study results showed that injections of experimental coxsackievirus drug V937, along with pembrolizumab, an immunotherapy drug known as pembro or Keytruda, were well tolerated. Moreover, the combined treatment shrank melanoma tumors in nearly half (47 percent) of 36 men and women who received the therapy every few weeks for at least two years. Researchers say most side effects, such as rash and fatigue, were minimal, while 13 patients (36 percent) had serious immune reactions in the liver, stomach, or lungs, not unlike side effects that are known to happen with pembrolizumab alone. Presented on April 10 at the virtual annual meeting of the American Association for Cancer Research(AACR) 2021 (Week 1: April 9-14; Week 2: May 17-21) (https://www.aacr.org/meeting/aacr-annual-meeting-2021/), the study also showed that eight patients who received both drugs (22 percent) experienced complete remission, with no remaining signs of skin cancer.

Yale Cancer Center Study Demonstrates Promise for Novel Immunotherapy Approach to Fight Melanoma

In a new study led by the Yale Cancer Center, researchers have advanced a tumor-targeting and cell-penetrating antibody that can deliver payloads to stimulate an immune response to help treat melanoma. The study was presented on April 11, 2021 at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Week 1: April 9-14; Week 2: May 17-21) (https://www.aacr.org/meeting/aacr-annual-meeting-2021/). "Most approaches rely on direct injection into tumors of ribonucleic acids (RNAs) or other molecules to boost the immune response, but this is not practical in the clinic, especially for patients with advanced cancer," said Peter M. Glazer, MD, PhD, Chair of the Department of Therapeutic Radiology at Yale, Chief of Radiation Oncology at Smilow Cancer Hospital, and senior author of the study. "In this study, we can deliver immune stimulatory RNA to tumors in vivo following systemic administration." RNA is a nucleic acid present in all living cells. Its principal role is to act as a messenger to carry instructions from DNA to control the synthesis of proteins, although, in some viruses, RNA rather than DNA carries the genetic information. In this study, using mice with melanoma tumors, members of the Glazer lab at Yale achieved almost complete tumor suppression upon intravenous injection of antibody/RNA complexes. "These results are very encouraging," added Dr. Glazer.

Codiak BioSciences Presents Data at AACR 2021 Demonstrating Potential of Engineered Exosomes to Enhance the Therapeutic Index of Well-Validated Cancer Immunotherapy Pathways

On April 10, 2021, Codiak BioSciences, Inc. (Nasdaq: CDAK), a clinical-stage biopharmaceutical company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, today reported new preclinical evidence from Codiak’s exoASO-STAT6 program and clinical results from the healthy volunteer portion of the ongoing Phase 1 trial of Codiak’s exoIL-12 program at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Week 1: April 9-14; Week 2: May 17-21) (https://www.aacr.org/meeting/aacr-annual-meeting-2021/). These data illustrate the potential of engineered exosomes to target previously undruggable, but well-validated, pathways in cancer immunotherapy and generate potent single-agent activity. “We now have a growing body of preclinical and clinical evidence across our pipeline programs demonstrating that engineering exosomes to deliver potent drug molecules enhances the therapeutic index of pathways known to drive the immune response to fighting tumors,” said Douglas E. Williams, PhD, President and Chief Executive Officer of Codiak. “In particular, data from multiple in vitro and in vivo studies of engineered exosomes incorporating an antisense oligonucleotide demonstrate potent single-agent and highly selective genetic reprogramming of tumor associated macrophages, which is unique among macrophage targeting strategies.

Exosome-Coated Stent Heals Vascular Injury, Repairs Damaged Tissue

Researchers from North Carolina State (NC State) University have developed an exosome-coated stent with a “smart-release” trigger that could both prevent reopened blood vessels from narrowing and deliver regenerative stem cell-derived therapy to blood-starved, or ischemic, tissue. Angioplasty--a procedure that opens blocked arteries--often involves placing a metal stent to reinforce arterial walls and prevent them from collapsing once the blockage is removed. However, the stent’s placement usually causes some injury to the blood vessel wall, which stimulates smooth muscle cells to proliferate and migrate to the site in an attempt to repair the injury. The result is restenosis: a re-narrowing of the blood vessel previously opened by angioplasty. “The inflammatory response that stents cause can decrease their benefit,” says Ke Cheng, PhD, corresponding author of the research. “Ideally, if we could stop smooth muscle cells from over-reacting and proliferating, but recruit endothelial cells to cover the stent, it would mitigate the inflammatory response and prevent restenosis.” Dr. Cheng is the Randall B. Terry Jr. Distinguished Professor in Regenerative Medicine at NC State and a Professor in the NC State/UNC-Chapel Hill Joint Department of Biomedical Engineering. There are drug-eluting stents currently in use coated with drugs that discourage cell proliferation, but these anti-proliferative drugs also delay stent coverage by endothelial cells--which are the cells healthcare providers want to coat the stent. To solve this problem, Dr. Cheng and his team developed a stent coating composed of exosomes derived from mesenchymal stem cells (MSCs). Exosomes are tiny nano-sized vesicles secreted by all cell types that have been studied.

Research Reveals Why Redheads May Have Higher Pain Thresholds

New research led by investigators at Massachusetts General Hospital (MGH) provides insights on why people with red hair exhibit altered sensitivity to certain kinds of pain. The findings were published online on April 2, 2021 in Science Advances. The open-access article is titled “Reduced MC4R Signaling Alters Nociceptive Thresholds Associated with Red Hair” (https://advances.sciencemag.org/content/7/14/eabd1310). Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. In people with red hair (as in numerous other species of animals with red fur), the pigment-producing cells of the skin--called melanocytes--contain a variant form of the melanocortin 1 receptor. This receptor sits on the cell surface, and if it becomes activated by circulating hormones called melanocortins, it causes the melanocyte to switch from generating yellow/red melanin pigment to producing brown/black melanin pigment. Earlier work by David E. Fisher, MD, PhD, Director of the Mass General Cancer Center's Melanoma Program and director of MGH's Cutaneous Biology Research Center, demonstrated that the inability of red-haired individuals to tan or darken their skin pigment is traced to inactive variants of this receptor. To investigate the mechanisms behind different pain thresholds in red-haired individuals, Fisher and his colleagues studied a strain of red-haired mice that (as in humans) contains a variant that lacks melanocortin 1 receptor function and also exhibits higher pain thresholds. The team found that loss of melanocortin 1 receptor function in the red-haired mice caused the animals' melanocytes to secrete lower levels of a molecule called POMC (proopiomelanocortin) that is subsequently cut into different hormones including one that sensitizes to pain and one that blocks pain.

13 Rare Gene Variants Associated with Alzheimer's Disease (AD) Are Identified in First-of-Its-Kind Whole Genome Sequencing (WGS) Analysis of AD; Variants Associated with Functioning of Synapses, Development of Neurons, and Neuroplasticity

In the first study to use whole genome sequencing (WGS) to discover rare genomic variants associated with Alzheimer's disease (AD), researchers have identified 13 such variants (or mutations). In another novel finding, this study establishes new genetic links between AD and the function of synapses, which are the junctions that transmit information between neurons, and neuroplasticity, or the ability of neurons to reorganize the brain's neural network. These discoveries could help guide development of new therapies for this devastating neurological condition. Researchers at Massachusetts General Hospital (MGH), the Harvard T. H. Chan School of Public Health, and Beth Israel Deaconess Medical Center reported these findings in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. The open-access article was published online on April 2, 2021 and is titled “Whole‐Genome Sequencing Reveals New Alzheimer's Disease-Associated Rare Variants in Loci Related to Synaptic Function and Neuronal Development” (https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12319). Over the last four decades, MGH has pioneered research on the genetic origins of AD, led by Rudolph Tanzi, PhD, Vice Chair of Neurology and Director of the hospital's Genetics and Aging Research Unit. Notably, Dr. Tanzi and colleagues co-discovered genes that cause early-onset (prior to age 60) familial AD, including the amyloid protein (A4) precursor (APP), and the presenilin genes (PSEN1 and PSEN2). Mutations in these genes lead to accumulation of amyloid plaques in the brain, a hallmark of AD. The next 30 AD gene variants that were discovered are primarily linked to chronic inflammation in the brain (or neuroinflammation), which also increases the risk for this cognitive disease.

Understanding Itch: New Insights Obtained at Intersection of Nervous System & Immune System; Collaborators Pinpoint Key Molecular Player (Cysteine Leukotriene Receptor 2) That Could Represent New Therapeutic Target for Intractable Chronic Itch of Eczema

Eczema, or atopic dermatitis (AD), is sometimes called "the itch that rashes." Often, the itch begins before the rash appears, and, in many cases, the itchiness of the skin condition never really goes away. Approximately 9.6 million children and 16.5 million adults in the U.S. have AD, which can have a serious effect on quality of life for patients. Although much has been learned about the uncomfortable sensation that triggers the desire to scratch, many mysteries remain about chronic itch, making it a challenge to treat. A paper by authors from Brigham and Women's Hospital and Harvard Medical School and collaborators, published online on March 30, 2021 in PNAS, offers new clues about the underlying mechanisms of itch. The article is titled “The CysLT2R Receptor Mediates Leukotriene C4-Driven Acute and Chronic Itch” (https://www.pnas.org/content/118/13/e2022087118). Findings suggest a key molecular player known as cysteine leukotriene receptor 2 (CysLT2R) may be a new target for intractable chronic itch. "In atopic dermatitis, the itching can be horrific and it can aggravate disease," said co-corresponding author K. Frank Austen, MD, a senior physician in the Division of Allergy and Clinical Immunology at the Brigham. Dr. Austen is also the AstraZeneca Professor of Respiratory and Inflammatory Diseases, Emeritus, at Harvard Medical School. "We began collaborating for two reasons: one is an interest in science--I wandered into the study of what is now the cysteine leukotriene pathway decades ago, and I've been pursuing it ever since. The second reason is itch--understanding its cause and connections to neurons." Dr. Austen and his lab, which focuses on the molecular components that contribute to allergic inflammation, collaborated with Isaac Chiu, PhD, an Assistant Professor of Immunology at Harvard Medical School (HMS).

Targeting MicroRNAs (miR-146a/b) Could Unmask Hidden Vulnerability In Breast Cancer Stem Cells

Researchers in Italy have identified a pair of microRNA molecules that help maintain a population of cancerous stem cells that drive the growth of breast cancers and initiate tumor relapse after treatment. The study, which was published online on April 2, 2021 in the Journal of Cell Biology (JCB), reveals that targeting these microRNAs makes cancer stem cells more susceptible to some chemotherapies and could potentially improve the prognosis of patients with aggressive forms of breast cancer. The open-access article is titled “miR-146 Connects Stem Cell Identity with Metabolism and Pharmacological Resistance in Breast Cancer” (https://rupress.org/jcb/article/220/5/e202009053/211945/miR-146-connects...). Many tumors contain a small population of cancer stem cells that initiate tumor growth and give rise to the various cell types found in tumors. Moreover, because cancer stem cells are often resistant to radio- and chemo-therapies, they can survive and promote tumor relapse and metastasis after initial rounds of treatment. In breast cancer, for example, tumors containing a relatively high number of cancer stem cells have a much poorer prognosis than tumors with fewer stem cells. Eliminating these stem cells may therefore be crucial for the successful treatment of breast cancer and other tumor types. One class of molecule that might help cancer stem cells to persist within tumors is microRNAs. These short RNA molecules control the fate and identity of cells by regulating the levels of hundreds of longer, protein-encoding "messenger" RNAs.

Anti-Inflammatory Drug (Topoisomerase 1 Inhibitor) Protects Against Lethal Inflammation from COVID-19 in Animal Models

Mount Sinai Health System researchers have found that a widely available and inexpensive drug targeting inflammatory genes has reduced morbidity and mortality in mice infected with SARS-CoV-2, the virus that causes COVID-19. In a study published online on March 30, 2021 in Cell, the team reported that the drug, topotecan (TPT), inhibited the expression of inflammatory genes in the lungs of mice as late as four days after infection, a finding with potential implications for treatment of humans. The Cell article is titled “TOP1 Inhibition Therapy Protects Against SARS-CoV-2-Induced Lethal Inflammation” (https://www.cell.com/cell/fulltext/S0092-8674(21)00382-2). "So far, in pre-clinical models of SARS-CoV-2, there are no therapies--either antiviral, antibody, or plasma--shown to reduce the SARS-CoV-2 disease burden when administered after more than one day post-infection" says senior author Ivan Marazzi, PhD, Associate Professor of Microbiology at the Icahn School of Medicine at Mount Sinai in New York City. "This is a huge problem because people who have severe COVID19 and get hospitalized, often do not present symptoms until many days after infection. We took a different approach, and sought to find a potential therapy that can be used during later stages of the disease. We found that the TOP1 inhibitors given days after the infection can still limit the expression of hyper-inflammatory genes in the lungs of infected animals and improve infection outcomes." Moreover, says Dr. Marazzi, topotecan (TPT), an FDA-approved topoisomerase I (TOP1) inhibitor, as well as its derivatives, are inexpensive clinical-grade inhibitors available in most countries around the world for use as antibiotic and anti-cancer agents.

Mutations Across the Genome Add Up to Blood Cancer Risk in Four Popular Dog Breeds; May Offer Clues to Similar Cancer in Humans

Six genetic variants add up to determine the risk of several blood cancers in pre-disposed dog breeds, according to a study by Benoît Hédan, DVM, PhD, at the University of Rennes (France) and colleagues, published online on April 1, 2021 in the open-access journal PLOS Genetics. The article is titled “Identification of Common Predisposing Loci to Hematopoietic Cancers in Four Dog Breeds.” The results confirm a known tumor-suppressor gene as a risk factor for histiocytic sarcoma (HS)--a rare and aggressive blood cancer that affects both dogs and humans--as well as identifying four new genetic loci associated with the disease. The researchers sequenced genomic DNA extracted from blood samples from Bernese mountain dogs (photo), Rottweilers, flat-coated retrievers, and golden retrievers, including 172 dogs diagnosed with HS, and 128 unaffected dogs. A genome-wide association analysis identified five chromosomal regions that cumulatively increased the risk of HS in the four breeds. Each of these regulatory regions accounted for 5-15% of cases, which may indirectly influence cancer risk. Dogs carrying five or more of these mutations had a very high risk of developing blood cancer during their lifetime. An expanded analysis including sequences from dogs diagnosed with two other blood cancers found that three of the five chromosomal regions associated with HS had multi-cancer effects, increasing the risk of lymphomas and osteosarcomas in Rottweilers, and mast cell tumors in Bernese mountain dogs and retrievers. Previous studies have used domestic dogs as a model to study the genetics of rare human cancers, but this is the largest multi-breed study of HS conducted to date. The authors hope the results can help inform an understanding of human HS, a cancer for which there are few diagnostic tools and limited clinical options.

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