Updated: Jun 15
The following is my second high-level overview of medical papers and news articles, panned primarily for my own purposes to raise my level of knowledge and awareness of the current efforts in the fields of personal interest to me. But even with this preliminary coverage, it is difficult not to notice some important observations:
Research is definitely moving quickly past just genomic testing, to more use of epigenomics and metabolomics.
As expected, new technology and big data analytics play significant roles in research.
This list of papers is not in any sequence (but all published recently, this month of January 2022) and I make only the smallest of comments, but perhaps there may be some gems for those with a voracious appetite for reading such things . . . enjoy. This review includes an eclectic gathering of 13 topics:
Metabolites s biomarkers
Re-programming of epigenetics (methylation)
RNA Switches for safety
Mapping of cancer archetypes to immune microenvironment
Molecular biology of the spleen
Cloud based genetic data available to include smaller research facilities
2nd generation of CAR-T
Magnetic removal of naïve T-Cells prior to aHSC Transplant procedures
- Russ Hardy
[Note: Russ' comments are offset in gray, and research article exerpts are included in "quotes".]
I found this article of some interest (looking at some of the elements of life form abilities to resist cancer).
More information: Angelo Fortunato et al, Upregulation of DNA repair genes and cell extrusion underpin the remarkable radiation resistance of Trichoplax adhaerens, PLOS Biology (2021). DOI: 10.1371/journal.pbio.3001471
Journal information: PLoS Biology
“A simple, marine-dwelling creature known as Trichoplax adhaerens has some remarkable properties. The organism can tolerate unusually high doses of radiation that would kill most other forms of life. T. adhaerens has another intriguing characteristic: the ability to resist cancer. T. adhaerens is an attractive model organism, enabling researchers to home in on fundamental processes of radiation tolerance as well as the underlying mechanisms guiding DNA repair, programmed cell death and other natural means of cancer resistance. A tumor-suppressing gene known as TP53, can act to repair damaged DNA. Through a combination of aggressive DNA repair and ejection of damaged cells, T. adhaerens engage in continual bodily renewal, keeping them cancer-free.”
An important cellular process that is needed in many cancer treatments is that of DNA Repair. This paper shows progress with visualization of these processes to enable better understanding of the underlying protein mechanisms.
More information: Raul Mostoslavsky, Assessing kinetics and recruitment of DNA repair factors using high content screens, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.110176. www.cell.com/cell-reports/full … 2211-1247(21)01676-4
Journal information: Cell Reports
“As soon as there is DNA damage, such as a DNA double-strand break, the cell activates a mechanism named DNA damage response that acts like a "call to the emergency services," Martinez explains. Proteins rapidly bind damaged DNA to send alarm signals, which will be recognized by other proteins specialized in repairing the damage. They visually monitored 300 proteins after generating genetic damage (and also discovered 9 additional proteins involved with DNA Repair). They saw that many proteins adhered to damaged DNA, and others did just the opposite: they moved away from the DNA lesions. “
This is a magazine article that introduces the concept of using Metabolites as a bio marker of cancer and related metastasis.
James R. Larkin, Susan Anthony, Vanessa A. Johanssen, Tianrong Yeo, Megan Sealey, Abi G. Yates, Claire Friedemann Smith, Timothy D.W. Claridge, Brian D. Nicholson, Julie-Ann Moreland, Fergus Gleeson, Nicola R. Sibson, Daniel C. Anthony and Fay Probert
The test, developed by researchers at University of Oxford, uses a new technique called NMR metabolomics, which identifies the presence of biomarkers in the blood, called metabolites. These are small chemicals that our body naturally produces.
“Metabolites are any small molecules in blood such as glucose, lactic acid, or amino acids,” explained oncologist Dr James Larkin, who worked on the study. “The exact pattern of metabolites present in your blood varies depending on what is going on in your body, something which is influenced by diseases like cancer.”
“The goal is to produce a test for cancer that any GP can request,” said Dr Fay Probert, lead researcher of the study. “We envisage that metabolomic analysis of the blood will allow accurate, timely and cost-effective triaging of patients with suspected cancer, and could allow better prioritisation of patients based on the additional early information this test provides on their disease.”
This paper covers recent treatment processes aimed at re-programming epigenetics (admittedly this particular paper was regarding solid brain tumours, but similar studies have also been done for leukemias).
Drug modifies epigenome in aggressive brain tumors by Vanderbilt University Medical Center, January 5, 2022, Cancer Research Communications. Stephen Clark, MD, Ph.D., a neuro-oncologist at Vanderbilt-Ingram Cancer Center
“A folic acid-like drug, L-methylfolate, when administered alongside the standard therapy for patients with recurrent glioblastoma, changed a DNA process within their brain tumors, according to results from a phase 1 clinical trial. The DNA methylome is one aspect of the epigenome; Epigenetic reprogramming is not a new concept; for instance, a DNA methyltransferase inhibitor treatment (5-Azacytidine) has been studied and is approved for the treatment of some leukemias. What is exciting about this work is that L-methylfolate, acts oppositely to 5-Azacytidine; it increases the availability of the active folate for the DNA methyltransferases.”
This paper reviews new Synthetic RNA Switches (micro RNA’s, miRNA) to improve the selectivity (and safety) of genetically engineered Induced pluripotent stem cells (iPSCs).
More information: Yoshihiko Fujita et al, A versatile and robust cell purification system with an RNA-only circuit composed of microRNA-responsive ON and OFF switches, Science Advances (2022). DOI: 10.1126/sciadv.abj1793
Journal information: Science Advances
“Because iPS cells can be made into just about any cell type in the body, they have great promise for cell therapies. One major problem, however, is that not all reprogramming cells successfully become iPS cells, resulting in an unwanted cell mixture. new synthetic RNA technology consisting of ON and OFF switches. These switches control specific genes to kill contaminating cells while leaving desired cells unscathed at rates superior to standard techniques. Our method is applicable to a wide range of cell types that can then be used to study disease, drugs, and cell therapies.”
This study attempts to match cancer archetypes with the microenvironment of immune defences (macrophages, NK, B-cells and T-cells) with a goal of better precision for immunotherapy treatments. The paper appears to be related primarily to solid tumour cancers, but since it is a subscription service, I was not able to read the details.
More information: Alexis J. Combes et al, Discovering dominant tumor immune archetypes in a pan-cancer census, Cell (2021). DOI: 10.1016/j.cell.2021.12.004, dx.doi.org/10.1016/j.cell.2021.12.004
Journal information: Cell
“Immunotherapy for cancer treatment harnesses the body's immune system to fight cancer. It has held great promise since it was first developed as a biological therapy used to treat a variety of cancers. While it has proven successful for some patients, immunotherapy does not work for all patients. The classification scheme not only identifies which tumors are likely to be vulnerable to current immunotherapies, it also helps identify which patients might be most responsive in which clinical trial."
This paper provides more information on the molecular biology of the spleen. The spleen is typically adversely impacted by MPN cancers, and the spleen is so important to immune system homeostasis and functionality. Currently, an important field for research and treatments of MPN is that of immunotherapies and thus more awareness of the underlying molecular functionalities of the spleen is of some importance/interest to those involved with clinical practices for MPN. Again, since the paper is a subscription-based service, I was not able to take a deep dive into this topic.
More information: Yannick O. Alexandre et al, A diverse fibroblastic stromal cell landscape in the spleen directs tissue homeostasis and immunity, Science Immunology (2022). DOI: 10.1126/sciimmunol.abj0641
Journal information: Science Immunology
“Researchers at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) have discovered a new gene (gene SpiB) that plays an important role in the way the spleen functions, potentially leading to new treatments; The study, published in Science Immunology, also uncovered multiple new spleen cells and revealed the distinct way they respond to attacks. By surveying the fibroblast landscape of the spleen and providing the first in-depth look at the gene expression, we have been able to create detailed plans to the scaffold of this unique organ, Professor Mueller said.”
This paper introduces Information Technology for genetic research by placing a large easily accessible database into a ”Cloud” base, paving the way for even small research facility to have better access to an increasingly data intensive environment.
More information: Michael C. Schatz, Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL), Cell Genomics (2022). DOI: 10.1016/j.xgen.2021.100085. www.cell.com/cell-genomics/ful … 2666-979X(21)00106-3
“Harnessing the power of genomics to find risk factors for major diseases relies on the costly and time-consuming ability to analyze huge numbers of genomes. Known as AnVIL (Genomic Data Science Analysis, Visualization, and Informatics Lab-space), the new platform gives any researcher with an internet connection access to thousands of analysis tools, patient records, and more than 300,000 genomes. AnVIL will be transformative for institutions of all sizes, especially smaller institutions that don't have the resources to build their own data centers. It is our hope that AnVIL levels the playing field, so that everyone has equal access to make discoveries. It also makes sharing datasets much easier so that data can be connected in new ways to find new associations, and it simplifies a lot of computing issues, like providing strong encryption and privacy for patient datasets."
This paper describes the “second generation” of CAR-T immunotherapy. The current therapy does not work for everyone and is prone to two vulnerabilities: CARs are highly reliant on target antigen density, and, as a consequence, CAR-T cells lose their functionality when antigen expression drops below a certain threshold and also sometimes CAR T cells don't persist long enough after transfusion. This may be solved by adding a second “receptor” to the therapy.
More information: Afroditi Katsarou et al, Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abh1962
Journal information: Science Translational Medicine
“CAR T cells—chimeric antigen receptor T cells—start out as the patients' own T cells isolated from a blood sample, but the cells are primed in a laboratory using a genetic modification process that causes T cells to express a cancer-seeking-and-destroying receptor on their surface. CAR T cell therapy is used in the treatment of certain cancers of the blood. The authors are using a novel approach that involves attaching not one, but two engineered receptors to T cells; one was the traditional chimeric antigen receptor and the other a chimeric costimulatory receptor, or CCR.”
“Currently, there are five CAR T cell drugs that have been approved by the U.S. Food and Drug Administration: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Kymriah (tisaglenlecleucel); Tecartus (brexucabtagene autoleucel), and Yescarta (axicabtagene ciloleucel)."
This clinical study describes an approach to aHSC transplant preparations and conditioning to improve the potential for more favourable outcomes (that is reduced chances of graft versus host disease complications).
Novel transplant approach improves the odds for leukemia patients; Naïve T cells that lead to graft-vs.-host disease removed with magnets. By Sabin Russell / Fred Hutch News Service , January 10, 2022
Fred Hutch physician-scientist Dr. Marie Bleakley is lead author of the study published in the Journal of Clinical Onocology
“In the latest and largest study yet of a novel technique for treating leukemia patients, researchers have affirmed that it dramatically reduces a common debilitating side effect — chronic graft-vs.-host disease — in those receiving blood stem cell transplants. The experimental approach, which uses a kind of magnetic filter to remove certain immune cells before transplant, reduced the rate of patients developing chronic GHVD to 7%, compared to rates ranging from 30% to 60% using the current standard of care. Unfortunately, these naïve cells are primed to go after the first “foreign” cells they encounter, which may be the patient’s own tissues. Her approach borrows from a 30-year-old technique used by basic researchers to separate cells in biological laboratories: They tap magnetism to pull them out of the mix. Naïve T cells are therefore coated with iron-bearing antibodies, latched to the telltale CD45RA proteins, and voila: They are drawn by a magnet out of the soup of about-to-be transplanted immune cells. “
“The team is awaiting results of trials in which results from the selective naïve-T cell depletion technique are compared to those of participants randomly assigned to a competing technology. Two such trials are now enrolling patients. Bleakley is principal investigator for both of them."
This paper proposes the use of safer delivery methods for therapeutics to diseased tissues.
More information: Huawei Wang et al, Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue, Nature Biomedical Engineering (2021). DOI: 10.1038/s41551-021-00815-9
Journal information: Nature Biomedical Engineering
“Researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health report successfully removing the nucleus out of a type of ubiquitous cell, known as enucleation, then using the genetically engineered cell as a unique cargo-carrier to deliver therapeutics precisely to diseased tissues. They genetically modified mesenchymal stromal cells (MSCs) to boost their disease-seeking behavior, then removed their nuclei while retaining organelles that produce energy and proteins needed for therapeutic functions.”
“Cargocytes have a more defined and predictable fate after administration to the body because they cannot perform new gene transcription, eliminating the possibility that they may produce unwanted factors, differentiate into unwanted cell types or graft onto tissues in undesirable ways. Klemke said next steps involve optimizing the ability of Cargocytes to deliver multiple different therapeutics to diseased tissues in vivo, explore opportunities to engineer and enucleate other cell types, such as immune cells, and develop a similar approach to seek out and eradicate metastatic cancers that have spread throughout the body.”
This paper shows some advances with testing beyond today’s genomic, limited throughput narrow focus testing. Using new technologies and processes they are improving the knowledgebase of “Variant-to-Impact” awareness on a spectrum of impacts beyond just the binary “cancer driver or passenger” classification models.
More information: Oana Ursu et al, Massively parallel phenotyping of coding variants in cancer with Perturb-seq, Nature Biotechnology (2022). DOI: 10.1038/s41587-021-01160-7
Journal information: Nature Biotechnology
“There are millions of mutations and other genetic variations in cancer. Understanding which of these mutations is an impactful tumor "driver" compared to an innocuous "passenger," and what each of the drivers does to the cancer cell, however, has been a challenging undertaking. Their results, gained through proof-of-concept experiments with cancer cell lines, also show that individual mutations can have a spectrum of effects not only on their impacted genes but also on molecular pathways and cell state as a whole, and add nuance to the long-accepted practice of dividing cancer mutations into so-called "drivers" and "passengers."
“The new method, called single-cell expression-based variant impact phenotyping (sc-eVIP), builds on Perturb-seq—an approach developed in 2016 by Regev and colleagues for manipulating genes and exploring the consequences of those manipulations using high-throughput single-cell RNA sequencing—and eVIP, a method also developed in 2016 by Boehm and colleagues for profiling cancer variants at low scale using RNA measurements.”
“The team chose to study TP53—the most commonly mutated gene in cancer—and KRAS—which encodes a key oncogene responsible for abnormal growth of many cancers. Initial findings suggest that biologically those categories (a binary conceptual framework of 'driver' mutations, ones that promote cancer development and progression, versus 'passenger' mutations) are likely overly simplistic, that there's actually a continuum of functional impact from inert to completely tumorigenic." "If we can map where every cancer-associated variant fits on the continuum of impact in a variety of cancers and cell types," Boehm said, "we'll have a much better grasp of how the interplay of variants affects cell state, which in turn affects cancer development, growth, and response. Such knowledge would represent a true advance toward cancer precision medicine."
This paper adds a third initiation of cancer mutations; traditionally the two primary groups are somatic or germline but now there is a third - this circumstance, called embryonic mosaicism, occurs when a mutation that increases the risk of cancer arises very early in development, when an embryo consists of only a few cells.
Cancer Causative Mutations Occurring in Early Embryogenesis,
DOI: 10.1158/2159-8290.CD-21-1110, December 2021
“Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSGs); establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers. “Our study suggests that it occurs in about 1 in 1,000 cancer patients, making it more common than we previously believed it to be.”
“One reason this finding is important is that, unlike a somatic mutation that develops only in certain tissues, these mutations can be passed down to future generations if they occur early and affect the gametes (eggs or sperm). Additionally, the presence of these mutations can have implications for treatment with certain types of personalized medicine. The presence of these mosaic mutations suggests that someone may be at risk for future cancers, which can influence cancer screening. By using advanced mathematical models, we have found that these mutations likely occurred in the first five cell divisions of embryogenesis.”
“These analyses established a causal relationship between the mosaic variants and the development of the respective cancers. The new study suggests that more patients could benefit from certain treatments — but only if their mosaicism is detected. For example, people with inherited BRCA mutations respond well to targeted therapies called PARP inhibitors. Those with Lynch syndrome respond well to immunotherapy drugs called checkpoint inhibitors.