Erica Maria Pimenta, MD, PhD, is a postdoctoral research fellow at Dana-Farber Cancer Institute

Dr Pimenta on Ongoing Therapeutic Challenges in Soft Tissue Sarcomas

"[Broadly] across sarcomas, there's a huge opportunity to improve treatment strategies and outcomes; for liposarcoma in particular, there's an unmet need for targeted therapies."

Erica Maria Pimenta, MD, a medical oncologist and clinical fellow in medicine at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, outlined the ongoing therapeutic and translational challenges in soft tissue sarcoma, highlighting the persistent unmet need in dedifferentiated liposarcoma (DDLPS) and other subtypes lacking effective targeted therapies.

Despite incremental advances, the treatment landscape for DDLPS remains largely dependent on empiric chemotherapy, which offers limited clinical benefit and is associated with substantial toxicity. Pimenta emphasized that although agents such as anthracyclines and ifosfamide remain the standard of care, there is an urgent need to move beyond non-specific cytotoxic regimens. One key barrier to this progress is the limited understanding of the molecular drivers of disease, particularly in DDLPS, where defining actionable targets has proven difficult.

Pimenta noted that ongoing research at Dana-Farber Cancer Institute aims to expand the therapeutic armamentarium for patients with liposarcoma by interrogating molecular and epigenetic underpinnings of disease progression. This includes efforts to identify novel biomarkers and signaling pathways that may inform precision oncology approaches. Pimenta noted that, unlike more genetically tractable malignancies, DDLPS is characterized by complex karyotypes and few recurrent point mutations, which complicates the identification of druggable targets.

Current investigative efforts are examining whether transcriptomic and epigenetic dysregulation may play a more prominent role than previously appreciated. Additionally, studies are exploring the interaction between tumor biology and the immune microenvironment—particularly macrophage infiltration—which may influence immune escape and resistance to checkpoint blockade.

Although previous clinical trials evaluating immune checkpoint inhibitors and targeted therapies such as MDM2 or CDK4 inhibitors have yielded modest results, Pimenta remains optimistic that a more granular understanding of tumor heterogeneity will allow for better trial design and therapeutic stratification. She underscored the importance of continuing to build comprehensive translational frameworks that integrate molecular profiling, preclinical modeling, and biomarker-driven trial development.

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Erica Maria Pimenta, MD, discusses ongoing therapeutic and translational challenges in the treatment of soft tissue sarcomas.

Pimenta

"This study has opened up many novel areas of research in liposarcoma, beyond the [epigenetic dysregulation] study in dedifferentiated liposarcoma."

Erica Maria Pimenta, MD, PhD, a clinical fellow in medicine at Brigham and Women's Hospitalmedical oncologist and translational researcher, discussed the implications of recent findings on epigenetic dysregulation in dedifferentiated liposarcoma (DDLPS), with a particular focus on the IGF1/PPARG2 signaling axis and ELF1 transcriptional activity.

The study, she noted, lays may set the foundation for a broader research agenda aimed at understanding non-genetic mechanisms of tumor progression and immune evasion in soft tissue sarcomas.

Historically, therapeutic research in liposarcoma has focused on genomic alterations such as 

 amplification. However, new transcriptomic analyses have identified 

 activation as a predominant feature in DDLPS, suggesting a key role in maintaining the dedifferentiated phenotype. Current investigations are evaluating the molecular pathways downstream of 

, including its potential influence on proliferative signaling and lineage plasticity. Given that ELF1 agonists are already available and widely used in other contexts, these findings offer a potential path toward therapeutic repurposing in sarcoma.

In addition to transcriptional regulation, the study also explored how dedifferentiation impacts the immune microenvironment. Pimenta noted that macrophages are the dominant immune cell type in the DDLPS tumor microenvironment. Ongoing research is examining how interactions between tumor cells and macrophages contribute to immune escape and whether these interactions could be modulated therapeutically. This line of inquiry is particularly relevant as immune checkpoint inhibition has shown limited efficacy in soft tissue sarcoma, and strategies to enhance antitumor immunity remain a critical unmet need.

Erica Maria Pimenta, MD, PhD, discusses the future for evaluating tumor progression and immune evasion in soft tissue sarcomas.

Dr Pimenta on Novel Approaches to Evaluate Tumor Progression and Immune Evasion in Soft Tissue Sarcomas

Dr Pimenta on Adipogenesis Defects Characteristic of Dedifferentiated Liposarcoma

“The key finding here is that [during adipogenesis], dedifferentiated liposarcoma cells [can] lose a lineage-specific protein that’s necessary for differentiation.”

Erica Maria Pimenta, MD, PhD, a postdoctoral research fellow at Dana-Farber Cancer Institute and a clinical fellow in medicine at Brigham and Women’s Hospital, discussed findings from a study investigating epigenetic dysregulation of the IGF1/PPARG2 signaling pathway in dedifferentiated liposarcoma.

This study used single-nucleus multiome sequencing and spatial profiling to characterize defects in adipocyte-specific differentiation within human well-differentiated liposarcoma cells, dedifferentiated liposarcoma cells, and normal human adipose.

Investigators found that insulin-mediated adipogenesis through IGF1 signaling was present in well-differentiated liposarcoma, but not in dedifferentiated liposarcoma, Pimenta said. Notably, this loss of IGF1 was associated with worse overall survival outcomes in patients with liposarcoma.

Additionally, gain of cellular programs related to early mesenchymal development and GLP-1–induced insulin secretion was also found to be a hallmark of dedifferentiated liposarcoma. Epigenomic analysis revealed similar findings, she noted.

Furthermore, this study indicated that GLP-1 signaling may regulate dedifferentiated disease, she explained. Spatial transcriptomics profiling validated this finding, she stated. In normal adipocytes, IGF1 signals upstream of PPARG and indices lineage-specific differentiation. Based on this knowledge, the investigators evaluated whether IDF1 exposure could cause liposarcoma cells to differentiate, Pimenta reported. However, in vitro stimulation of the IFG1 signaling pathway showed a deficiency in the PPARG isoform PPARG2, which prevents PPARG1 from binding to its transcription start site, according to Pimenta.

IGF1/PPARG2 signaling is accordingly disrupted, and dedifferentiated liposarcoma cells are unable to respond to differentiation signals in the TME, she explained. These barriers were not able to be reversed with the addition of exogenous IGF1 or pro-adipogenic PPARG and GLP-1 agonists, she added. Overall, this study showed that dedifferentiated liposarcoma cells can develop lineage-specificdefects during adipogenesis that result in the loss of necessary components for proper differentiation, she concluded.

Erica Maria Pimenta, MD, PhD, discusses a study investigating potential defects in molecular pathways involved in adipocyte-specific differentiation

Erica Maria Pimenta, MD, PhD

Articles

Dr Pimenta on Ongoing Therapeutic Challenges in Soft Tissue Sarcomas

Dr Pimenta on Novel Approaches to Evaluate Tumor Progression and Immune Evasion in Soft Tissue Sarcomas

Dr Pimenta on Adipogenesis Defects Characteristic of Dedifferentiated Liposarcoma