“Polygenic Adaptation”
Researchers at Northwestern have discovered a genetic "kill code" that might enable the destruction of cancer cells.
This novel new therapy "downstream" of chemo might destroy cancer cells without affecting the body's immune system.
While no animal trials have been conducted, this potential therapy could signal the demise of chemotherapy.
Abstract—Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2–7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing a preference for guanine in positions 1 and 2 and a high overall G or C content in the seed of the most toxic siRNAs for four tested human and mouse cell lines. Toxicity of these siRNAs stems from targeting survival genes with C-rich 3′UTRs. The master tumor suppressor miRNA miR-34a-5p is toxic through such a G-rich 6mer seed and is upregulated in cells subjected to genotoxic stress. An analysis of all mature miRNAs suggests that during evolution most miRNAs evolved to avoid guanine at the 5′ end of the 6mer seed sequence of the guide strand. In contrast, for certain tumor-suppressive miRNAs the guide strand contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.
A new study led by scientists in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI) sheds light on one way tumors may continue to grow despite the presence of cancer-killing immune cells. The findings, published March 29, 2019, in Science, suggest a way to enhance the effectiveness of immunotherapies for cancer treatment. NCI is part of the National Institutes of Health.
Dying cancer cells release the chemical potassium, which can reach high levels in some tumors. The research team reported that elevated potassium causes T cells to maintain a stem-cell-like quality, or “stemness,” that is closely tied to their ability to eliminate cancer during immunotherapy. The findings suggest that increasing T cells’ exposure to potassium—or mimicking the effects of high potassium—could make cancer immunotherapies more effective.
ROXANNE KHAMSI (WIRED)
“Even if cancer therapies kill most of the cells they target, a small subset can survive, largely thanks to genetic changes that render them resistant. In advanced-stage cancer, it’s generally a matter of when, not if, the pugnacious surviving cells will become an unstoppable force. Gatenby thought this deadly outcome might be prevented. His idea was to expose a tumor to medication intermittently, rather than in a constant assault, thereby reducing the pressure on its cells to evolve resistance.“
“In our recent publication in Science Advances, we describe the use of an in vivo-based functional genomics screen to identify genes whose inhibition potentiates a response to anti-PD-1 immunotherapy. Specifically, we define a novel mechanism whereby targeting the collagen receptor, discoidin domain receptor 2 (DDR2), elicits a significantly enhanced response to immune checkpoint blockade with PD-1 inhibitors. Of specific note is the observation this combination is robust across multiple tumor models including melanoma, sarcoma, breast, bladder and colon cancer indicating that DDR2 expression is an important and broadly used mechanism by cancer cells to escape checkpoint blockade therapy“
Deep in the cells of the human immune system, DNA is constantly being replicated, transcribed and even mutated — but rarely does it change dramatically. Like every other living organism, humans and their genes developed from millions of years of evolutionary pruning.
But to Yale microbiologists, altering the entire genomes of T-cells — the body’s main offensive weapon against diseases such as cancer — is as simple as putting together a Lego set.
Science (Review article)
Abstract—Cancer treatment decisions are increasingly based on the genomic profile of the patient’s tumor, a strategy called “precision oncology.” Over the past few years, a growing number of clinical trials and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors.
Epic Sciences has commercialized a blood test that can predict how likely a patient with late-stage prostate cancer treated with hormones is likely to respond to an additional course of such therapy. Now, the San Diego-based company has additional data that it says supports use of its tests to determine when not to use hormone therapy
A 290-gene expression signature and IGHV mutation status stratified patients with chronic lymphocytic leukemia to identify those with high-risk disease who might benefit from prompt initiation of therapy, according to a study published in Frontiers in Oncology.
Although CLL treatment is typically delayed until disease progression, it is uncertain whether patients would benefit from treatment immediately following diagnosis, when they have a smaller tumor mass and are in better physical condition.
Lucence Diagnostics, a genomic medicine company focused on personalizing cancer care, today announced a new project to develop AI algorithms for improving diagnosis and treatment of liver cancer. The goal is to combine the imaging and molecular data from liver cancer patients into smarter software tools that help physicians make better treatment decisions.
Lucence will be working with Olivier Gevaert, PhD, Assistant Professor of Medicine (Biomedical Informatics) and of Biomedical Data Science at the Stanford University School of Medicine. Having developed LiquidHALLMARK®, the world's first liquid biopsy next-generation sequencing test that analyzes the DNA of cancer-causing mutations and viruses, Lucence will contribute its genomics expertise and proprietary sequencing technology to this project.
Abstract
Cisplatin-based chemotherapeutic regimens are frequently used for treatments of solid tumors. However, tumor cells may have inherent or acquired cisplatin resistance, and the underlying mechanisms are largely unknown. We performed genome-wide screening of genes implicated in cisplatin resistance in A375 human melanoma cells. A substantial fraction of genes whose disruptions cause cisplatin sensitivity or resistance overlap with those whose disruptions lead to increased or decreased cell growth, respectively. Protein translation, mitochondrial respiratory chain complex assembly, signal recognition particle–dependent cotranslational protein targeting to membrane, and mRNA catabolic processes are the top biologic processes responsible for cisplatin sensitivity. In contrast, proteasome-mediated ubiquitin-dependent protein catabolic process, negative regulations of cellular catabolic process, and regulation of cellular protein localization are the top biologic processes responsible for cisplatin resistance. ZNRF3, a ubiquitin ligase known to be a target and negative feedback regulator of Wnt–β-catenin signaling, enhances cisplatin resistance in normal and melanoma cells independently of β-catenin. Ariadne-1 homolog (ARIH1), another ubiquitin ligase, also enhances cisplatin resistance in normal and melanoma cells. By regulating ARIH1, neurofibromin 2, a tumor suppressor, enhances cisplatin resistance in melanoma but not normal cells. Our results shed new lights on cisplatin resistance mechanisms and may be useful for development of cisplatin-related treatment strategies.—Ko, T., Li, S. Genome-wide screening identifies novel genes and biological processes implicated in cisplatin resistance.
NEW YORK (GenomeWeb) – The Centers for Medicare & Medicaid Services issued a notice this week acknowledging the confusion over its coverage policy for germline next-generation sequencing for cancer patients.
DNA is small. Really, really, small. So, when researchers want to study the structure of a single-stranded DNA, they can’t just pull out their microscopes: they have to get creative.
In a study published this week in Scientific Reports, researchers from Japan’s Osaka University explain how they came up with a really small solution to the challenge of studying anti-cancer drugs incorporated into single strands of DNA.
Identifying positions at which anticancer drug molecules incorporate into DNA is essential to define mechanisms underlying their activity, but current methodologies cannot yet achieve this. The thymidine fluorine substitution product trifluridine (FTD) is a DNA-damaging anticancer agent thought to incorporate into thymine positions in DNA. This mechanism, however, has not been directly confirmed. Here, we report a means to detect FTD in a single-stranded oligonucleotide using a method to distinguish single molecules by differences in electrical conductance. Entire sequences of 21-base single-stranded DNAs with and without incorporated drug were determined based on single-molecule conductances of the drug and four deoxynucleosides, the first direct observation of its kind. This methodology may foster rapid development of more effective anticancer drugs.
Chimeric antigen receptor (CAR) T cells are about as cutting-edge as cancer care gets today. Having demonstrated the ability to eradicate tumor cells in up to 90% of patients with certain blood cancers, these engineered immune cells became the first class of gene therapy to win FDA approval in 2017—with Novartis’ Kymriah getting the nod in August, followed by Kite Therapeutics’ Yescarta in October.3 But Alexander Marson, MD, PhD, knows these sophisticated cells are capable of so much more.
Marson, an immunologist at the University of California at San Francisco, is exploring this potential by using the CRISPR-Cas9 system to introduce precisely targeted genome modifications. The idea is that by adding or deleting specific genomic sequences, one can make these cells more lethal for tumors but also safer for the patient. Marson’s team recently developed a platform called SLICE4—single-guide RNA (sgRNA) lentiviral infection with Cas9 protein electroporation—to perform diverse CRISPR modifications in many cells in parallel, in hopes of rapidly identifying changes that measurably improve CAR T-cell performance. “We’re pretty good at manufacturing the ‘hardware’ of gene edited cells, and we’re continuing to improve that,” says Marson. “The really interesting thing will be what genetic ‘software’ we can put into them.”
