Dozens of clinical trials are testing mRNA treatment vaccines in people with various types of cancer, including pancreatic cancer, colorectal cancer, and melanoma. Some vaccines are being evaluated in combination with drugs that enhance the body’s immune response to tumors. But no mRNA cancer vaccine has been approved by the US Food and Drug Administration for use either alone or with other cancer treatments.

“mRNA vaccine technology is extremely promising for infectious diseases and may lead to new kinds of vaccines,” said Elad Sharon, M.D., M.P.H., of NCI‘s Division of Cancer Treatment and Diagnosis. “For other applications, such as the treatment of cancer, research on mRNA vaccines also appears promising, but these approaches have not yet proven themselves.”

With findings starting to emerge from ongoing clinical trials of mRNA cancer vaccines, researchers could soon learn more about the safety and effectiveness of these treatments, Dr. Sharon added. Over the past 30 years, researchers have learned how to engineer stable forms of mRNA and deliver these molecules to the body through vaccines. Once in the body, the mRNA instructs cells that take up the vaccine to produce proteins that may stimulate an immune response against these same proteins when they are present in intact viruses or tumor cells. Among the cells likely to take up mRNA from a vaccine are dendritic cells, which are the sentinels of the immune system. After taking up and translating the mRNA, dendritic cells present the resulting proteins, or antigens, to immune cells such as T cells, starting the immune response.

“Dendritic cells act as teachers, educating T cells so that they can search for and kill cancer cells or virus-infected cells,” depending on the antigen, said Karine Breckpot, Ph.D., of the Vrije Universiteit Brussel in Belgium, who studies mRNA vaccines. The mRNA included in the Pfizer-BioNTech and the Moderna coronavirus vaccines instructs cells to produce a version of the “spike” protein that studs the surface of SARS-CoV-2. The immune system sees the spike protein presented by the dendritic cells as foreign and mobilizes some immune cells to produce antibodies and other immune cells to fight off the apparent infection. Having been exposed to the spike protein free of the virus, the immune system is now prepared, or primed, to react strongly to a subsequent infection with the actual SARS-CoV-2 virus.

Source: https://www.cancer.gov/

In the early 1990s, mRNA technology emerged as an alternative to traditional vaccine development, building on research conducted by Wolff et al. involving direct gene transfer into mouse muscle in vivo. Initially, mRNA technology came with drawbacks as it caused severe inflammation upon administration, degraded quickly in the body and was difficult to move across the membrane into the cell. However, breakthroughs using nanotechnology overcame some of these challenges; scientists encased the RNA and used synthetic RNA that the body’s immune system recognizes.

Other major technological innovation and research investment has improved the delivery, translation and stability, enabling mRNA to become a promising tool for vaccine development. These breakthroughs have allowed further research and development of mRNA vaccines, particularly against viruses such as HIV and influenza. In 2020, when the COVID-19 pandemic hit, several human clinical trials were underway to test mRNA vaccines against influenza and HIV. As a result of the pandemic, research efforts, funding and facilities prioritized the development of mRNA vaccines for COVID-19. Combined efforts of global research teams working on COVID-19 mRNA vaccinations accelerated the field of research, improving the knowledge, understanding and methods of mRNA vaccine technology. This allowed the progression of mRNA vaccines for other diseases, such as cancer, and clinical trials for mRNA cancer vaccinations are now underway. The MD Anderson Cancer Center (TX, USA) is conducting a clinical trial to test whether mRNA technology can be used to prevent the recurrence of colorectal cancer.

A B cell displays antibodies specific to antigens on a colorectal cancer cell and signals killer T cells to destroy it.

People with colorectal cancer often undergo surgery to remove the cancerous tumor; however, cancer cells remain in the body and shed DNA into the bloodstream, which is known as circulating tumor DNA (ctDNA) and can cause further complications and metastasis. Van Morris and Scott Kopetz are leading the Phase II trial (NCT04486378) for a personalized mRNA cancer vaccine. People who have stage II or III colorectal cancer are given a blood test after their surgery to check for ctDNA. The patient’s tumor tissue is genetically profiled to identify mutations that fuel cancer growth. The tumor mutations are then ranked from the most to the least common to create a personalized mRNA vaccine for the patient. “We’re hopeful that with the personalized vaccine, we’re priming the immune system to go after the residual tumor cells, clear them out and cure the patient,” explains Morris.

Source: https://www.future-science.com/

The recent approval of Lumakras (Amgen, AMG 510) by the US Food and Drug Administration as a treatment for non-small cell lung cancer is a breakthrough in cancer therapy. The drug acts as an irreversible inhibitor of KRAS, a mutant protein common to many troubling tumors, including lung, pancreatic and colorectal cancers.

KRAS has been the Moby Dick of cancer therapy. Over the last forty years, its elusive nature has stymied generations of drug developers. Discovered in 1983, it was one of the very first oncogenes ever identified. An oncogene is the mutated form of a normal human gene that often lies at the very origin of many cancers. KRAS is present in 32% of non-small cell lung cancers, 40% of colorectal cancers, and 85% to 90% of pancreatic cancers.

The normal cellular KRAS protein plays a central role in healthy cells by acting as an on/off switch for cell growth. KRAS is activated by binding to guanosine triphosphate (GTP). Once activated, the KRAS protein signals the cell to grow and divide. It is turned off when it converts GTP to guanosine diphosphate (GDP). The mutation that transforms KRAS into an oncogene locks the protein into an active state, permanently bound to GTP, causing cells to grow uncontrollably.

Why has KRAS been such a difficult problem to solve? Most drugs work by binding to sites within the crevices in a protein structure. According to Victor Cee, a research scientist formerly with Amgen,

“There’s almost nowhere that a drug can stick to on that protein.” After screening a subset of chemicals, the team of researchers from Amgen found one that weakly bound to the KRAS molecule resting in a shallow pocket of the protein near the GDP binding site. Structural analysis showed that entry to a deeper crevice below was blocked by a histidine residue. Eventually, they found a family of drugs that could displace the histidine, thus allowing entry to the deeper cleft. Binding to this site alters the conformation of the nearby GDP binding site, fixing the GDP in place and permanently locking KRAS in the inactivated position.

Source: https://www.forbes.com/

Rapid detection of the SARS-CoV-2 virus, in about 30 seconds following the test, has had successful preliminary results in Mano Misra’s lab at the University of Nevada, Reno. The test uses a nanotube-based electrochemical biosensor, a similar technology that Misra has used in the past for detecting tuberculosis and colorectal cancer as well as detection of biomarkers for food safety.

Professor Misra, in the University’s College of Engineering Chemical and Materials Department, has been working on nano-sensors for 10 years. He has expertise in detecting a specific biomarker in tuberculosis patients’ breath using a metal functionalized nano sensor.

Testing a nanotube-based electrochemical biosensor

“I thought that similar technology can be used to detect the SARS-CoV-2 virus, which is a folded protein,” Misra said. “

This is Point of Care testing to assess the exposure to COVID-19. We do not need a laboratory setting or trained health care workers to administer the test. Electrochemical biosensors are advantageous for sensing purposes as they are sensitive, accurate and simple.”

The test does not require a blood sample, it is run using a nasal swab or even exhaled breath, which has biomarkers of COVID-19. Misra and his team have successfully demonstrated a simple, inexpensive, rapid and non-invasive diagnostic platform that has the potential to effectively detect the SARS-CoV-2 virus.

The team includes Associate Professor Subhash Verma, virologist, and Research Scientist Timsy Uppal at the University’s School of Medicine, and Misra’s post-doctoral researcher Bhaskar Vadlamani.

“Our role on this project is to provide viral material to be used for detection by the nanomaterial sensor developed by Mano,” Verma said. “Mano contacted me back in April or May and asked whether we can collaborate to develop a test to detect SARS-CoV-2 infection by analyzing patients’ breath. That’s where we came in, to provide biological material and started with providing the surface protein of the virus, which can be used for detecting the presence of the virus.”

Source: https://www.unr.edu

Reports show that cancer is the second-highest leading cause of death globally, with the possibility that every one in four to five people in Singapore may develop cancer in their lifetime. A recent study by scientists from Duke-NUS Medical School provides new evidence supporting the presence of a key mechanism behind progression and relapse in cancer. The study, published in Proceedings of the National Academy of Sciences (PNAS), discusses the role of MBNL1 protein as a biomarker for cancer prognosis, which can lead to the development of new treatment strategies for cancer.

Cancer cases have been rising over the years and according to the statistics, the number of people living with cancer will continue to increase. Despite decades of research, cancer treatments are still inefficient and have unacceptable side effects that continue to prompt an urgent need for new approaches to prevention and treatment. Uncovering novel mechanisms associated with cancer would fill current knowledge gaps and help meet this need.

“We discovered a mechanism involving MBNL1 protein that predicts several characteristics of cancer such as progression and relapse,” said Dr Debleena Ray, Senior Research Fellow at Duke-NUS’ Cancer and Stem Cell Biology (CSCB) programme, the lead author of this study. ”We found that MBNL1 protein is present in low amounts in many of the common cancers in the world, including breast, colorectal, stomach, lung and prostate cancers, which when combined account for about 49 per cent of all cancers diagnosed in 2018. This can cause poor overall survival in many of these commonly-occurring cancers.”

The team also found that this mechanism can be reversed by blocking the JNK protein, a well-known target in cancer treatment, in cancer cells with low levels of MBNL1.

“While JNK inhibitors have been tested as a cancer drug previously, currently there are no clinical trials for the same. However, if in the future there is a JNK inhibitor against cancer, MBNL1 could be used as a biomarker to select patients for the treatment,” said Adjunct Associate Professor David Epstein at the Duke-NUS’ CSCB programme and the co-corresponding author of this study.

“Cancer is a global health challenge and Singapore is no exception. This study provides important information about novel targets and biomarkers that are implicated in several major cancers, which could lead to the development of new treatment strategies that can improve the lives of patients,” said Prof Patrick Casey, Senior Vice Dean for Research at Duke-NUS.

Over the next year, the team will be investigating the role of MBNL1 in colorectal cancer and exploring the potential of anti-JNK therapeutic for cancer using antisense technology, a tool that is used for the inhibition of gene expression.

Reference: Debleena Ray, Yu Chye Yun, Muhammad Idris, Shanshan Cheng, Arnoud Boot, Tan Bee Huat Iain, Steven G. Rozen, Patrick Tan and David M. Epstein (2020). A tumor associated splice-isoform of MAP2K7 drives de- differentiation in MBNL1-low cancers via JNK activation. PNAS. Complete research paper available at this link: https://www.pnas.org/content/early/2020/06/25/2002499117

Source: Duke-NUS

All cells in the human body have a shelf-life, but those of the cancerous variety use some cunning trickery to outlive their expiry dates and continue spreading throughout the body. Scientists at the University of Tokyo have developed a synthetic version of a fungal compound that could help swing things back in our favor, by reactivating a missing gene that would normally drive these sinister cells to self-destruction.

As our cells fulfill their roles and edge towards the end of their lives, they undergo a form of programmed death called apoptosis, clearing the way for fresher and healthier cells. But with the help of genetic mutations, cancer cells are able to avoid this fate and go on multiplying to form tumors.

Targeting this mechanism and initiating apoptosis in cancer cells has been a major focus for researchers in the field, with compounds in olive oil and others that flush them with salt a couple of techniques that have shown promise in recent times. And in a naturally occurring compound found in the fungus species Ascochyta, scientists uncovered another exciting possibility.

Previous experiments had shown this compound, called FE399, could trigger apoptosis in cancer cells in vitro, by reinstating the self-destruct gene that drives the programmed death process. The compound had shown particular promise against colorectal cancer, but the complex nature of the compound meant that reproducing it in meaningful quantities was a tall order. Extracting natural versions of FE399 from the fungus was not a viable option, setting up a significant roadblock for use of this promising anti-cancer compound. But the University of Tokyo team was determined to find a way forward, and set out to develop a complete, synthetic version of the compound to pave the way for mass production.

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“We wanted to create a lead compound that could treat colon cancer, and we aimed to do this through the total synthesis of FE399,” says Professor Isamu Shiina, study author.

The team started by identifying the complex structure of the compound. A long process of trial and error followed until, in what the researchers describe as a major breakthrough, they produced a trio of spots on a plate bearing exactly the same chemical signature as FE399.

“We hope that this newly produced compound can provide an unprecedented treatment option for patients with colorectal cancer, and thus improve the overall outcomes of the disease and ultimately improve their quality of life,” says Professor Shiina.

The research was published in the journal European Journal of Organic Chemistry.

Source: https://newatlas.com/