Novel Approaches to Treatment of Leiomyosarcomas

Collins, Ian M.; Thomas, David M.

doi:10.1007/s11912-011-0173-0

Cited by 10 publications

(5 citation statements)

References 54 publications

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“…In an attempt to improve treatment results, hormone therapy has been evaluated in hormone-receptor positive uterine LMS, but with disappointing results [96]. Likewise, anti-angiogenic therapy has been evaluated in several studies with disappointing results, according to Collins et al [97]. Novel treatment strategies in LMS are therefore needed.…”

Section: Sarcomasmentioning

confidence: 99%

Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin

Olsen

Sellevold

Theodossiou

et al. 2017

Photodiagnosis and Photodynamic Therapy

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The low curative response to current treatment regimens for most soft tissue sarcomas indicates a strong need for alternative treatment strategies and predictive markers for treatment outcome. PCI (photochemical internalization) is a novel treatment strategy to translocate drugs into cytosol that otherwise would have been degraded in lysosomes. Two highly geno-and phenotypically different uterine and vulvar leiomyosarcoma cell lines, MES-SA and SK-LMS-1, were treated with bleomycin (BLM) activated by PCI (PCI). The MES-SA cells were much more sensitive to PCI than the SK-LMS-1 cells and the treatment induced a 7-8 fold higher increase in DNA double-strand breaks at the same dose of light as measure by γH2AX staining. A 3-fold higher induction of apoptosis and stronger activation of Bax and p21 was also measured in the P53WT MES-SA cells, compared to the P53mut SK-LMS-1 cells. The basal formation of reactive oxygen species (ROS) was 3-fold higher in SK-LMS-1 cells than in the MES-SA cells and SK-LMS-1 cells expressed glutathione peroxidase 1 (GPx1) and more superoxide dismutase 2 (SOD2) than the MES-SA cells. Glutathione depletion with the glutathione synthetase inhibitor buthionine sulfoximine increased the cytotoxic effect of the photochemical treatment (PDT) most strongly in the SK-LMS-1 cells, and reduced PCI-induced H2AX activation in the MES-SA cells, but not in the SK-LMS-1 cells. The results indicate PCI as a potential novel treatment strategy for soft tissue sarcomas, with antioxidant enzymes, in particular GPx1, and the P53 status as potential predictive markers for response to PCI.

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Section: Sarcomasmentioning

confidence: 99%

Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin

Olsen

Sellevold

Theodossiou

et al. 2017

Photodiagnosis and Photodynamic Therapy

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“…Soft tissue sarcoma (STS) is a broadly defined category that accounts for less than 1% of all reported malignancies (Aragon-Ching & Maki 2012 ; Collins & Thomas 2011 ). This group includes high-grade undifferentiated pleomorphic sarcoma, liposarcoma, synovial sarcoma, and leiomyosarcoma (LMS).…”

Section: Introductionmentioning

confidence: 99%

“…This group includes high-grade undifferentiated pleomorphic sarcoma, liposarcoma, synovial sarcoma, and leiomyosarcoma (LMS). Amongst these neoplastic processes, LMS accounts for 10% to 24% of all reported STS’s (Aragon-Ching & Maki 2012 ; Collins & Thomas 2011 ). Usually, LMS originates in the retroperitoneum, the uterus, and areas surrounding the inferior vena cava, with symptoms attributable to the physical consequence of the sizable tumor mass(Aragon-Ching & Maki 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Potential benefit of hormonal therapy for non-uterine soft tissue sarcoma (STS) – a case report and literature review

Schuster

Jacob

et al. 2013

SpringerPlus

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The expression of hormone receptors (HR) is considered a good prognostic marker in uterine sarcoma. Hormonal therapy is widely employed in the therapy of HR positive breast and gynecologic cancers, however, there is little information concerning hormonal therapy in HR positive extrauterine sarcoma.A 55-60 year age group female presented with an estrogen receptor positive metastatic retroperitoneal leiomyosarcoma (LMS). She was treated with four cycles of a combination of Gemcitabine and Paclitaxel. Her disease remained stable for 29 months when tamoxifen was initiated. The patient succumbed to an unrelated malignancy after a total of 44 months of treatment.Despite emerging reports about the potential benefit of hormonal therapy, selective estrogen and progesterone receptor modulators and aromatase inhibitors, for uterine sarcoma, there is a paucity of information regarding the application of these therapies to sarcomas arising at other sites. Our patient survived significantly longer than expected with metastatic retroperitoneal sarcoma. In part this may be due to the survival benefit associated with HR positive tumors, but it may also indicate a role for hormonal therapy which has yet to be explored.

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“…However, despite these advances, there are no standard therapies for metastatic LMS. Targeted therapies, particularly pazopanib, 13 and conventional cytotoxic agents (including doxorubicin, ifosfamide, gemcitabine, docetaxel, and trabectedin) have modest clinical activity, 14‐17 but more effective strategies are needed for patients with advanced LMS.…”

Section: Introductionmentioning

confidence: 99%

Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas

Schaefer

Lundberg

Demicco

et al. 2021

Cancer

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Background Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np‐LMS), including local recurrences and distant metastases. Methods TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np‐LMS and a comparison group of 262 primary leiomyosarcomas (p‐LMS). Thirty‐five of the np‐LMS had a matched p‐LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization. Results Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np‐LMS, respectively. PTEN inactivation was more common in soft tissue np‐LMS than uterine np‐LMS (55% vs 31%; P = .0005). Moderate‐strong ER expression was more common in uterine np‐LMS than soft tissue np‐LMS (50% vs 7%; P < .0001). Co‐inactivation of TP53 and RB1 was found in 81% of np‐LMS and was common in both soft tissue and uterine np‐LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p‐LMS and np‐LMS from the same patients. Conclusions These studies show that nearly all np‐LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.

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Novel Approaches to Treatment of Leiomyosarcomas

Cited by 10 publications

References 54 publications

Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin

Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin

Potential benefit of hormonal therapy for non-uterine soft tissue sarcoma (STS) – a case report and literature review

Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas

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