Using Epigenetic Profiling Tools to Understand Pediatric Cancers
Identifying and testing chromatin-altering drugs for reduced toxicity, treatment resistance, and relapse
Technology Overview
Epigenetic abnormalities often influence childhood cancers, in contrast with adult cancers, which are most often driven by mutations in oncogenes. Epigenetics, which refers to the packaging and accessibility of DNA, affects gene expression. Access to DNA is regulated in part by how tightly the DNA associates with histones and other proteins into a chromatin structure. Histone methylation is an example of one such regulator.
Jay F. Sarthy, MD, PhD, a hematologist-oncologist who specializes in pediatric bone marrow transplantation, studies new pediatric cancer treatments that act through epigenetic targets. He is working on several treatment approaches that have strong potential to be effective against cancers such as lymphomas that evade treatment or tend to reappear after treatment.
One million cancer patients a year are treated with chemotherapy using anthracyclines, which damage the DNA of cancer cells. These compounds, while effective, are also cardiotoxic. Comparison of two anthracyclines, doxorubicin (Adriamycin) and aclarubicin, has shown aclarubicin is much less toxic. It has been used in Europe and is widely used in Asia for older adult patients because of its lower toxicity.
In mice, aclarubicin kills cancer cells more effectively and safely than doxorubicin. Work from the Sarthy Lab and others has found that anthracyclines have an overlooked epigenetic effect that underlies their potency in cancer. Aclarubicin is ideal for frontline treatment of pediatric cancers due to its reduced potential to cause long-term effects such as heart problems, infertility and secondary cancers. As more children are surviving cancer and living longer, lower toxicity is particularly important because patients may live for decades after cancer treatment.
Another line of research in the Sarthy Lab includes identifying ways to target specific histone variants that are involved in several cancers, including lymphomas. Sarthy and team have determined that a specific DNA-binding protein, H2A.B, which is normally expressed only in developing sperm cells, can be abnormally expressed in some cancers but not in healthy cells in the body. This differential expression makes variants such as H2A.B an excellent selective target for anticancer therapies.
More broadly, Sarthy’s research seeks to understand whether epigenetic diversity enables cancer cells to resist treatment or come back after treatment. In proof-of-concept studies, Sarthy and team demonstrated that variation among individual cells from a single tumor sample can explain and predict resistance to treatment and possible relapse in patients. The Sarthy Lab arrived at this finding using an advanced method for automated quantification of gene expression and chromatin accessibility in single cells called high-throughput CUT&Tag (cleavage under targets and tagmentation). This epigenomic profiling method is similar to chromatin immunoprecipitation (ChIP) but more powerful for pinpointing chromatin features, including histone modifications that are associated with individual genes. Sarthy also developed a related method for careful quantitation of gene-specific histone modification levels using high-throughput CUT&RUN (cleavage under targets and release using nuclease) profiling that is ideal for characterizing response of cancer cells and specimens to epigenetic therapies.
More recently, Sarthy’s team also used this method of chromatin profiling to identify the chromatin-associated factor BRG1 as a driver of a rare but lethal form of infant leukemia driven by the CBF-GLIS2 fusion protein. The team is now working with industry to test BRG1 inhibitors in children with this deadly disease. Sarthy's lab has expertise in murine pediatric cancer models, including hematological, solid tumor and CNS malignancies, and thus the team is able to test epigenetic therapies in these models quickly and efficiently.
The Sarthy Lab is interested in industry partnerships that either seek to capitalize on their expertise in rigorous, high-throughput CUT&RUN/Tag chromatin profiling methods, and/or apply novel epigenetic therapies to pediatric and adult cancers. Sarthy is available to work with industry partners on other new and existing drugs that target epigenetic factors. His group could contribute their expertise in CUT&Tag single-cell gene expression and chromatin accessibility assays to drug screening programs.
Stage of Development
- Pre-clinical in vitro and in vivo
Partnering Opportunities
- Collaborative research and development
- Sponsored research agreement
- Consultation agreement
- High-throughput screening
- Clinical trial development
- Investigator-initiated clinical trials
- Contract research
Publications
- Kaonis S, Smith JL, Katiyar N, … Sarthy JF. Chromatin profiling of CBFA2T3-GLIS2 AMLs identifies key transcription factor dependencies and BRG1 inhibition as a novel therapeutic strategy. bioRxiv. Published online September 1, 2023.
- Janssens DH, Meers MP, Wu SJ, … Sarthy JF, Ahmad K, Henikoff S. Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia. Nat Genet. 2021;53(11):1586-1596.
- Wu SJ, Furlan SN, Mihalas AB, … Sarthy JF, Gottardo R, Ahmad K, Henikoff S, Patel AP. Single-cell CUT&Tag analysis of chromatin modifications in differentiation and tumor progression. Nat Biotechnol. 2021;39(7):819-824.
- Chew GL, Bleakley M, Bradley RK, Malik HS, Henikoff S, Molaro A, Sarthy J. Short H2A histone variants are expressed in cancer. Nat Commun. 2021;12(1):490.
- Sarthy JF, Meers MP, Janssens DH, et al. Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones. Elife. 2020;9:e61090.
Learn More
To learn more about partnering with Seattle Children’s Research Institute on this or other projects, email the Office of Science-Industry Partnerships.