Dissecting DNA damage and repair pathways in leiomyosarcomas: Improving therapy by understanding biology

Dissecting DNA damage and repair pathways in leiomyosarcomas: Improving therapy by understanding biology

Leiomyosarcomas (LMS) are aggressive tumors of the smooth muscle with no available effective treatments and a 2-year survival rate of 20%. They represent up to 25% of all soft tissue sarcomas (STS) and are the most common form of STS in the U.S. next to gastrointestinal stromal tumors (GISTs). Not one single genetic abnormality is known to be responsible for the development of LMS. Although a subset of tumors shows activation of the PI3K/AKT/mTOR axis, targeting this signaling pathway with small molecule kinase inhibitors has only led to minimal improvement in outcome. Therefore, new therapy options are urgently needed. The…  Read More »

Modulation of Cold Sarcoma Microenvironments to Enable T Cells in Experimental Systems

We are trying to improve immunotherapy for patients with synovial sarcoma (SS) and myxoid/round cell liposar-coma (MRCL); these cancers “should” be ideal candidates for immunotherapy as they have uniquely high and consistent expression of the immunogenic target, NY-ESO-1. Indeed, NY-ESO-1-targeting vaccines and adoptive cellular therapy (ACT) can induce regression of these tumors, but these responses are rarely durable. Our data suggests that these are classic ‘cold’ tumors (labeled C5 in a recent analysis),5 with generally low mutation burdens, few infiltrating T cells, low expression of major histocompatibility (MHC) / human leukocyte antigen (HLA) molecules, and failure to respond to single-agent…  Read More »

Uncovering polygenic signatures of Ewings Sarcoma drug sensitivity during the evolution of resistance

The trajectory of cancer progression is shaped by evolutionary processes on a variety of time scales. Evolutionary selection forces drive populations towards more fit phenotypes over generations, yet individual cancer cells can escape these forces by modifying their intracellular signaling on short times scales. While these facts are becoming more and more accepted, little, if any, of this knowledge has been translated into clinically actionable information. And, more frustratingly, it has failed to change the pursuit of ‘silver bullets’: drugs that act on single targets awash in a sea of heterogeneity. We submit that even if such approaches yield new…  Read More »

Single-cell transcriptomics and epigenomics to identify tumor-microenvironment Interactions for targeted treatment of MPNST

MPNST (malignant peripheral nerve sheath tumors) are highly aggressive soft tissue sarcomas of Schwann cell (SC) origin, representing a major cause of mortality in neurofibromatosis (NF) patients, which affects 1 in 3500 individuals worldwide. The prognosis of MPNST patients is dismal due to invasive tumor growth, metastatic proclivity and resistance to radiation and conventional chemotherapy, posing an urgent need for improved effective therapeutic modalities for this challenging disease. MPNST are heterogeneous tumors with a distinct microenvironment that contributes to the establishment of a tumor niche. Cancer behaviors including progression, metastasis and drug resistance cannot be fully defined by genetic mutations…  Read More »

Intratumoral heterogeneity in dedifferentiated liposarcoma

Soft tissue sarcomas are a rare entity of very heterogeneous tumors, both epidemiological, histological and molecular. Clinically, sarcomas can occur at any age of life and develop throughout the body. They are associated with a generally unfavorable prognosis, with local relapse and metastatic spread in more than one third of the cases, across subtypes. Liposarcomas (LPS) are one of the most common soft tissue sarcoma subtypes. The incidence peaks between the ages of 40 and 60. The most common LPS subtype is well-differentiated liposarcoma (WDLPS), in which cancer cells resemble highly differentiated adipose cells. While WDLPS carries a relatively good…  Read More »

Immunotargeting of the prognostic NG2/CSPG4 cell surface proteoglycan in soft-tissue histotypes

NG2/CSPG4 transmembrane proteoglycan (PG) is a multivalent cell surface macromolecule whose impact on tumour growth and dissemination has been extensively documented in a variety of tumours and animal models. The PG is abundantly expressed in numerous soft-tissue sarcoma subtypes where it tightly links to disease progression and evolvement of metastases. Several of our previous studies have highlighted primary mechanisms through which NG2/CSPG4 may enhance malignancy and promote metastasis formation in sarcomas and have established a clear value of the PG a theranostic factor. With the intent to generate highly unique, proprietary anti-NG2/CSPG4 monoclonal antibodies (mAbs) that could be proposed as…  Read More »

Resetting the epigenetic addiction in leiomyosarcomas: a therapeutic perspective

Leiomyosarcomas (LMS) are rare highly malignant tumors of mesenchymal origin. Standard treatment is surgery and adjuvant radiotherapy. Unfortunately, local recurrence and metastasis develop in approximately 40% of cases, which drastically reduce overall survival. In order to provide better perspective to patients, new therapeutic strategy are urgently needed. The reset of the epigenetic status of the neoplastic cells is a promising strategy to impact on tumor aggressiveness. Class IIa HDACs are important epigenetic regulators which are overexpressed in 25% of LMS. Gene editing by CRISPR/Cas9 has proved that LMS cells (SK-UT-1) depends on HDAC9 for survival. HDAC9 can buffer the level…  Read More »

Switching the tumor immune microenvironment from “cold” to “hot” in UPS

Undifferentiated Pleiomorphic Sarcoma (UPS) is one of the most aggressive subtypes of soft tissue sarcoma. Besides earlier detection by novel imaging techniques, little has been found to improve the overall survival of these patients in recent years. Novel therapeutic modalities such as immunotherapies have been largely ineffective in many UPS patients. Accordingly, we have found that UPS tumors are most often characterized by a paucity of immune cells, which are excluded from contacting tumor cells. One possible explanation is the heavy presence within UPS of populations of sarcoma associated-fibroblasts (SAFs), which can exclude immune cells from the tumor parenchyma and…  Read More »

Identification of molecular targets promoting differentiation and loss of self renewal in osteosarcoma

Osteosarcoma is the most common primary bone cancer affecting children and adolescences worldwide. However, since the introduction of chemotherapy, the overall survival rate has been plateaued for more than 30 years, remaining an unmet medical need. Here, we explore the potential of differentiation therapy in osteosarcoma, which aims specifically to promote terminal differentiation and loss of self-renewal in cancer cells. By performing a high-throughput drug screening in a mouse osteosarcoma cell model, we identified chemical compounds that triggered differentiation and decreased proliferation of osteosarcoma. Differentiated tumor cells exhibited the characteristics of mature osteoblasts or osteocytes including limited cell growth, the…  Read More »

Deciphering the effects of IDH mutations on chromatin and differentiation in chondrosarcoma

The discovery of oncogenic neomorphic mutations in the genes coding for the metabolic enzymes Isocitrate Dehydrogenase (IDH) 1 & 2 has driven a search to uncover their oncogenic mechanism and to target them therapeutically. IDH mutations are seen in 50% of chondrosarcomas, which represent approximately 25% of malignant bone neoplasms. The oncogenic proteins they code for result in the inhibition of enzymes normally associated with the removal of repressive chromatin marks. Hence, the outcome of these mutations is usually one of increase heterochromatin content. The consequences of this increased heterochromatin content to tumor development and sensitivity to therapies are not…  Read More »