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Risk Factors For Leukemia
Family History of LeukemiaYour risk of getting leukemia may be greater if one of your family members has also been diagnosed with it. (1)
Having a parent with leukemia doesn't seem to raise a child's risk for leukemia. But siblings of children with leukemia are more likely to develop the cancer.
This risk is also increased for identical twins. If a twin develops childhood leukemia, the other twin has about a 1 in 5 chance of having it as well. (7)
Environmental Factors Linked to LeukemiaMany environmental factors have been linked to leukemia, including:
You may have heard that living near power lines or a nuclear power plant can raise the risk of leukemia. There's not enough hard evidence to show these exposures are strong risk factors. Researchers continue to study this possible link. (7)
Blood DisordersHaving certain blood disorders, such as myelodysplastic syndrome (MDS), polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis, can increase your risk of developing AML.
Related: What Are the Risk Factors for Cancer?
Since scientists don't know exactly what causes it, there's no surefire way to prevent leukemia.
But avoiding certain triggers, such as exposure to cigarette smoke, chemicals, pesticides, and radiation, may lower your chances of getting leukemia.
Maintaining a healthy diet along with regular exercise may also help you avoid many types of cancer, including leukemia. (9)
FDA Awards Grant For Phase 1 Clinical Trial Of Experimental AML/MDS Treatment
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)-;two related blood diseases that disproportionally strike older adults-;are notoriously difficult to treat and associated with high relapse rates. Although new therapies have improved survival, treatment options remain limited, and the prognosis for the 50% of people who experience disease relapse remains poor.
Researchers at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC) were recently awarded a four-year, $2.6 million grant from the U.S. Food and Drug Administration (FDA) to conduct an innovative phase 1 clinical trial of a new drug for patients with relapsed and treatment-resistant forms of AML and MDS. It is one of only 10 grants issued this year by the FDA through its Office of Orphan Products Development.
"This is a tremendous opportunity to apply the knowledge we have developed in our MECCC labs over the past decade to develop a novel therapeutic strategy," said Aditi Shastri, M.D., the principal investigator of the grant, a member of MECCC's Stem Cell and & Cancer Biology Research Program and Blood Cancer Institute, and associate professor of oncology, medicine, and developmental and molecular biology at Albert Einstein College of Medicine.
Drugs that initially work against AML are ineffective when the disease returns. Research suggests that those treatments leave behind leukemic stem cells that are resistant to existing medications and lead to relapsed and drug-resistant AML and MDS.
We have identified a molecular target in leukemic stem cells and a novel drug that performed well against those stem cells in pre-clinical studies. We are eager to see if this drug and its combinations can provide clinical benefit for our patients."
Aditi Shastri, M.D., principal investigator of the grant
AML and MDS are rare diseases with among the worst prognoses of all cancers: most people who develop relapsed or treatment-resistant disease live for only another 4 to 10 months. Since AML is so difficult to treat, most patients receive care at academic cancer centers. MECCC, with its Blood Cancer Institute and Stem Cell and Cancer Biology Research Program, is one of a few institutions in the country specializing in AML and MDS.
In 2018, Dr. Shastri and colleagues found that relapsed AML and MDS patients with the worst prognosis have leukemic stem cells that express excessive levels of the protein STAT3. In subsequent studies, her lab found that STAT3 does several things to help MDS and AML cancer cells survive; most importantly, STAT3 prevents cancer cells from undergoing apoptosis, known as programmed cell death-;the goal of a major AML/MDS drug called venetoclax. Dr. Shastri hypothesized that blunting the impact of STAT3 could make venetoclax more effective and lead to better outcomes for patients.
Dr. Shastri then looked for compounds that specifically targeted STAT3 and identified the novel targeted drug danvatirsen: a STAT3 inhibitor developed by Flamingo Therapeutics and Ionis Pharmaceuticals that is now being developed as a cancer treatment in early-phase clinical trials. After conducting preclinical tests indicating that danvatirsen shows promise against AML/MDS, Dr. Shastri is investigating the drug in a phase 1 clinical trial.
The trial is slated to begin this month and will enroll patients with therapy-resistant MDS and AML at MECCC and MD Anderson Cancer Center in Houston, Texas. "Since this is a phase 1 trial, our first priority is to determine the safety of danvatirsen when used alone and in combination with venetoclax, as well as the optimal dosages for the two drugs," Dr. Shastri said. "We will investigate the effect of danvatirsen, alone and in combination with venetoclax, on leukemic stem cells."
If the researchers find evidence that the experimental treatment has clinical activity, they will expand the study to a phase 2 trial to further assess the treatment's effectiveness. The co-principal investigator of the clinical trial is Naval Daver, M.D., at the MD Anderson Cancer Center. MECCC co-investigators on this grant are Marina Konopleva, M.D., and Ulrich Steidl, M.D., Ph.D.
Scientists Uncover New Therapeutic Targets For High-risk Pediatric Leukemia
Scientists at St. Jude Children's Research Hospital comprehensively identified genes directly regulated by a protein associated with high-risk pediatric leukemias. High-risk leukemias, particularly MLL-rearranged (MLL-r) leukemia, often overexpress the homeodomain transcription factor HOXA9 protein, which cannot currently be targeted with drugs. This study provides a foundation for revealing the HOXA9 regulation network and finding novel drug targets downstream of HOXA9 that can form the basis of new treatments. The findings were published today in Nature Communications.
HOXA9 is a transcription factor, a type of protein that binds DNA to regulate the expression of other genes. Overexpression of HOXA9 is a hallmark in many cancers, including high-risk leukemias, such as the MLL-r subtype. Finding the genes regulated by HOXA9 could reveal new ways to treat leukemia by undermining how the protein helps cancers grow and survive.
Due to the technical challenges of working with HOXA9, the downstream regulation network of the protein was poorly understood. The St. Jude team established a unique system to find these genes regulated by HOXA9.
We confirmed two major known targets, FLT3 and CDK6. Both genes can be therapeutically targeted by drugs, which shows good outcomes in preclinical models with HOXA9 overexpression. Our results provided direct evidence to support the enhancer regulation of FLT3 and CDK6 through HOXA9."
Chunliang Li, Ph.D., corresponding author, St. Jude Department of Tumor Cell Biology
In addition to these well-studied genes, the scientists found 227 other target sites bound by HOXA9. Many of those sites were located at noncoding regulatory regions, likely enhancers. They validated the top 10 candidates in cell-based experiments conducted in collaboration with computational biologists from the St. Jude Center for Applied Bioinformatics. Several of these hits explained previous results observed using current Food and Drug Administration-approved drugs, which lends credibility to the other results from the screen and suggests they may be productive targets for novel leukemia drugs.
To perform the screen, the St. Jude group established a TetOn-inducible system to express tagged HOXA9 in MLL-r leukemia cell lines. Using this unique research tool followed with chromatin immunoprecipitation sequencing (ChIP-seq) technology, they successfully identified where in the genome HOXA9 binds DNA in MLL-r leukemic cells.
"Using state-of-the-art research tools and elegant model systems, we have a better understanding of how HOXA9 works in high-risk leukemia cells," said co-first author Shaela Fields, St. Jude Department of Tumor Cell Biology. "Now, we can start the long process to find and develop new drugs to make our patients healthier by taking advantage of that information."
Overcoming a HOXA9 family problemWhile it was previously known that HOXA9 is overexpressed in high-risk pediatric leukemias, it has historically been challenging to study and target. The HOX family of proteins contains 39 members, which are all very similar to each other. The similarity also makes it challenging to study because current techniques have trouble distinguishing between the HOX proteins. Functionally, other HOX family members could potentially compensate for HOXA9 function upon targeting.
With that in mind, the researchers created a system that identified the genes bound specifically by HOXA9 in a certain leukemia subtype (mixed-lineage leukemia rearrangement or MLL-r) by inserting a tag onto HOXA9.
"Imagine you are in a dog park and need to find a certain golden retriever, but there are a bunch of them running around, and you don't know which one is yours because all the dogs look the same," said Li. "If you put a neon pink harness on your dog beforehand, it's easy to find among the group. That is how we could track everywhere HOXA9 went."
The small tag does not affect HOXA9's regular function and makes HOXA9 easy to trace in cells. The researchers then sequenced the attached DNA to identify the leukemia-related genes bound by HOXA9, allowing scientists to study this relatively small list of genes that may be amenable to therapeutic development.
"We narrowed hundreds of thousands of targets to just over two hundred by comparing to controls," said Fields. "And when we can investigate the regulation mechanism and network of HOXA9, and what's happening in the cells, that's where hopefully we can find ways to help kids with high-risk cancers get better."
Authors and fundingThe study's other co-first author is Xujie Zhao, formerly of St. Jude. The study's other authors are Wojciech Rosikiewicz, Judith Hyle, Wenjie Qi, Zhenling Liu, Siqi Yi, Yong Cheng and Beisi Xu, all of St. Jude; and Shelby Mryncza, Rhodes College.
The study was supported by grants from the National Cancer Institute (5P30CA021765), American Cancer Society (RSG-476 23-874240-01-DMC), V-Foundation (V2021-010) and ALSAC, the fundraising and awareness organization of St. Jude.
Source:
Journal reference:
Wright, S., et al. (2023). Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens. Nature Communications, 14(1), 7464. Doi.Org/10.1038/s41467-023-43264-5.
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