A preclinical in vivo model for alveolar soft part sarcoma

[Olga]

It is very encouraging to see a progress in a work of our David T. Vistica which may enable to perform preclinical evaluation of potential ASPS therapeutics:

2007 AACR Annual Meeting
April 14-18, 2007 Los Angeles, CA

Poster Session
Mouse Models of Cancer 2: Therapeutic Approaches

Abstract Number:2206

Presentation Title:

A preclinical in vivo model for alveolar soft part sarcoma (ASPS): application to experimental therapeutic studies

Presentation Start/End Time:

Monday, Apr 16, 2007, 8:00 AM -12:00 PM

David T. Vistica, Suzanne D. Borgel, Melinda Hollingshead, Susan Kenney, Robert H. Shoemaker. NCI-Frederick, Frederick, MD, SAIC-Frederick, Frederick, MD

Alveolar soft part sarcoma (ASPS) is a rare malignant neoplasm found predominantly in adolescents and young children. Clinically, ASPS is characterized by slow growth of primary tumors and a predilection for metastasis to many sites including the lung and brain. Investigation into the biology of ASPS as well as preclinical evaluation of potential ASPS therapeutics has been severely hampered by the lack of both in vitro and in vivo models of the disease. We report here on an in vivo model for the growth of ASPS in immunocompromised NOD.SCID\NCr mice. In vivo growth of ASPS tumors obtained from patients was initially observed following subcutaneous implantation in NOD.SCID\NCr sex-matched mice. The tumors, currently at passage 4, have been maintained in vivo for 20 months. During this period, the xenograft tumors have maintained characteristics consistent with those of the original tumor including (1) tumor histology and staining with Periodic Acid Schiff/Diastase (2) ASPL-TFE3 fusion transcript (3) nuclear staining with antibodies to ASPL-TFE3 type 1 or ASPL-TFE3 type 2 fusion proteins and (4) presence of the t(X;17)(p11;q25) translocation characteristic of ASPS. At present the tumor is passaged every 4-5 months. During the 20 month period encompassing 4 passages, a significant increase in the percentage of mice growing ASPS tumors, from approximately 2% (original tumor) to 50-75% (passage 4), has been observed thus providing the opportunity to generate sufficient numbers of tumor-bearing mice for experimental therapeutic studies. The growth kinetics of these ASPS tumors is characterized by a 2 month lag phase during which minimal tumor growth is observed followed by an increase in tumor volume over the ensuing 2-3 months. Additionally, these ASPS xenograft tumors serve as a source of ASPS cells for in vitro experimentation. In summary, the current results demonstrate establishment of an in vivo model for ASPS which will allow both the investigation into the biology of ASPS as well as provide a means for preclinical testing of potential ASPS therapeutics.

[D.ap]

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

Olga and all,
We’ve come along way since TKIs and chemo huh .
Thanks for all you’ve provided in research and development over the years .
Here’s to hope of a cure for ASPS.


“Highlights

Multiplexed and spatially resolved technologies can aid immune biomarker discovery.

Sarcomas are a heterogenous group of mesenchymal cancers comprising over 100 subtypes. Current chemotherapy for all but a very few subtypes has limited efficacy, resulting in 5-year relative survival rates of 16% for metastatic patients. While sarcomas have often been regarded as an “immune cold” tumor category, recent biomarker studies have confirmed a great deal of immune heterogeneity across sarcoma subtypes. Reports from the first generation of clinical trials treating sarcomas with immunotherapy demonstrate a few positive responses, supporting efforts to stratify patients to optimize response rates. This review summarizes recent advances in knowledge around immune biomarker expression in sarcomas, the potential use of new technologies to complement these study results, and clinical trials particularly of immune checkpoint inhibitor therapy in sarcomas.

Each of the immune biomarkers assessed was reviewed for subtype-specific expression patterns and correlation with prognosis. Overall, there is extensive heterogeneity of immune biomarker presence across sarcoma subtypes, and no consensus on the prognostic effect of these biomarkers. New technologies such as multiplex immunohistochemistry and high plex in situ profiling may offer more insights into the sarcoma microenvironment. To date, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits. Combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma and alveolar soft-part sarcoma. Better understanding of the sarcoma immune status through biomarkers may help decipher the reasons behind differential responses to immunotherapy.“

https://www.sciencedirect.com/science/a ... 7220301535

[D.ap]

Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial

https://www.sciencedirect.com/science/a ... 4519302153

[D.ap]

Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Researchand Treatment of Cancer (EORTC) phase II trial90101


https://reader.elsevier.com/reader/sd/p ... 1211164217

[D.ap]

Abstract A11: An alveolar soft part sarcoma model to explore the mechanisms of tumorigenesis and metastasis

https://cureasps.org/forum/viewtopic.php?f=2&t=2026

[D.ap]

Pazopanib in advanced soft tissue sarcomas

https://cureasps.org/forum/viewtopic.php?f=63&t=1996

[D.ap]

PD-L1 Expression Is Associated with FOXP3+ Regulatory T-Cell Infiltration of Soft Tissue Sarcoma and Poor Patient Prognosis


Abstract

Background: Programmed death ligand-1(PD-L1) functions as a negative mediator of immune response through different pathways in anti-tumor immunity. Recent studies have reported that PD-L1 plays a pivotal role in the function of regulatory T-cells (Tregs). Although increases in FOXP3+ Tregs infiltration and PD-L1 expression have been revealed in several cancers, their correlation with soft tissue sarcoma remains unknown.

Methods: We included 163 cases of soft tissue sarcoma who were diagnosed and underwent extensive and radical resection at the Sun Yat-sen University Cancer Center, Guangzhou, China, from 2000-2010. PD-L1 and FOXP3 expression was evaluated by immunohistochemistry. Correlation between their expressions and associations with clinicopathological features were studied.

Results: Among 163 STS samples, 19 (11.7%) exhibited PD-L1 positivity, and 41 (25.2%) cases expressed high FOXP3+ Treg infiltration. Significant correlation between PD-L1 expression and FOXP3+Treg infiltration in STS was identified (r=0.450, p<0.001). In univariate analysis, PD-L1 expression was significantly associated with high tumor grade and the age of patients, while the presence of FOXP3+ in tumor infiltrating Tregs was significantly associated with the age of patients, high tumor stage, higher tumor grade and tumor depth. Multivariate analysis revealed PD-L1 and FOXP3 as independent prognostic indicators significantly associated with OS and DFS.

Conclusions: Our study revealed that PD-L1 and FOXP3+Tregs may work synergistically in promoting immune evasion of the tumors in soft tissue sarcoma. A combined strategy to block PD-L1/PD-1 with simultaneous depletion of Tregs may show promise in enhancing the therapeutic efficacy of these patients.

Keywords: Soft tissue sarcoma, PD-L1, FOXP3+, prognosis

https://www.jcancer.org/v08p2018.htm

[D.ap]

PD-L1 Expression Is Associated with FOXP3+ Regulatory T-Cell Infiltration of Soft Tissue Sarcoma and Poor Patient Prognosis

Table 1
The expression of PD-L1 and FOXP3 in different histological type of soft tissue sarcoma

Histological type N PD-L1 FOXP3 PD-L1/FOXP3
positive High expression
-/- -/+ or +/- +/+
Fibrosarcoma 29 2(6.9) 7(24.1) 22(75.9) 5(17.2) 2(6.9)
liposarcoma 23 0 1(4.3) 22(95.7) 1(4.3) 0
Undifferentiated pleomorphic sarcoma/MFH 47 7(14.9) 16(34.0) 31(66.0) 9(19.1) 7(14.9)
Leiomyosarcoma 9 2(22.2) 2(22.2) 5(55.6) 4(44.4) 0
Synovial sarcoma 21 1(4.8) 6(28.6) 15(71.4) 5(23.8) 1(4.8)
Rhabdomyosarcoma 8 3(37.5) 4(50.0) 4(50.0) 1(12.5) 3(37.5)
MPNST 9 1(11.1) 0 8(88.9) 1(11.1) 0
PNET 6 1(16.7) 0 5(83.3) 1(16.7) 0
Angiosarcoma 5 1(20.0) 2(40.0) 3(60.0) 1(20.0) 1(20.0)
Alveolar soft part sarcoma 5 1(20.0) 3(60.0) 2(40.0) 2(40.0) 1(20.0)
Malignant Triton Tumor 1 0 0 1(100.0) 0 0
Total 163 19 41(25.2) 118(72.4) 30(18.4) 15(9.2)