(Press-News.org) EMBARGOED UNTIL DECEMBER 9, 2023, AT 12:45 P.M. ET
A new study from researchers with Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and collaborating organizations provides insight into the underlying mechanisms of gene mutations commonly seen in patients with myelodysplastic syndromes (MDS) and other myeloid neoplasms.
Their findings, to be presented at ASH 2023, the American Society of Hematology’s annual meeting in Santa Diego, Dec. 9-12, could lead to development of more effective drug combinations and targeted therapies for MDS patients carrying these mutations.
Background
About half of MDS patients carry genetic alterations, also known as somatic mutations, in the spliceosome genes, with SF3B1 being the most common one. However, no successful therapy exists to target this pathway.
Previous findings from a phase 2 clinical trial of selinexor, an Exportin-1 (XPO1) inhibitor for relapsed or refractory MDS, showed increased effectiveness in patients with SF3B1-mutated MDS. Exportin-1 is the nuclear export receptor responsible for exporting more than 200 proteins, but also plays a role in transporting multiple small nuclear RNAs and select messenger RNAs.
Sylvester researchers and collaborators hypothesized that 1) inhibiting XPO1 may preferentially affect SF3B1-mutant cells via altered splicing and 2) high-risk MDS patients with this mutation would have a better response to dose-controlled, targeted drug combinations with next-generation XPO1 inhibitors.
Methodology
For this study, the researchers deployed a combination of scientific techniques in their analysis, including:
RNA sequencing to evaluate the underlying mechanism for the SF3B1 mutation’s sensitivity to XPO1 inhibitors.
Whole genome CRISPR screens in two myeloid leukemia cell lines with eltanexor, a next-generation XPO1 inhibitor with lower toxicity than the drug selinexor. The analyses identified several novel targets that were tested for synergy in combination with eltanexor for the specific SF3B1 mutation. Two drugs were identified for strong synergy with eltanexor: venetoclax and navitoclax.
In vitro studies to test combinations identified from the CRISPR screen using cell viability tests and western blots.
In vivo studies to further validate these combinations through use of transplant tests in laboratory mice.
Expert Commentary
“This is the first study to examine the effects of XPO1 inhibition on RNA export to better understand the underlying mechanisms involved with the most common mutation seen in MDS patients,” explained Sana Chaudhry, Sylvester researcher and lead presenter at the ASH conference.
“Our study’s findings may contribute to development of synergistic therapeutic combinations to better treat SF3B1-mutant MDS,” said Justin Taylor, M.D., senior author and a member of the Translational and Clinical Oncology Program at Sylvester.
Additionally, Taylor noted, recent data from human studies has shown that venetoclax can overcome the poor prognosis often associated with acute myeloid leukemia patients with mutations. “As a result, combining eltanexor with venetoclax could represent a potentially effective SF3B1-specific therapy,” he concluded.
_ _ _
Disclosures
The authors had no relevant conflicts of interest to declare.
# # #
Presentation Title:
44 “Altered RNA Export in SF3B1 Mutants Increases Sensitivity to Nuclear Export Inhibition”
Presentation Date/Time:
Saturday, Dec. 9, 2023, 9:45 am
END
SAN DIEGO – Early results from a Phase I clinical trial of AT101, a new CAR T cell therapy that uses a distinct binding mechanism to target CD19, show a 100 percent complete response (CR) rate at the higher dose levels studied in the trial, according to researchers from the University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center. The findings were published today in Molecular Cancer and presented at the 65th American Society of Hematology (ASH) Annual Meeting ...
Older patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who were not good candidates for the standard treatment of intensive chemotherapy had a median overall survival (OS) of 6.5 years on an alternate regimen of dasatinib and blinatumomab.
These long-term results from the S1318 clinical trial will be presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego on December 9 (abstract 1499).
Anjali S. Advani, MD, a SWOG investigator at Cleveland Clinic Cancer Institute, led the study, with ...
Mindfulness-Oriented Recovery Enhancement (MORE) — a behavioral intervention that integrates training in mindfulness, emotion regulation strategies and savoring of natural rewards — could hold the key to mitigating relapse in women undergoing medically assisted opioid use disorder treatment, a Rutgers study found.
The pilot study published in the journal Explore, is the first to evaluate the potential neural changes that underlie women’s emotion regulation and craving after an eight-week MORE intervention.
Previous studies have shown that women report higher opioid craving and show a greater inability to ...
Imagine if scientists developed a customizable cancer vaccine that was available — and affordable — for everyone. What if a patient scheduled for surgery also had the option of taking a pill whose composition includes nanorobotics capable of performing the procedure?
These and other medical scenarios may seem far-fetched and better suited to a science fiction thriller. However, the Advanced Research Projects Agency for Health (ARPA-H) is seeking to take such ideas from the drawing board to ...
Almost US$7 trillion per year in government subsidies and private investment - around 7 per cent of global GDP - has a direct negative impact on nature.
Nature-based solutions remain dramatically underfunded. Current public and private finance flows are only US$200 billion per year. To meet climate, biodiversity, and restoration targets, this needs to triple by 2030 and quadruple by 2050.
Realignment of public and private nature-negative finance flows is urgently needed
Dubai, 9 December 2022 – Close to $7 trillion is invested globally each year in activities that have a direct negative impact on nature from both public and private sector sources - equivalent to ...
Tokyo, Japan – Researchers from Tokyo Metropolitan University have measured how oxygenated hemoglobin levels in the blood change in infants’ brains in response to touch. Using spectroscopy methods with external sensors placed on the scalp of sleeping infants, they found that the time at which levels peak doesn’t change with infant age, but the amount by which it varies over time does. Insights like this shed light on how the physiology of infants develop.
The first phase of a newborn’s life is a dazzling array of rapid developmental ...
Which charities will be most effective in ensuring your donation is put to good use? For the first time in the Netherlands, researchers applied scientific methods to pinpoint which charities achieve the most with the donations they receive. The University of Amsterdam and Stichting Doneer Effectief (Donate Effectively Foundation) unveiled the list on Friday, 8 December, during a sold out evening in Rotterdam. ‘We are talking about the Champions League of good causes,’ says professor of Philanthropy & Sustainable Investment Paul Smeets of the University of Amsterdam. The ranking ...
The shimmering green, red and purple curtains of the northern and southern lights — the auroras — may be the best-known phenomena lighting up the nighttime sky, but the most mysterious are the mauve and white streaks called Steve and their frequent companion, a glowing green "picket fence."
First recognized in 2018 as distinct from the common auroras, Steve — a tongue-in-cheek reference to the benign name given a scary hedge in a 2006 children's movie — and its associated picket fence were nevertheless thought to be caused by the same physical processes. But scientists were left scratching their heads about how these glowing emissions ...
The High Energy Physics Advisory Panel (HEPAP) to the High Energy Physics program of the Office of Science of the U.S. Department of Energy and the National Science Foundation’s Division of Physics has released a new Particle Physics Project Prioritization Panel (P5) report, which outlines particle physicists’ recommendations for research priorities in a field whose projects — such as building new accelerator facilities — can take years or decades, contributions from thousands of scientists, and billions of dollars.
The 2023 P5 report represents the major activity in the field of particle physics that ...
CHAPEL HILL, NC — Eating food and absorbing its nutrients is an everyday occurrence, but this normal activity can look different for someone who suffers from inflammatory bowel disease. IBD, which includes Crohn’s disease and ulcerative colitis, can cause chronic inflammation of the digestive tract – which for many reasons can lead to malnutrition. This malnourished state is associated with an increased risk of morbidity and mortality, and new findings show that many patients in IBD clinic screen positive for malnutrition, leading to the critical need for same-day ...
