2022
DOI: 10.3390/cancers14061362
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Targetable Pathways in the Treatment of Retroperitoneal Liposarcoma

Abstract: Liposarcoma (LPS) is the most prevalent soft tissue sarcoma histological subtype. When it occurs in the abdomen the overall survival rate is as low as 10% at 10 years and is fraught with high rates of recurrence, particularly for the more aggressive dedifferentiated subtype. Surgery remains the mainstay of treatment. Systemic therapies for the treatment of metastatic or unresectable disease have low response rates. Deep understanding of well-differentiated and de-differentiated LPS (WDLPS and DDLPS, respective… Show more

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Cited by 19 publications
(10 citation statements)
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References 77 publications
(107 reference statements)
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“…In both WDLPS and DDLPS the overexpression of MDM2 targets p53 for degradation, thereby interfering with tumor suppressor pathways within the cell cycle. Targeting the MDM2-p53 axis is an enticing chemotherapeutic strategy, and several drugs have been developed to block this interaction; however, many early phase clinical studies have reported only partial patient responses and multiple adverse events limiting their clinical use [ 22 , 35 ]. A current clinical trial is also investigating the combined effect of MDM2 inhibition in combination with RT [ 36 ].…”
Section: Liposarcoma (Lps)mentioning
confidence: 99%
“…In both WDLPS and DDLPS the overexpression of MDM2 targets p53 for degradation, thereby interfering with tumor suppressor pathways within the cell cycle. Targeting the MDM2-p53 axis is an enticing chemotherapeutic strategy, and several drugs have been developed to block this interaction; however, many early phase clinical studies have reported only partial patient responses and multiple adverse events limiting their clinical use [ 22 , 35 ]. A current clinical trial is also investigating the combined effect of MDM2 inhibition in combination with RT [ 36 ].…”
Section: Liposarcoma (Lps)mentioning
confidence: 99%
“…Given the aberrant activation of the PI3K/ AKT/mTOR pro-survival pathway observed in DDLPS (55), idasanutlin was tested in combination with the PI3K/mTOR inhibitor NVP-BEZ235 resulting in enhanced cell growth inhibition, apoptotic cell death, and reduction of tumor growth rate (38). Roy et al (48) described a p53-dependent paradoxical activation of ERK pathway as a mechanism of 18 F-Fluorodeoxy-D-glucose uptake (56). CDK4/6 inhibitors can induce a senescent-like cell state which could variably impact tumor growth/progression (58).…”
Section: Overexpressed Biomarkers As Therapeutic Targets: Mdm2 and Cdk4mentioning
confidence: 99%
“…Herein, after briefly summarizing the current standard-ofcare and recent findings from clinical investigations on new therapeutic strategies for WD/DDLPS, we focus on the rationale behind emerging treatment options exploiting potential vulnerabilities based on LPS biology. We do not address here immunotherapeutic approaches, which are summarized in other reviews (8,18).…”
Section: Introductionmentioning
confidence: 99%
“…Surgical resection is the mainstay of treatment. For those that are unresectable or metastasize, systemic non‐specific multi‐drug chemotherapy regimens are mainstays but have modest efficacy for most LPS patients with overall response rates of only 20%–30% (Casadei et al., 2022 ). Radiotherapy also lacks overall survival impact.…”
Section: Introductionmentioning
confidence: 99%
“…Major cargos in liposarcoma EVs include MDM2 DNA (Casadei et al., 2019 ) and specific miRNAs (miR‐25‐3p, mir‐92a‐3p (Casadei et al., 2017 )). RL EV cargo has been described to play an important role inducing tumour progression and metastasis (Casadei & Pollock, 2020 ; Casadei et al., 2019 , 2022 ) Specifically, it has been shown that the transfer of EV‐derived MDM2 DNA from RL to preadipocytes in the RL microenvironment promotes production of metalloproteinases (specifically MMP2) which could lead to pre‐metastatic niche preparation and subsequent recurrences in RL.…”
Section: Introductionmentioning
confidence: 99%