scholarly journals Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 675
Author(s):  
Jeffrey D. Rytlewski ◽  
Nicholas Scalora ◽  
Keith Garcia ◽  
Munir Tanas ◽  
Fatima Toor ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Soft Tissue ◽  
Hippo Pathway ◽  
Soft Tissue Sarcomas ◽  
Standard Of Care ◽  
Proliferative Effect ◽  
Mechanistic Approach ◽  
Cellular Necrosis ◽  
Sarcoma Treatment

Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment.

scholarly journals Translating Molecular Profiling of Soft Tissue Sarcomas into Daily Clinical Practice

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 512
Author(s):  
Celine Jacobs ◽  
Lore Lapeire
Keyword(s):  
Soft Tissue ◽  
Unmet Need ◽  
Soft Tissue Sarcomas ◽  
Molecular Profiling ◽  
Point Of View ◽  
Molecular Techniques ◽  
Mesenchymal Tumors ◽  
The Past ◽  
Cancer Types ◽  
Sarcoma Treatment

Soft tissue sarcomas are a group of rare mesenchymal tumors with more than 70 subtypes described. Treatment of these subtypes in an advanced setting is mainly according to a one-size-fits-all strategy indicating a high unmet need of new and more targeted therapeutic options in order to optimize survival. The introduction of advanced molecular techniques in cancer has led to better diagnostics and identification of new therapeutic targets, leading to more personalized treatment and improved prognosis for several cancer types. In sarcoma, a likewise evolution is seen, albeit at a slower pace. This manuscript describes how in the past years advanced molecular profiling in soft tissue sarcomas was able to identify specific and often pathognomonic aberrations, deferring standard sarcoma treatment in favor of more targeted treatment from an oncologist’s point of view.

Mesenchymal Stem Cell Differentiation Markers Shared with Soft Tissue Sarcomas

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4755-4755
Author(s):  
Stefan Wirths ◽  
Hans-Joerg Buehring ◽  
Lothar Kanz ◽  
Joerg T Hartmann ◽  
Hans-Georg Kopp
Keyword(s):  
Stem Cells ◽  
Soft Tissue ◽  
Expression Pattern ◽  
Cell Lines ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Soft Tissue Sarcomas ◽  
Stem Cell Differentiation ◽  
Antibody Panel

Abstract Malignant tumors are hypothesized to harbor small populations of self-renewing cancer stem cells. Targeting these cells may be the decisive step to overcome treatment resistance and achieve tumor eradication in cancer patients. Advanced soft tissue sarcomas (STS) are rare tumors with a dismal prognosis and a small number of systemic treatment options. STS may originate from mesenchymal stem cells (MSC); the latter have mainly been isolated from adult bone marrow (BM) as non-hematopoietic, self-renewing cells whose in vitro progeny comprises osteoblasts, chondroblasts, myocytes, and adipocytes. While in vitro expression profiles of MSC have been investigated extensively, the in vivo counterparts of MSC are still hypothetical. To target rare human cell BM populations including MSC, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), the recently described W8B2 antigen as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, three STS cell lines were tested for expression of these antigens. In addition, snap-frozen primary STS sections were analyzed by immunohistochemistry using the same antibody panel. All cell lines revealed expression of selected markers including CD340, W8B2, and CD140b. Several MSC markers were restricted to a subpopulation of cells. In addition, leiomyosarcoma cells displayed a different expression pattern as compared to liposarcoma and Ewing’s sarcoma cells. Results of immunohistochemistry analysis of primary leiomyosarcoma tumor samples correlated strongly with expression patterns established by FACS analysis. However, important cytoarchitectural features regarding selected markers were revealed by immunohistochemistry: while primary leiomyosarcomas displayed uniform expression of W7C6, HEK3D6, CD10, and CD318, other markers such as CD34, W5C5, and 57D2 were expressed by tumor endothelia only. Moreover, a population of perivascular tumor cells was found to express the MSC-markers W4A5, W8B2, CD140b, W3D5, and W5C4. Novel MSC-markers are expressed by subpopulations in STS cell lines as well as in primary sarcoma tissue. Further studies on the functional significance of these phenotypical studies are underway and may help to identify novel specific targets recognizing the self-renewing STS-compartment.

scholarly journals Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Javier Escudero ◽  
Victoria Heredia-Soto ◽  
Yinyin Wang ◽  
Patricia Ruiz ◽  
Yingying Hu ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Cell Line ◽  
Antitumour Activity ◽  
Three Dimensional ◽  
Soft Tissue Sarcomas ◽  
Migration And Invasion ◽  
2D And 3D ◽  
First Time ◽  
Dimensional Cell

Abstract Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

scholarly journals Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3525
Author(s):  
Junaid Arshad ◽  
Philippos A. Costa ◽  
Priscila Barreto-Coelho ◽  
Brianna Nicole Valdes ◽  
Jonathan C. Trent
Keyword(s):  
Monoclonal Antibodies ◽  
Soft Tissue ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Soft Tissue Sarcomas ◽  
Standard Of Care ◽  
Current Standard ◽  
Molecular Alterations

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. The management of locally advanced or metastatic unresectable GIST involves detecting KIT, PDGFR, or other molecular alterations targeted by imatinib and other tyrosine kinase inhibitors. The role of immunotherapy in soft tissue sarcomas is growing fast due to multiple clinical and pre-clinical studies with no current standard of care. The potential therapies include cytokine-based therapy, immune checkpoint inhibitors, anti-KIT monoclonal antibodies, bi-specific monoclonal antibodies, and cell-based therapies. Here we provide a comprehensive review of the immunotherapeutic strategies for GIST.

scholarly journals Evaluation of In Vitro Activity of the Class I PI3K Inhibitor Buparlisib (BKM120) in Pediatric Bone and Soft Tissue Sarcomas

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0133610 ◽  
Author(s):  
Jennifer L. Anderson ◽  
Ann Park ◽  
Ryan Akiyama ◽  
William D. Tap ◽  
Christopher T. Denny ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcomas ◽  
Pi3k Inhibitor ◽  
Vitro Activity ◽  
Class I ◽  
In Vitro Activity

scholarly journals Application of Proteomics to Soft Tissue Sarcomas

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Tadashi Kondo ◽  
Daisuke Kubota ◽  
Akira Kawai
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Target Identification ◽  
Low Frequency ◽  
Soft Tissue Sarcomas ◽  
Disease Mechanisms ◽  
A Genome ◽  
Array Technology ◽  
Associated Proteins

Soft tissue sarcomas are rare and account for less than 1% of all malignant cancers. Other than development of intensive therapies, the clinical outcome of patients with soft tissue sarcoma remains very poor, particularly when diagnosed at a late stage. Unique mutations have been associated with certain soft tissue sarcomas, but their etiologies remain unknown. The proteome is a functional translation of a genome, which directly regulates the malignant features of tumors. Thus, proteomics is a promising approach for investigating soft tissue sarcomas. Various proteomic approaches and clinical materials have been used to address clinical and biological issues, including biomarker development, molecular target identification, and study of disease mechanisms. Several cancer-associated proteins have been identified using conventional technologies such as 2D-PAGE, mass spectrometry, and array technology. The functional backgrounds of proteins identified were assessed extensively using in vitro experiments, thus supporting expression analysis. These observations demonstrate the applicability of proteomics to soft tissue sarcoma studies. However, the sample size in each study was insufficient to allow conclusive results. Given the low frequency of soft tissue sarcomas, multi-institutional collaborations are required to validate the results of proteomic approaches.

EXTH-04. ELUCIDATING THE PLEIOTROPIC EFFECTS OF VERTEPORFIN PHOTODYNAMIC THERAPY IN PRECLINICAL GLIOBLASTOMA MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi164-vi164
Author(s):  
Gabrielle Price ◽  
Sweta Sudhir ◽  
Concetta Brusco ◽  
Alexandros Bouras ◽  
Nadejda Tsankova ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Antitumor Effects ◽  
Cell Dynamics ◽  
The Hippo Pathway

Abstract Glioblastoma (GBM) has the highest mortality rate, incidence, and therapy resistance of all primary brain tumors. Deregulation of the epidermal growth factor receptor (EGFR) has been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), is an FDA-approved drug for photodynamic therapy (PDT) of macular degeneration. VP has been shown to have antitumor effects both in vitro and in vivo in GBM preclinical models. As a porphyrin derivative, VP can also exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate for the first time that VP-PDT reduces GBM cell viability to a greater extent than VP treatment alone (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.

Detection of MSC-like cells in soft tissue sarcoma cell lines and primary tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11000-11000
Author(s):  
S. Wirths ◽  
E. Malenke ◽  
T. Wiesner ◽  
H. Buehring ◽  
J. Hartmann ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Cell Lines ◽  
Primary Tumor ◽  
Growth Factor Receptor ◽  
Soft Tissue Sarcomas ◽  
Proliferative Capacity ◽  
Differentiation Potential ◽  
Primary Tumors

11000 Background: Soft tissue sarcomas (STS) are a heterogeneous group of mesodermal tumors hypothetically originating from mesenchymal stem cells (MSC). While the expression profile of bone marrow derived MSCs and their in vitro differentiation potential have been examined extensively, knowledge regarding the in vivo counterparts of MSC is still evolving. We hypothesized that MSC-like cells within STS could represent sarcoma initiating cells. Methods: To target rare human cell populations including MSCs, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), TNFRSF16 (CD217), frizzled-4 (CD344), the recently described W8B2 antigen, as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, both cell lines and primary tumor samples in suspension and in snap frozen sections were investigated. To reveal functional differences between identified rare tumor populations single cell proliferation kinetics were investigated after FACS-sorting. Results: All cell lines und primary tumor samples revealed expression of selected markers. Antigens identifying subpopulations within all sarcoma samples investigated, were selected for functional studies. These included frizzled-4, TNFRSF16, W5C5 and W8B2. Liposarcoma (SW872), leiomyosarcoma (SK-LMS) and fibrosarcoma (HT1080) cell lines enclosed subpopulations with differential expression of above markers and by FACS based limiting dilution it was demonstrated that only fractions of viable cells contained proliferative capacity. Cells lacking expression of CD271 had lower proliferative capacity compared to mock sorted HT1080 or SK-LMS, while CD271+ SW872 had significantly higher proliferation. The antigen defined by W5C5 identified cells with high proliferative capacity compared to control in SW872 and SK-LMS and its lack in HT1080 identified a subpopulation with largely reduced proliferation. Conclusions: Subpopulations within STS cell lines and primary sarcoma tissue express novel MSC-markers and display increased proliferative capacity, potentially reflecting the existence of sarcoma initiating cells. No significant financial relationships to disclose.

scholarly journals Pathology of Soft Tissue Sarcoma

2007 ◽  
Vol 5 (4) ◽  
pp. 411-418 ◽  
Author(s):  
Brian P. Rubin ◽  
John R. Goldblum
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Molecular Pathology ◽  
Frozen Section ◽  
Soft Tissue Sarcomas ◽  
Treatment Team ◽  
Expert Consultation ◽  
Sarcoma Treatment

The evaluation and treatment of soft tissue sarcomas has never been more demanding than it is today. The pathologist plays a central role in this process and is an integral member of the multidisciplinary sarcoma treatment team. This article provides a brief summary of the role of the soft tissue pathologist and includes sections on methods of diagnosis, frozen section, classification of sarcomas, expert consultation, molecular pathology, grading, assessment of treatment response, and tumor banking.

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