Dataset Information

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

ABSTRACT:

Purpose

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.

Patients and methods

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.

Results

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.

Conclusions

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.

SUBMITTER: Gleason CE

PROVIDER: S-EPMC10870201 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

Gleason Caroline E CE Dickson Mark A MA Klein Dooley Mary E ME Antonescu Cristina R CR Gularte-Mérida Rodrigo R Benitez Marimar M Delgado Juliana I JI Kataru Raghu P RP Tan Mark Wei Yi MWY Bradic Martina M Adamson Travis E TE Seier Kenneth K Richards Allison L AL Palafox Marta M Chan Eric E D'Angelo Sandra P SP Gounder Mrinal M MM Keohan Mary Louise ML Kelly Ciara M CM Chi Ping P Movva Sujana S Landa Jonathan J Crago Aimee M AM Donoghue Mark T A MTA Qin Li-Xuan LX Serra Violetta V Turkekul Mesruh M Barlas Afsar A Firester Daniel M DM Manova-Todorova Katia K Mehrara Babak J BJ Kovatcheva Marta M Tan Nguan Soon NS Singer Samuel S Tap William D WD Koff Andrew A

Clinical cancer research : an official journal of the American Association for Cancer Research 20240201 4

<h4>Purpose</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>Thirty patients with progre ...[more]

PMID: 37695642

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Project description:PurposePatients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options.Experimental designPatients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes.ResultsThirty-eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow-up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%-29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease-specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090).ConclusionsThis is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications.

Project description:BackgroundRetroperitoneal dedifferentiated liposarcoma is associated with a high risk of recurrence; however, treatment strategies that are more effective than surgery remain to be established. This study aimed to determine the optimal number of surgeries that would be effective for patients with recurrent disease. Furthermore, the improvement in prognosis was evaluated according to the malignancy level.MethodsThe effect of each type of surgery on the prognosis of 118 patients with retroperitoneal dedifferentiated liposarcoma treated at the Osaka International Cancer Institute between 1997 and 2022 was investigated. Among the 118 patients, 103 underwent initial surgery, while 54 and 30 patients underwent second and third surgeries, respectively. The overall and disease-free survival rates of each group were compared using the Kaplan-Meier method, and the log-rank test was used to determine statistical significance in univariate analysis. 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was used to assess malignancy. Maximum standardized uptake values (SUVmax) of ≥ 4 and < 4 were classified as high and low malignancy, respectively.ResultsThe first and second surgeries resulted in a significant improvement in the overall survival rate, regardless of the malignancy level (p < 0.001); however, no significant improvement in prognosis was observed after the third surgery (p = 0.077). Low-grade malignancies are associated with a better postoperative prognosis, even in cases of recurrence. In contrast, high-grade malignancies exhibit a reduction in surgical efficacy.ConclusionsThis study highlights the importance of considering the tumor malignancy level and the patient's overall condition when deciding whether to perform repeated surgical interventions. Surgical treatment can prolong overall survival, even in patients with recurrence; however, it is advisable to assess malignancy levels when determining the suitability of surgery beyond the second recurrence.

Dataset Information

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

Purpose

Patients and methods

Results

Conclusions

Publications

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

Similar Datasets

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