journal contribution
posted on 2024-02-16, 09:40 authored by Caroline E. Gleason, Mark A. Dickson, Mary E. Klein (Dooley), Cristina R. Antonescu, Rodrigo Gularte-Mérida, Marimar Benitez, Juliana I. Delgado, Raghu P. Kataru, Mark Wei Yi Tan, Martina Bradic, Travis E. Adamson, Kenneth Seier, Allison L. Richards, Marta Palafox, Eric Chan, Sandra P. D'Angelo, Mrinal M. Gounder, Mary Louise Keohan, Ciara M. Kelly, Ping Chi, Sujana Movva, Jonathan Landa, Aimee M. Crago, Mark T.A. Donoghue, Li-Xuan Qin, Violetta Serra, Mesruh Turkekul, Afsar Barlas, Daniel M. Firester, Katia Manova-Todorova, Babak J. Mehrara, Marta Kovatcheva, Nguan Soon Tan, Samuel Singer, William D. Tap, Andrew Koff ANGPTL4 is the most widely expressed and highly enriched transcript in treated cells compared to untreated cells
Funding
Sarcoma Foundation of America (SFA)
Mitchell Goodman Fund for Sarcoma research
The Maloris Foundation
Eli Lilly and Company (Lilly)
National Institutes of Health (NIH)
Jennifer Linn Fund/Cycle for Survival
History
ARTICLE ABSTRACT
We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans.
We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion.
Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%–90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response.
Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes.See related commentary by Weiss et al., p. 649
