Back

Comparative oncology reveals DNMT3B as a therapeutic vulnerability in soft-tissue sarcoma

Fuller, A. M.; DeVine, A.; Murazzi, I.; Mason, N. J.; Weber, K.; Eisinger, T. S. K.

2021-12-23 cancer biology
10.1101/2021.12.22.473852 bioRxiv
Show abstract

Undifferentiated pleomorphic sarcoma (UPS), an aggressive subtype of soft-tissue sarcoma (STS), is exceedingly rare in humans and lacks effective, well-tolerated therapies. In contrast, STS are relatively common in canine companion animals; thus, incorporation of veterinary patients into studies of UPS offers an exciting opportunity to develop novel therapeutic strategies for this rare human disease. Genome-wide studies have demonstrated that UPS is characterized by aberrant patterns of DNA methylation. However, the mechanisms and impact of this epigenetic modification on UPS biology and clinical behavior are poorly understood. Leveraging cell lines and tissue specimens derived from human and canine patients, we discovered that the DNA methyltransferase DNMT3B is overexpressed in UPS relative to normal mesenchymal tissues and associated with a poor prognosis. Consistent with these findings, genetic DNMT3B depletion strongly inhibited UPS cell proliferation and tumor progression. However, existing hypomethylating agents, including the clinically approved drug 5-aza-2-deoxycytidine and the DNMT3B-inhibiting tool compound nanaomycin A, were ineffective in UPS due to cellular uptake and toxicity issues. Thus, further development of DNMT3B-targeting strategies for these patients is critical.

Matching journals

The top 8 journals account for 50% of the predicted probability mass.

1
JCI Insight
● 277 papers in training set
Top 0.2%
12.3%
Similar papers in this journal
2
Cancers
○ 213 papers in training set
Top 0.5%
9.4%
Similar papers in this journal
3
Molecular Cancer Therapeutics
● 40 papers in training set
Top 0.1%
6.1%
Similar papers in this journal
4
Cancer Research Communications
● 51 papers in training set
Top 0.1%
5.3%
Similar papers in this journal
5
Journal of Clinical Investigation
● 179 papers in training set
Top 0.8%
5.3%
Similar papers in this journal
6
Disease Models & Mechanisms
139 papers in training set
Top 0.4%
5.0%
7
eLife
● 5828 papers in training set
Top 27%
4.7%
8
Science Translational Medicine
● 127 papers in training set
Top 0.4%
4.7%
50% of probability mass above
9
Cancer Research
● 130 papers in training set
Top 1%
3.1%
10
EMBO Molecular Medicine
○ 95 papers in training set
Top 0.3%
2.7%
11
Cell Reports
○ 1498 papers in training set
Top 14%
2.7%
12
Journal of Experimental Medicine
● 119 papers in training set
Top 1%
2.3%
13
Clinical Cancer Research
● 64 papers in training set
Top 0.9%
2.3%
14
Molecular Cancer Research
● 49 papers in training set
Top 0.5%
2.3%
15
Oncogene
○ 85 papers in training set
Top 1%
1.7%
16
Cancer Discovery
● 66 papers in training set
Top 1%
1.7%
17
Nature Communications
○ 5641 papers in training set
Top 46%
1.7%
18
Science Advances
● 1243 papers in training set
Top 21%
1.6%
19
Cell Reports Medicine
○ 153 papers in training set
Top 3%
1.5%
20
Cancer Letters
○ 35 papers in training set
Top 0.8%
1.3%
21
Proceedings of the National Academy of Sciences
● 2444 papers in training set
Top 33%
1.3%
22
Scientific Reports
○ 3612 papers in training set
Top 68%
1.0%
23
NAR Cancer
◐ 37 papers in training set
Top 0.6%
1.0%
24
iScience
○ 1154 papers in training set
Top 32%
1.0%
25
npj Precision Oncology
○ 53 papers in training set
Top 2%
0.8%
26
Molecular Therapy Oncology
○ 10 papers in training set
Top 0.2%
0.8%
27
Molecular Therapy Nucleic Acids
○ 39 papers in training set
Top 0.9%
0.8%
28
Communications Biology
○ 993 papers in training set
Top 32%
0.8%
29
Oncotarget
○ 18 papers in training set
Top 0.6%
0.6%
30
Cancer Immunology Research
● 35 papers in training set
Top 1%
0.6%

"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.