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August 2, 2026

Targeting ATRX mutation in UPS

Undifferentiated pleomorphic sarcoma (UPS) is one of the most aggressive and difficult-to-treat forms of soft tissue sarcoma. It can occur almost anywhere in the body, often in the muscles or connective tissues, and tends to spread quickly to the lungs and other organs. Unlike many other sarcomas, UPS does not resemble any normal tissue. Because of this, it is often diagnosed by ruling out other types of sarcomas rather than by its own defining features. This lack of a clear identity has made it very difficult to understand how UPS begins and why it behaves so aggressively. UPS is often associated with poor clinical outcome because of its rapid growth, tendency to spread, and resistance to therapy. No effective targeted therapy has been developed for UPS patients, and their long-term survival remains poor despite surgery, chemotherapy, and radiation. Recent genomic profiling of human sarcomas has identified major genetic alterations for UPS. Among them, ATRX is altered in about one-third of UPS patients. ATRX functions to maintain the proper packing of DNA in human cells. It plays important roles in normal development and has been found to be mutated in many cancer types. However, how does ATRX mutations contribute to tumor development and how tumors with ATRX mutations can be treated remain largely unknown. These knowledge gaps further highlight the urgent need of relevant models to understand the mechanisms of ATRX function and identify targeting strategies. To address this, we have built new animal model that mimic the key genetic alterations of human UPS, including the loss of ATRX. Our novel model not only recapitulates the pathological feature of human UPS, but also reproduces the molecular features of human disease, giving us a powerful tool for discovering disease mechanism and identify therapeutic strategies. Using these tools, we have revealed novel functions of ATRX in regulating cell development and growth. More importantly, we identified pathways that are specifically required for the growth of tumor cells lack functional ATRX and thus can serve as therapeutic target. Built upon our findings, this proposal will utilize our unique animal model and newly established patient-derived models to further decipher the molecular mechanisms underlying ATRX function in tumor cells and, more importantly, evaluate novel therapy strategies that can be readily translated into clinical trials for UPS patients with ATRX mutations. Since ATRX is mutated in several sarcoma types, the impact of our proposal will go beyond the scope of UPS and eventually benefit different types of sarcoma patients.

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Targeting ATRX mutation in UPS

Undifferentiated pleomorphic sarcoma (UPS) is one of the most aggressive and difficult-to-treat forms of soft tissue sarcoma. It can occur almost anywhere in the body, often in the muscles or connective tissues, and tends to spread quickly to the lungs and other organs. Unlike many other sarcomas, UPS does not resemble any normal tissue. Because of this, it is often diagnosed by ruling out other types of sarcomas rather than by its own defining features. This lack of a clear identity has made it very difficult to understand how UPS begins and why it behaves so aggressively. UPS is often associated with poor clinical outcome because of its rapid growth, tendency to spread, and resistance to therapy. No effective targeted therapy has been developed for UPS patients, and their long-term survival remains poor despite surgery, chemotherapy, and radiation. Recent genomic profiling of human sarcomas has identified major genetic alterations for UPS. Among them, ATRX is altered in about one-third of UPS patients. ATRX functions to maintain the proper packing of DNA in human cells. It plays important roles in normal development and has been found to be mutated in many cancer types. However, how does ATRX mutations contribute to tumor development and how tumors with ATRX mutations can be treated remain largely unknown. These knowledge gaps further highlight the urgent need of relevant models to understand the mechanisms of ATRX function and identify targeting strategies. To address this, we have built new animal model that mimic the key genetic alterations of human UPS, including the loss of ATRX. Our novel model not only recapitulates the pathological feature of human UPS, but also reproduces the molecular features of human disease, giving us a powerful tool for discovering disease mechanism and identify therapeutic strategies. Using these tools, we have revealed novel functions of ATRX in regulating cell development and growth. More importantly, we identified pathways that are specifically required for the growth of tumor cells lack functional ATRX and thus can serve as therapeutic target. Built upon our findings, this proposal will utilize our unique animal model and newly established patient-derived models to further decipher the molecular mechanisms underlying ATRX function in tumor cells and, more importantly, evaluate novel therapy strategies that can be readily translated into clinical trials for UPS patients with ATRX mutations. Since ATRX is mutated in several sarcoma types, the impact of our proposal will go beyond the scope of UPS and eventually benefit different types of sarcoma patients.

August 2, 2026

Understanding and targeting MYC in angiosarcoma

Angiosarcoma is a rare, aggressive malignant neoplasm of endothelial origin, frequently arising in previously irradiated tissues. In radiation-associated angiosarcoma (RAAS), focal amplification leads to marked overexpression of MYC, a bHLH LZ transcription factor that normally regulates proliferation, differentiation, and cellular stemness. How MYC overexpression drives endothelial tumor initiation, progression, dedifferentiation, and therapy resistance remains poorly defined. We developed an endothelial-specific, reversible, doxycycline inducible MYC overexpression genetically engineered mouse model (GEMM) in which MYC can be toggled on and off in the vascular lineage. MYC induction rapidly led to the development of pulmonary angiosarcoma that progressed from low- to high-grade and to dedifferentiated angiosarcoma with loss of endothelial markers (e.g., CD31, ERG) within approximately 6 weeks. MYC removal arrested tumor growth and restored endothelial identity, demonstrating strict MYC dependency and tumor intrinsic plasticity. Leveraging this model and complementary human RAAS systems, we will dissect MYC-driven transcriptional and chromatin reprogramming using single nucleus RNA/ATAC profiling and MYC/MAX cistrome profiling (e.g., CUT&RUN), and evaluate direct MYC targeted therapeutics (e.g., Omomyc/OMO 103) and strategies that modulate MYC dosage. These studies aim to define the mechanisms of MYC mediated angiosarcomagenesis and identify actionable vulnerabilities to guide clinical translation in RAAS and other MYC addicted cancers.

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Understanding and targeting MYC in angiosarcoma

Angiosarcoma is a rare, aggressive malignant neoplasm of endothelial origin, frequently arising in previously irradiated tissues. In radiation-associated angiosarcoma (RAAS), focal amplification leads to marked overexpression of MYC, a bHLH LZ transcription factor that normally regulates proliferation, differentiation, and cellular stemness. How MYC overexpression drives endothelial tumor initiation, progression, dedifferentiation, and therapy resistance remains poorly defined. We developed an endothelial-specific, reversible, doxycycline inducible MYC overexpression genetically engineered mouse model (GEMM) in which MYC can be toggled on and off in the vascular lineage. MYC induction rapidly led to the development of pulmonary angiosarcoma that progressed from low- to high-grade and to dedifferentiated angiosarcoma with loss of endothelial markers (e.g., CD31, ERG) within approximately 6 weeks. MYC removal arrested tumor growth and restored endothelial identity, demonstrating strict MYC dependency and tumor intrinsic plasticity. Leveraging this model and complementary human RAAS systems, we will dissect MYC-driven transcriptional and chromatin reprogramming using single nucleus RNA/ATAC profiling and MYC/MAX cistrome profiling (e.g., CUT&RUN), and evaluate direct MYC targeted therapeutics (e.g., Omomyc/OMO 103) and strategies that modulate MYC dosage. These studies aim to define the mechanisms of MYC mediated angiosarcomagenesis and identify actionable vulnerabilities to guide clinical translation in RAAS and other MYC addicted cancers.

August 2, 2026

An Implantable Microdevice in Soft Tissue Sarcoma

Therapeutic development in soft tissue sarcoma is limited by the rarity and heterogeneity of the disease and is an increasingly cost-prohibitive undertaking in both academic and industry settings. The community can benefit from methods to generate clinical data on current and novel therapeutic agents prior to initiation of first-in-human trials. These data can be used to inform clinical decisions for currently available treatment options and serve as motivation to proceed with dedicated clinical trials of investigational drugs. One method to accelerate data generation in sarcoma drug development is a drug-eluting implantable microdevice. We have developed device roughly the size of a grain of rice which can expose a single tumor to multiple potential therapies within a single patient. The device has been deployed in multiple settings including mouse models of human tumors and in patients with brain tumors at the Mass General Brigham Cancer Institute. It can be safely implanted and removed in each setting, and the surrounding tissue can be analyzed for markers of drug response. In each setting, in situ drug response has correlated with systemic response to that same treatment. We aim to utilize our tumor microdevice in patients with soft tissue sarcoma who are likely to require systemic therapy. The goals of this proposal are to demonstrate that our microdevice device can be safely placed and removed in patients with treatment-naïve sarcomas, and to analyze the effect of multiple drugs on an individual tumor. Readouts will include markers of cell death, DNA damage, proliferation, and changes to the immune component of the tumor (tumor microenvironment). For therapies indented to target a specific pathway, we will include assays aimed at investigating the unique effect of that drug such as expression profiling or single cell assays. A single device can be loaded with up to 20 drugs or combinations of drugs including chemotherapy, immunotherapy, and investigational agents. Systemic exposure to microdevice agents is less than 1/100,000 of typical drug dosing, which allows for testing of drugs and combinations which have not been tested in patients before without risking toxicity. A successful study will not only demonstrate that this method is feasible in soft tissue sarcoma but generate data that is useful to patients. For approved therapies, data from microdevices can be used to inform treatment options. This will allow providers to pick the most active agent for an individual tumor. For novel therapies, data can be aggregated across all participants to identify new vulnerabilities. We anticipate the data generated from this study will serve as motivation for dedicated clinical trials of novel agents in patients with soft tissue sarcoma.

Read more

An Implantable Microdevice in Soft Tissue Sarcoma

Therapeutic development in soft tissue sarcoma is limited by the rarity and heterogeneity of the disease and is an increasingly cost-prohibitive undertaking in both academic and industry settings. The community can benefit from methods to generate clinical data on current and novel therapeutic agents prior to initiation of first-in-human trials. These data can be used to inform clinical decisions for currently available treatment options and serve as motivation to proceed with dedicated clinical trials of investigational drugs. One method to accelerate data generation in sarcoma drug development is a drug-eluting implantable microdevice. We have developed device roughly the size of a grain of rice which can expose a single tumor to multiple potential therapies within a single patient. The device has been deployed in multiple settings including mouse models of human tumors and in patients with brain tumors at the Mass General Brigham Cancer Institute. It can be safely implanted and removed in each setting, and the surrounding tissue can be analyzed for markers of drug response. In each setting, in situ drug response has correlated with systemic response to that same treatment. We aim to utilize our tumor microdevice in patients with soft tissue sarcoma who are likely to require systemic therapy. The goals of this proposal are to demonstrate that our microdevice device can be safely placed and removed in patients with treatment-naïve sarcomas, and to analyze the effect of multiple drugs on an individual tumor. Readouts will include markers of cell death, DNA damage, proliferation, and changes to the immune component of the tumor (tumor microenvironment). For therapies indented to target a specific pathway, we will include assays aimed at investigating the unique effect of that drug such as expression profiling or single cell assays. A single device can be loaded with up to 20 drugs or combinations of drugs including chemotherapy, immunotherapy, and investigational agents. Systemic exposure to microdevice agents is less than 1/100,000 of typical drug dosing, which allows for testing of drugs and combinations which have not been tested in patients before without risking toxicity. A successful study will not only demonstrate that this method is feasible in soft tissue sarcoma but generate data that is useful to patients. For approved therapies, data from microdevices can be used to inform treatment options. This will allow providers to pick the most active agent for an individual tumor. For novel therapies, data can be aggregated across all participants to identify new vulnerabilities. We anticipate the data generated from this study will serve as motivation for dedicated clinical trials of novel agents in patients with soft tissue sarcoma.

August 2, 2026

WEE1/PKMYT1 Dual Targeting in CIC::DUX4 Sarcoma

CIC::DUX4 sarcoma is an aggressive and ultra-rare cancer affecting children, adolescents, and young adults (AYA), characterized by poor clinical outcomes and limited effective treatment options. These tumors grow rapidly and frequently metastasize, highlighting an urgent need for biologically targeted therapies. The CIC::DUX4 fusion oncoprotein drives uncontrolled proliferation and elevated replication stress, a condition in which cancer cells accumulate DNA damage during cell division. To survive this stress, tumor cells rely on the G2/M checkpoint, a protective regulatory pathway that delays mitosis and permits DNA repair. This checkpoint is regulated by two complementary kinases, WEE1 and PKMYT1, which together inhibit CDK1 and control cell cycle progression. We hypothesize that simultaneous inhibition of WEE1 and PKMYT1 will abrogate this checkpoint, prevent repair of replication-associated damage, and induce tumor cell death. To test this hypothesis, we will evaluate the clinically advanced WEE1 inhibitor ZN-c3 and the PKMYT1 inhibitor Lunresertib, alone and in combination, in patient-derived CIC::DUX4 sarcoma models. Therapeutic efficacy will be assessed using quantitative cell-viability and drug-synergy analyses. Mechanistic studies will measure replication stress and DNA damage (pRPA32, ?H2AX), checkpoint disruption (phospho-CDK1), and apoptosis (cleaved PARP) to confirm that dual checkpoint inhibition induces premature and lethal mitotic entry. In vivo xenograft studies will further evaluate tumor growth suppression and treatment tolerability. To our knowledge, this is the first study to investigate combined WEE1 and PKMYT1 inhibition in CIC::DUX4 sarcoma. This work represents a mechanism-based therapeutic strategy targeting G2/M checkpoint dependence in this disease. Because both agents are already in clinical development, these studies establish a strong translational foundation for advancing a rational therapeutic strategy for patients with this high-risk disease.

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WEE1/PKMYT1 Dual Targeting in CIC::DUX4 Sarcoma

CIC::DUX4 sarcoma is an aggressive and ultra-rare cancer affecting children, adolescents, and young adults (AYA), characterized by poor clinical outcomes and limited effective treatment options. These tumors grow rapidly and frequently metastasize, highlighting an urgent need for biologically targeted therapies. The CIC::DUX4 fusion oncoprotein drives uncontrolled proliferation and elevated replication stress, a condition in which cancer cells accumulate DNA damage during cell division. To survive this stress, tumor cells rely on the G2/M checkpoint, a protective regulatory pathway that delays mitosis and permits DNA repair. This checkpoint is regulated by two complementary kinases, WEE1 and PKMYT1, which together inhibit CDK1 and control cell cycle progression. We hypothesize that simultaneous inhibition of WEE1 and PKMYT1 will abrogate this checkpoint, prevent repair of replication-associated damage, and induce tumor cell death. To test this hypothesis, we will evaluate the clinically advanced WEE1 inhibitor ZN-c3 and the PKMYT1 inhibitor Lunresertib, alone and in combination, in patient-derived CIC::DUX4 sarcoma models. Therapeutic efficacy will be assessed using quantitative cell-viability and drug-synergy analyses. Mechanistic studies will measure replication stress and DNA damage (pRPA32, ?H2AX), checkpoint disruption (phospho-CDK1), and apoptosis (cleaved PARP) to confirm that dual checkpoint inhibition induces premature and lethal mitotic entry. In vivo xenograft studies will further evaluate tumor growth suppression and treatment tolerability. To our knowledge, this is the first study to investigate combined WEE1 and PKMYT1 inhibition in CIC::DUX4 sarcoma. This work represents a mechanism-based therapeutic strategy targeting G2/M checkpoint dependence in this disease. Because both agents are already in clinical development, these studies establish a strong translational foundation for advancing a rational therapeutic strategy for patients with this high-risk disease.

August 2, 2026

Translation of Autophagy-Reprogrammed B7-H3 CAR T

Despite major advances in pediatric oncology, outcomes for children with relapsed or refractory sarcomas remain dismal, with survival rates below 25 percent and limited therapeutic options. Immunotherapy with chimeric antigen receptor (CAR) T cells has transformed the treatment of leukemia and lymphoma, but its success in solid tumors has been modest. The main barriers are the poor persistence of CAR T cells, their metabolic exhaustion and the highly immunosuppressive tumor microenvironment (TME) that characterizes most sarcomas. Our research focuses on improving the metabolic fitness and longevity of CAR T cells through a process known as autophagy, a natural mechanism that allows cells to recycle energy and maintain homeostasis under stress. We recently demonstrated that the manufacturing process of CAR T cells profoundly suppresses autophagy, impairing their survival and antitumor activity. Using gene engineering, we successfully restored this pathway by reintroducing the protein Beclin1, which reactivates autophagy. This intervention markedly improved CAR T cell persistence, mitochondrial function and tumor-killing capacity in preclinical models, without toxicity. These findings were obtained through our previous Sarcoma Foundation of America funded project (SFA-1070868). In parallel, we developed a CAR targeting B7-H3, a molecule abundantly expressed across multiple pediatric sarcoma subtypes, including osteosarcoma, Ewing sarcoma, synovial sarcoma and rhabdomyosarcoma. B7-H3 is also found on immunosuppressive cells within the TME, such as M2 macrophages and myeloid-derived suppressor cells, suggesting that its targeting could simultaneously attack tumor cells and remodel the immune environment. Our preclinical studies show that the new B7-H3.CAR performs as effectively as our clinically validated GD2.CAR platform, while offering broader coverage across sarcoma types. This proposal seeks to complete the translational development of autophagy-reprogrammed B7-H3.CAR T cells, advancing them toward clinical evaluation. The project will (1) perform in vivo safety and biodistribution studies; (2) establish a stable GMP-grade viral producer line to ensure reproducible manufacturing; and (3) define GMP release criteria and B7-H3 expression thresholds for patient selection in an academic phase I clinical trial. The proposed work integrates strong mechanistic innovation with a direct path to patient benefit. By combining metabolic reprogramming through autophagy restoration with a broadly expressed and immunomodulatory target, this strategy has the potential to overcome the major limitations of CAR T therapy in solid tumors. Successful completion of the project will lay the foundation for a first-in-human trial in children with relapsed or refractory B7-H3+ sarcomas, ultimately offering a novel and durable immunotherapeutic option where few alternatives exist.

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Translation of Autophagy-Reprogrammed B7-H3 CAR T

Despite major advances in pediatric oncology, outcomes for children with relapsed or refractory sarcomas remain dismal, with survival rates below 25 percent and limited therapeutic options. Immunotherapy with chimeric antigen receptor (CAR) T cells has transformed the treatment of leukemia and lymphoma, but its success in solid tumors has been modest. The main barriers are the poor persistence of CAR T cells, their metabolic exhaustion and the highly immunosuppressive tumor microenvironment (TME) that characterizes most sarcomas. Our research focuses on improving the metabolic fitness and longevity of CAR T cells through a process known as autophagy, a natural mechanism that allows cells to recycle energy and maintain homeostasis under stress. We recently demonstrated that the manufacturing process of CAR T cells profoundly suppresses autophagy, impairing their survival and antitumor activity. Using gene engineering, we successfully restored this pathway by reintroducing the protein Beclin1, which reactivates autophagy. This intervention markedly improved CAR T cell persistence, mitochondrial function and tumor-killing capacity in preclinical models, without toxicity. These findings were obtained through our previous Sarcoma Foundation of America funded project (SFA-1070868). In parallel, we developed a CAR targeting B7-H3, a molecule abundantly expressed across multiple pediatric sarcoma subtypes, including osteosarcoma, Ewing sarcoma, synovial sarcoma and rhabdomyosarcoma. B7-H3 is also found on immunosuppressive cells within the TME, such as M2 macrophages and myeloid-derived suppressor cells, suggesting that its targeting could simultaneously attack tumor cells and remodel the immune environment. Our preclinical studies show that the new B7-H3.CAR performs as effectively as our clinically validated GD2.CAR platform, while offering broader coverage across sarcoma types. This proposal seeks to complete the translational development of autophagy-reprogrammed B7-H3.CAR T cells, advancing them toward clinical evaluation. The project will (1) perform in vivo safety and biodistribution studies; (2) establish a stable GMP-grade viral producer line to ensure reproducible manufacturing; and (3) define GMP release criteria and B7-H3 expression thresholds for patient selection in an academic phase I clinical trial. The proposed work integrates strong mechanistic innovation with a direct path to patient benefit. By combining metabolic reprogramming through autophagy restoration with a broadly expressed and immunomodulatory target, this strategy has the potential to overcome the major limitations of CAR T therapy in solid tumors. Successful completion of the project will lay the foundation for a first-in-human trial in children with relapsed or refractory B7-H3+ sarcomas, ultimately offering a novel and durable immunotherapeutic option where few alternatives exist.

August 2, 2026

Optimizing CDK4/6 blockade in epithelioid sarcoma

Epithelioid sarcoma (EPS) is a cancer caused by the loss of the SMARCB1 gene. EPS primarily occurs in adolescents and young adults and often becomes highly aggressive. Although the recent approval of the molecularly-targeted drug Tazemetostat offers a new treatment option for EPS, the response rate is only 15%, so most EPS patients do not benefit. To search for more effective EPS therapies, we conducted a comprehensive genetic study to identify potential therapeutic targets. We applied CRISPR/Cas9-mediated genetic screens to human EPS cell lines to characterize how deletion of thousands of genes affects EPS cancer cell survival. This revealed several potential vulnerabilities in EPS cancer cells and provided a comprehensive view of potential drug targets. Through target prioritization based on drug availability with success in other cancers, and our follow-up validation studies, we identified that cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in EPS cell growth. Importantly, CDK4/6 inhibitors are already used for patients with hormone receptor-positive breast cancer, where combining them with hormone therapy has dramatically improved patient outcomes. This inspired us to hypothesize that durable or potentially curative tumor remission is achievable in EPS when maximizing the anti-cancer activity of CDK4/6 inhibitor by combining it with other anti-cancer drugs. This study aims to identify the best combination drug approach with CDK4/6 inhibition through two complementary approaches. First, we will perform CRISPR screening in both human EPS cells and EPS mouse models treated with a CDK4/6 inhibitor. We will determine which gene, when inactivated, enhances the effect of the CDK4/6 inhibitor to reduce EPS cancer cell survival. Cell-based screens serve as an initial step to discover target genes that could be targeted by drugs, while screens in our novel mouse models can validate these results in conditions closer to those of patients. Second, we will study how EPS cancer cells develop resistance to CDK4/6 inhibitors by analyzing tumors that survive long-term drug treatment in mice. This analysis will reveal mechanisms that allow cancer cells to escape therapy and help identify targets to overcome resistance. The results from these approaches are complementary: large-scale screening provides new candidate drug targets and resistance analysis uncovers pathways EPS cancers use to survive with treatment with CDK4/6 inhibitors. Drug combinations suggested through this study will then be tested in cells and animal models using compounds that are already available either clinically for other cancers or under investigation in clinical trials. With these strategies, we aim to develop effective combination therapies for EPS that can achieve long-lasting control. This research may also provide insights for other cancers with SMARCB1 loss or those driven by the similar mechanisms.

Read more

Optimizing CDK4/6 blockade in epithelioid sarcoma

Epithelioid sarcoma (EPS) is a cancer caused by the loss of the SMARCB1 gene. EPS primarily occurs in adolescents and young adults and often becomes highly aggressive. Although the recent approval of the molecularly-targeted drug Tazemetostat offers a new treatment option for EPS, the response rate is only 15%, so most EPS patients do not benefit. To search for more effective EPS therapies, we conducted a comprehensive genetic study to identify potential therapeutic targets. We applied CRISPR/Cas9-mediated genetic screens to human EPS cell lines to characterize how deletion of thousands of genes affects EPS cancer cell survival. This revealed several potential vulnerabilities in EPS cancer cells and provided a comprehensive view of potential drug targets. Through target prioritization based on drug availability with success in other cancers, and our follow-up validation studies, we identified that cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in EPS cell growth. Importantly, CDK4/6 inhibitors are already used for patients with hormone receptor-positive breast cancer, where combining them with hormone therapy has dramatically improved patient outcomes. This inspired us to hypothesize that durable or potentially curative tumor remission is achievable in EPS when maximizing the anti-cancer activity of CDK4/6 inhibitor by combining it with other anti-cancer drugs. This study aims to identify the best combination drug approach with CDK4/6 inhibition through two complementary approaches. First, we will perform CRISPR screening in both human EPS cells and EPS mouse models treated with a CDK4/6 inhibitor. We will determine which gene, when inactivated, enhances the effect of the CDK4/6 inhibitor to reduce EPS cancer cell survival. Cell-based screens serve as an initial step to discover target genes that could be targeted by drugs, while screens in our novel mouse models can validate these results in conditions closer to those of patients. Second, we will study how EPS cancer cells develop resistance to CDK4/6 inhibitors by analyzing tumors that survive long-term drug treatment in mice. This analysis will reveal mechanisms that allow cancer cells to escape therapy and help identify targets to overcome resistance. The results from these approaches are complementary: large-scale screening provides new candidate drug targets and resistance analysis uncovers pathways EPS cancers use to survive with treatment with CDK4/6 inhibitors. Drug combinations suggested through this study will then be tested in cells and animal models using compounds that are already available either clinically for other cancers or under investigation in clinical trials. With these strategies, we aim to develop effective combination therapies for EPS that can achieve long-lasting control. This research may also provide insights for other cancers with SMARCB1 loss or those driven by the similar mechanisms.

August 19, 2025

EWS::FLI1 drives tumorigenesis in part by creating aberrant, phase-separated, nuclear speckle-related biomolecular condensates that dysregulate mRNA splicing

Many types of cancers, particularly sarcomas, are caused and maintained by specific oncogenic fusion proteins. These fusion proteins are like the mythical chimera and contain parts of two proteins. The EWS::FLI1 chimera, is the major driver of Ewing Sarcoma (ES). EWS::FLI1 is part EWS, which a protein that normally performs many tasks in the nucleus, including participating in making mRNA from DNA. The FLI1 part of EWS::FLI1 causes this chimera protein to stick to DNA; the sticking to DNA helps the chimera decide which genes it might alter. In directing which mRNA is produced, EWS::FLI1 acts as a conductor of the symphony. However, EWS::FLI1 does much more including changing the mRNA in a process called splicing. Splicing eliminates parts of the mRNA so that it is another level of control by EWS::FLI1 as to what proteins are made when the mRNA goes to the cytoplasm. If EWS::FLI1 is the conductor, the mRNA is music, then splicing might be sending the harp player away for a section of the music that does not require a harp.

The proposal is based on a deeper understanding of EWS::FLI1 as it regulates mRNA splicing. There is strong agreement that EWS::FLI1 regulates splicing, but it requires protein partners to change the splicing. Think of the orchestra manager escorting the harp player away when they are not needed. Our challenge is to find those protein partners that are critical for EWS::FLI1 to control splicing, e.g. find out who the orchestra manager is. By finding out which proteins are required for the EWS::FLI1 altered splicing, we can use that information to eventually create new treatments to target those interactions. Our laboratory has significant experience in this area since we were the first to create a treatment, TK-216, that sticks to EWS::FLI1. TK-216 prevents EWS::FLI1 from interacting with some proteins. We showed in a recently published clinical trial of TK-216 that while it helped some patients, others did not respond for long periods of time. We are going to use this proposal to find some new protein partners and better understand how they work with EWS::FLI1. Future work would be directed to finding the next generation of inhibitory treatments.

We hypothesize that EWS::FLI1 drives tumorigenesis in part by creating aberrant nuclear speckle-related biomolecular condensates that dysregulate mRNA splicing. This project will address 2 aims in order to support an R01 resubmission. Aim 1: We will interrogate the composition and dynamic properties of cellular biomolecular condensates composed of EWSR1 or EWS::FLI1. Translated: we will look for new, key, partner proteins. Aim 2: We will monitor mRNA splicing in cells by direct visualization of biomolecular condensate markers, comparing splicing alterations and protein localization from EWSR1 with EWS::FLI1. Translated: we will investigate where the interactions are happening and begin to think about future new treatments to block those interactions.

Read more

EWS::FLI1 drives tumorigenesis in part by creating aberrant, phase-separated, nuclear speckle-related biomolecular condensates that dysregulate mRNA splicing

Many types of cancers, particularly sarcomas, are caused and maintained by specific oncogenic fusion proteins. These fusion proteins are like the mythical chimera and contain parts of two proteins. The EWS::FLI1 chimera, is the major driver of Ewing Sarcoma (ES). EWS::FLI1 is part EWS, which a protein that normally performs many tasks in the nucleus, including participating in making mRNA from DNA. The FLI1 part of EWS::FLI1 causes this chimera protein to stick to DNA; the sticking to DNA helps the chimera decide which genes it might alter. In directing which mRNA is produced, EWS::FLI1 acts as a conductor of the symphony. However, EWS::FLI1 does much more including changing the mRNA in a process called splicing. Splicing eliminates parts of the mRNA so that it is another level of control by EWS::FLI1 as to what proteins are made when the mRNA goes to the cytoplasm. If EWS::FLI1 is the conductor, the mRNA is music, then splicing might be sending the harp player away for a section of the music that does not require a harp.

The proposal is based on a deeper understanding of EWS::FLI1 as it regulates mRNA splicing. There is strong agreement that EWS::FLI1 regulates splicing, but it requires protein partners to change the splicing. Think of the orchestra manager escorting the harp player away when they are not needed. Our challenge is to find those protein partners that are critical for EWS::FLI1 to control splicing, e.g. find out who the orchestra manager is. By finding out which proteins are required for the EWS::FLI1 altered splicing, we can use that information to eventually create new treatments to target those interactions. Our laboratory has significant experience in this area since we were the first to create a treatment, TK-216, that sticks to EWS::FLI1. TK-216 prevents EWS::FLI1 from interacting with some proteins. We showed in a recently published clinical trial of TK-216 that while it helped some patients, others did not respond for long periods of time. We are going to use this proposal to find some new protein partners and better understand how they work with EWS::FLI1. Future work would be directed to finding the next generation of inhibitory treatments.

We hypothesize that EWS::FLI1 drives tumorigenesis in part by creating aberrant nuclear speckle-related biomolecular condensates that dysregulate mRNA splicing. This project will address 2 aims in order to support an R01 resubmission. Aim 1: We will interrogate the composition and dynamic properties of cellular biomolecular condensates composed of EWSR1 or EWS::FLI1. Translated: we will look for new, key, partner proteins. Aim 2: We will monitor mRNA splicing in cells by direct visualization of biomolecular condensate markers, comparing splicing alterations and protein localization from EWSR1 with EWS::FLI1. Translated: we will investigate where the interactions are happening and begin to think about future new treatments to block those interactions.

August 19, 2025

Siglec15 Regulation of Immune Suppressive Microenvironment in Sarcoma

Soft tissue sarcomas present a significant challenge in medical research, being inadequately explored and often resistant to conventional treatments. Among the various subtypes, undifferentiated pleomorphic sarcoma, a major subtype of adult sarcomas, is particularly understudied, with 50% of patients developing fatal lung metastases and a median survival of less than 15 months.

To address this, understanding how sarcoma cells develop and spread to other organs is critical for developing targeted treatments. Employing a primary mouse model initiated with gene mutations commonly found in human sarcomas, co-evolving with immune cells, provides a unique platform for both studying sarcoma biology and conducting preclinical trials for effective therapies, such as immunotherapy. This model becomes indispensable given the limited availability of sarcoma patients for basic and translational research.

A small percentage of undifferentiated pleomorphic sarcoma cases responding to the immunotherapy called anti-PD-1 immune checkpoint blockade, but most are resistant. Therefore, an urgent unmet need is to develop more effective immunotherapies for this devastating disease, which lags behind other common cancers. One main reason is that current primary models used in research lack genetic relevance to human undifferentiated pleomorphic sarcomas or are unsuitable for testing immunotherapies.

In our study, we introduce a novel mouse model established in our lab, the first to genetically mimic human undifferentiated pleomorphic sarcoma. This model allows us to systematically investigate how Bap1 gene mutations regulate sarcoma development and metastasis to the lung. Also, it enables the examination of immune cell infiltration, offering insights into potential strategies for immunotherapies and combination therapy.

Using our mouse model, we identified Siglec15 transmembrane protein as a potential immunotherapy target for undifferentiated pleomorphic sarcoma. Preliminary research has identified that high levels of Siglec15 expression are associated with poor survival in sarcoma, and Siglec15 is drastically upregulated in both human and mouse undifferentiated pleomorphic sarcoma. Ablation of Siglec15 induced an immune response and resulted in tumor growth inhibition. Additionally, the percentage of immune cells dramatically increased in tumors upon deletion of Siglec15. Therefore, we propose to test our hypothesis that a Siglec15 antagonist alone or combined with anti-PD-1 blockade can suppress the growth and metastasis of undifferentiated pleomorphic sarcoma.

The Siglec15 antagonist proposed in the study is currently being tested in human clinical trials. However, sarcoma patients are not included in the trials, and no prior research has explored the role of Siglec15 in sarcomas. Thus, our results may pave the way for moving a Siglec15 antagonist from bench to bedside, potentially treating patients with this challenging disease within two years.

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Siglec15 Regulation of Immune Suppressive Microenvironment in Sarcoma

Soft tissue sarcomas present a significant challenge in medical research, being inadequately explored and often resistant to conventional treatments. Among the various subtypes, undifferentiated pleomorphic sarcoma, a major subtype of adult sarcomas, is particularly understudied, with 50% of patients developing fatal lung metastases and a median survival of less than 15 months.

To address this, understanding how sarcoma cells develop and spread to other organs is critical for developing targeted treatments. Employing a primary mouse model initiated with gene mutations commonly found in human sarcomas, co-evolving with immune cells, provides a unique platform for both studying sarcoma biology and conducting preclinical trials for effective therapies, such as immunotherapy. This model becomes indispensable given the limited availability of sarcoma patients for basic and translational research.

A small percentage of undifferentiated pleomorphic sarcoma cases responding to the immunotherapy called anti-PD-1 immune checkpoint blockade, but most are resistant. Therefore, an urgent unmet need is to develop more effective immunotherapies for this devastating disease, which lags behind other common cancers. One main reason is that current primary models used in research lack genetic relevance to human undifferentiated pleomorphic sarcomas or are unsuitable for testing immunotherapies.

In our study, we introduce a novel mouse model established in our lab, the first to genetically mimic human undifferentiated pleomorphic sarcoma. This model allows us to systematically investigate how Bap1 gene mutations regulate sarcoma development and metastasis to the lung. Also, it enables the examination of immune cell infiltration, offering insights into potential strategies for immunotherapies and combination therapy.

Using our mouse model, we identified Siglec15 transmembrane protein as a potential immunotherapy target for undifferentiated pleomorphic sarcoma. Preliminary research has identified that high levels of Siglec15 expression are associated with poor survival in sarcoma, and Siglec15 is drastically upregulated in both human and mouse undifferentiated pleomorphic sarcoma. Ablation of Siglec15 induced an immune response and resulted in tumor growth inhibition. Additionally, the percentage of immune cells dramatically increased in tumors upon deletion of Siglec15. Therefore, we propose to test our hypothesis that a Siglec15 antagonist alone or combined with anti-PD-1 blockade can suppress the growth and metastasis of undifferentiated pleomorphic sarcoma.

The Siglec15 antagonist proposed in the study is currently being tested in human clinical trials. However, sarcoma patients are not included in the trials, and no prior research has explored the role of Siglec15 in sarcomas. Thus, our results may pave the way for moving a Siglec15 antagonist from bench to bedside, potentially treating patients with this challenging disease within two years.

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