Targeting CDK4 (cyclin-dependent kinase) amplification in liposarcoma: A comprehensive review

Assi, Tarek; Kattan, Joseph; Rassy, Elie El; Nassereddine, Hussein; Farhat, Fadi; Honoré, Charles; Cesne, Axel Le; Adam, Julien; Mir, Olivier

doi:10.1016/j.critrevonc.2020.103029

Cited by 44 publications

(31 citation statements)

References 40 publications

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“…The most common subtype, well-differentiated liposarcoma (WDLPS) can dedifferentiate from the characteristic adipocyte-laden phenotype to the low-adipocytic dedifferentiated liposarcoma (DDLPS), an aggressive subtype associated with a significantly lower 5-year survival rate compared to WDLPS [ 39 ]. Both subtypes are characterized by highly amplified expression of MDM2 and CDK4, making inhibition of these proteins an attractive therapeutic target in the treatment of DDLPS and WDLPS [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of the preadipocyte marker ZFP423 is dysregulated between well-differentiated and dedifferentiated liposarcoma

et al. 2022

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Background Well-differentiated and dedifferentiated liposarcomas are rare soft tissue tumors originating in adipose tissue that share genetic abnormalities but have significantly different metastatic potential. Dedifferentiated liposarcoma (DDLPS) is highly aggressive and has an overall 5-year survival rate of 30% as compared to 90% for well-differentiated liposarcoma (WDLPS). This discrepancy may be connected to their potential to form adipocytes, where WDLPS is adipogenic but DDLPS is adipogenic-impaired. Normal adipogenesis requires Zinc Finger Protein 423 (ZFP423), a transcriptional coregulator of Perixosome Proliferator Activated Receptor gamma (PPARG2) mRNA expression that defines committed preadipocytes. Expression of ZFP423 in preadipocytes is promoted by Seven-In-Absentia Homolog 2 (SIAH2)-mediated degradation of Zinc Finger Protein 521 (ZFP521). This study investigated the potential role of ZFP423, SIAH2 and ZFP521 in the adipogenic potential of WDLPS and DDLPS. Methods Human WDLPS and DDLPS fresh and paraffin-embedded tissues were used to assess the gene and protein expression of proadipogenic regulators. In parallel, normal adipose tissue stromal cells along with WDLPS and DDLPS cell lines were cultured, genetically modified, and induced to undergo adipogenesis in vitro. Results Impaired adipogenic potential in DDLPS was associated with reduced ZFP423 protein levels in parallel with reduced PPARG2 expression, potentially involving regulation of ZFP521. SIAH2 protein levels did not define a clear distinction related to adipogenesis in these liposarcomas. However, in primary tumor specimens, SIAH2 mRNA was consistently upregulated in DDLPS compared to WDLPS when assayed by fluorescence in situ hybridization or real-time PCR. Conclusions These data provide novel insights into ZFP423 expression in adipogenic regulation between WDLPS and DDLPS adipocytic tumor development. The data also introduces SIAH2 mRNA levels as a possible molecular marker to distinguish between WDLPS and DDLPS.

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Section: Discussionmentioning

confidence: 99%

Expression of the preadipocyte marker ZFP423 is dysregulated between well-differentiated and dedifferentiated liposarcoma

et al. 2022

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“…New antitumor drugs for STS (especially dedifferentiated liposarcoma, which is frequent among retroperitoneal/intra-abdominal sarcomas) are now under investigation; examples are a CDK4/6 inhibitor, an MDM2 inhibitor, and an XPO1 inhibitor [37][38][39]. Clinical trials of these new drugs should determine whether there are differences in patient prognoses and in the efficacy of systemic chemotherapy depending on the primary site (especially the retroperitoneum/intra-abdomen and other sites), as this knowledge will contribute to the selection of the most appropriate systemic chemotherapies.…”

Section: Discussionmentioning

confidence: 99%

Post-Systemic Chemotherapy Prognoses of Recurrent/Metastatic Soft Tissue Sarcoma Patients with Retroperitoneal/Intra-Abdominal Origin versus Those with Extremities/Trunk Origin

et al. 2022

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Background: The clinical benefit of systemic chemotherapy for recurrent/metastatic retroperitoneal/intra-abdominal soft tissue sarcoma (STS) compared to its benefits for other primary lesions has not been known or sufficiently evaluated. Methods and Patients: We retrospectively reviewed the cases of the STS patients who consulted a department of medical oncology in Tokyo between June 2011 and March 2018, and we extracted the cases of patients with primary sites at the retroperitoneum/intra-abdomen (cohort R) or extremities/trunk (cohort E) who received systemic chemotherapy in a recurrent/metastatic setting, comparing the cohorts' characteristics, chemotherapy details, and prognoses. Results: Of all 337 STS patients, we enrolled 49 patients in cohort R and 75 patients in cohort E. Liposarcoma was more frequently observed in cohort R (51.0%) than cohort E (22.7%). The median chemotherapy treatment line was two lines (range: 1–6) in cohort R and three lines (range: 1–9) in cohort E. The doxorubicin usage rates differed in recurrent/metastatic settings (90.0% in cohort R and 55.0% in cohort E), due mainly to the higher rate of a perioperative chemotherapy treatment history in cohort E (52.0% vs. 6.1% in cohort R). The median overall survival from the start of salvage chemotherapy was 31.9 months (cohort R; 95%CI: 20.9–42.8) and 27.1 months (cohort E; 95%CI: 21.6–32.5) (p=0.549). Conclusion: There were differences in the distributions of pathology and antitumor drugs used in a salvage setting between retroperitoneal/intra-abdominal and extremities/trunk STS patients in recurrent/metastatic settings, but the prognoses with salvage chemotherapy were similar in the two cohorts.

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“…A phase 2 prospective study of Palbociclib, a CDK4/6 inhibitor, in WDLPS/DDLPS led to complete response in 1 patient out of a total of 57 evaluable patients, with a 12-week PFS of 57%, and a median PFS of 17.9 weeks. 23 , 30 Abemaciclib, which is more selective for CDK4, has shown more promising results in a phase 2 study. 23 Abemaciclib 200 mg twice daily demonstrated 1 PR out of a total of 30 patients, 12-week PFS of 76%, and median PFS of 30.4 weeks.…”

Section: Currently Available Systemic Therapiesmentioning

confidence: 99%

“… 23 , 30 Abemaciclib, which is more selective for CDK4, has shown more promising results in a phase 2 study. 23 Abemaciclib 200 mg twice daily demonstrated 1 PR out of a total of 30 patients, 12-week PFS of 76%, and median PFS of 30.4 weeks. A larger randomized study with abemaciclib in DDLPS is underway (NCT04967521).…”

Section: Currently Available Systemic Therapiesmentioning

confidence: 99%

Overview of systemic therapy options in liposarcoma, with a focus on the activity of selinexor, a selective inhibitor of nuclear export in dedifferentiated liposarcoma

Thirasastr

Somaiah

2022

Ther Adv Med Oncol

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Liposarcoma (LPS) is a common soft tissue sarcoma that encompasses diverse subtypes of well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic LPS. There is heterogeneity among the various LPS types with regard to prognosis, molecular pathogenesis, and response to treatment. Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) are most common types, which share common genetic alteration of chromosome 12q13-15 amplification resulting in amplification of oncogenes, including MDM2 (Mouse double minute 2), CDK4 (cyclin-dependent kinase 4), and HMGA2 (High mobility group protein AT-hook 2). Despite sharing the same molecular alteration, DDLPS has a worse prognosis, with a higher recurrence rate and higher propensity for metastases compared to WDLPS. Here we provide an overview of the LPS treatment landscape focusing on recent developments in the treatment of DDLPS with a focus on selinexor. Selinexor, a selective inhibitor of XPO1, was recently evaluated in a phase 3 trial, the first prospective randomized trial in DDLPS, and we discuss its efficacy in context of other available agents for DDLPS.

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Targeting CDK4 (cyclin-dependent kinase) amplification in liposarcoma: A comprehensive review

Cited by 44 publications

References 40 publications

Expression of the preadipocyte marker ZFP423 is dysregulated between well-differentiated and dedifferentiated liposarcoma

Expression of the preadipocyte marker ZFP423 is dysregulated between well-differentiated and dedifferentiated liposarcoma

Post-Systemic Chemotherapy Prognoses of Recurrent/Metastatic Soft Tissue Sarcoma Patients with Retroperitoneal/Intra-Abdominal Origin versus Those with Extremities/Trunk Origin

Overview of systemic therapy options in liposarcoma, with a focus on the activity of selinexor, a selective inhibitor of nuclear export in dedifferentiated liposarcoma

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