bims-myxlip 2023-03-05 papers

Issue of 2023–03–05
five papers selected by
Laura Mannarino, Humanitas Research

Curr Treat Options Oncol. 2023 Mar 03.

Myxoid Liposarcoma: How to Stage and Follow.

OPINION STATEMENT: Myxoid liposarcoma (MLPS) is a rare soft tissue sarcoma, with propensity to metastasize to locations such as soft tissue and bone. Thus, whole-body MRI should be a consideration as part of staging for patients with a new diagnosis of MLPS since PET and CT may not identify extrapulmonary disease. Surveillance imaging should be tailored, with consideration of more frequent and longer duration of monitoring for large tumors or tumors with round cell component. This review focuses on studies evaluating imaging in MLPS as well as recent publications on survival and prognostic tools in MLPS.

Keywords: Imaging; Myxoid liposarcoma; Round cell liposarcoma; Staging; Surveillance

DOI: https://doi.org/10.1007/s11864-023-01064-5

Curr Treat Options Oncol. 2023 Feb 28.

Myxoid Liposarcomas: Systemic Treatment Options.

Elise F Nassif, Emily Z Keung, Prapassorn Thirasastr, Neeta Somaiah.

OPINION STATEMENT: Myxoid/round-cell liposarcoma (MRCL) account for 30% of liposarcomas and are the most chemo-sensitive subtype of liposarcoma. The 5-year local relapse and distant metastasis rates are 10% and 20%, respectively. In the advanced setting, the first-line median progression-free survival and overall survival is 9 and 30 months, respectively. The overall response rate (ORR) by RECIST with anthracycline-based chemotherapy is around 40% and with trabectedin is 20%, although response is higher when captured by CHOI criteria. Anthracycline-based combination chemotherapy regimens remain the standard of care first-line treatment option. However, trabectedin is also effective and may be considered in the first-line setting when anthracyclines cannot be prescribed. Beyond chemotherapy, new therapeutic classes are being developed, including autologous adoptive modified T cell receptor cellular therapies which have shown promising results thus far. These new therapies utilize the immunogenic potential of cancer testis antigens, NY-ESO-1 and MAGE-A4, which are expressed in the vast majority of MRCL. Early phase trials have shown encouraging results with up to 40% ORR and a median progression-free survival up to 8.7 months. Other innovative strategies are being developed, tailored to the molecular biology of MRCL. This review summarizes current evidence for the use of standard chemotherapy and the new biomarker-selected treatments under development.

Keywords: Adoptive T cell therapies; Cancer testis antigens; Doxorubicin; Myxoid liposarcoma; Round-cell liposarcoma; Trabectedin

DOI: https://doi.org/10.1007/s11864-023-01057-4

Cell Death Dis. 2023 Feb 27. 14(2): 169

Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors.

Sho Isoyama, Naomi Tamaki, Yutaka Noguchi, Mutsumi Okamura, Yuki Yoshimatsu, Tadashi Kondo, Takeshi Suzuki, Shin-Ichi Yaguchi, Shingo Dan.

Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing's sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.

DOI: https://doi.org/10.1038/s41419-023-05690-7

PLoS One. 2023 ;18(3): e0280508

Clinical characteristics of sarcoma cases in which long-term disease control was achieved with trabectedin treatment: A retrospective study.

Trabectedin is a therapeutic option for patients with advanced sarcoma. While a randomized trial demonstrated its prolonged progression-free survival (PFS), the reported PFS was <6 months. Some patients can achieve long-term disease control with this treatment. However, the reference information is insufficient. Herein, we retrospectively reviewed 51 sarcoma patients who received trabectedin. We analyzed the clinicopathological features, trabectedin dose, administration schedule, and clinical outcomes, including the overall response rate (ORR) and PFS. Among them, we assessed the detailed data of patients who achieved long-term disease control (PFS >1 year). The ORR in the 49 evaluable patients was 8%, and the median PFS in 51 patients was 7.5 months. Six patients (12%) achieved PFS of >1 year. Five of the six patients had metastatic lesions at trabectedin initiation. The pathological subtypes were myxoid liposarcoma (n = 2), leiomyosarcoma (n = 2), synovial sarcoma (n = 1), and Ewing sarcoma (n = 1). The final administration dose was the minimum dose (0.8 mg/m2) in two patients who continued the treatment over 20 cycles. The best radiological response was partial response (PR) in two myxoid liposarcoma patients and stable disease in four. The durations from trabectedin initiation to the first response in the two PR cases were 163 and 176 days, respectively. Our results support the validity of continuing trabectedin at a sustainable dose and interval in patients who can tolerate it. These results may be useful when considering the clinical application of trabectedin.

DOI: https://doi.org/10.1371/journal.pone.0280508

Adv Pharmacol. 2023 ;pii: S1054-3589(22)00078-3. [Epub ahead of print]96 283-317

Genetic and environmental reprogramming of the sarcoma epigenome.

Anne Grand'Maison, Rachael Kohrn, Emmanuel Omole, Mahek Shah, Peter Fiorica, Jennie Sims, Joyce E Ohm.

Sarcomas are rare and heterogenous mesenchymal tumors occurring in soft tissue and bone. The World Health Organization Classification of sarcomas comprises more than hundred different entities which are very diverse in their molecular, genetic and epigenetic signatures as they are in their clinical presentations and behaviors. While sarcomas can be associated with an underlying hereditary cancer predisposition, most sarcomas developed sporadically without identifiable cause. Sarcoma oncogenesis involves complex interactions between genetic, epigenetic and environmental factors which are intimately related and intensively studied. Several molecular discoveries have been made over the last decades leading to the development of new therapeutic avenues. Sarcoma research continues its effort toward a more specific and personalized approach to all sarcoma sub-types to improve patient outcomes and this through world-wide collaboration. This chapter on "Genetic and Environmental Reprogramming of the Sarcoma Epigenome" provides a comprehensive review of general concepts and epidemiology of sarcoma as well as a detailed description of the genetic, molecular and epigenetic alterations seen in sarcomas, their therapeutic implications and ongoing research. This review also presents evidenced-based data on the environmental and occupational factors possibly involved in the etiology of sarcomas and a brief discussion on the role of the microbiome in sarcoma.

Keywords: Cancer biology; Environmental exposures; Epigenetics; Sarcoma

DOI: https://doi.org/10.1016/bs.apha.2022.10.001