Ester Calvo Fernández, Postdoctoral Researcher at Harvard Medical School, shared a post on LinkedIn about a recent article she and her colleagues co-authored, adding:
“Publication alert!
Finally one of my first author PhD papers is out in Nature Genetics today!
One of the biggest challenges in cancer isn’t just the tumor itself — it’s the fact that a single tumor is made up of multiple, coexisting cell states, each with its own vulnerabilities and drug sensitivities. Treating only one population often leaves others behind, driving resistance and relapse.
In this work, we took a different approach. By mapping tumors at single-cell resolution, we identified distinct cell states and their underlying master regulator dependencies, then systematically matched them to drugs capable of disrupting those programs. What emerged was a clear principle: effective therapy requires targeting complementary cell states at the same time.
The results were striking. Drugs predicted to target specific states worked as expected in vivo, but more importantly, rational combinations significantly outperformed monotherapies. In one case, combining avapritinib with ruxolitinib extended survival nearly threefold compared to control.
Beyond DMG, this study provides a general framework for designing combination therapies — not based on trial and error, but on the biology of tumor heterogeneity itself.
I am so grateful for the mentorship and support of Jovana Pavisic and Andrea Califano (and the whole team involved!) at Columbia University Irving Medical Center, whose guidance was instrumental in making this work possible.”
Title: Systematic design of combination therapy by targeting master regulators of coexisting diffuse midline glioma cell states
Authors: Ester Calvo Fernández, Lorenzo Tomassoni, Xu Zhang, Junqiang Wang, Aleksandar Obradovic, Pasquale Laise, Aaron T. Griffin, Lukas Vlahos, Hanna E. Minns, Diana V. Morales, Christian Simmons, Matthew Gallitto, Hong-Jian Wei, Timothy J. Martins, Pamela S. Becker, John R. Crawford, Theophilos Tzaridis, Robert J. Wechsler-Reya, James Garvin, Robyn D. Gartrell, Luca Szalontay, Stergios Zacharoulis, Cheng-Chia Wu, Zhiguo Zhang, Andrea Califano, Jovana Pavisic
Read the Full Article on Nature Genetics
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