Radiation therapy is a crucial treatment modality required to control soft tissue and advanced bone sarcomas. Despite technological advancements used to treat radioresistant sarcomas, local recurrence and metastasis continue to pose clinical challenges. Ionizing radiation can elicit anti-tumor responses by releasing tumor-specific antigens that are then visible to the immune system to promote potent T-lymphocyte priming, characterized as in situ vaccination. Radiation alone is rarely able to induce durable systemic antitumor immune responses. New immunotherapy drugs using antibody fragments such as bispecific antibodies and checkpoint inhibitors actively enhance the immune system to help fight cancer are approved for use in…  Read More »

Metastatic Synovial Sarcoma (mSS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathogenomic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, an FDA-approved BCL-2 inhibitor that is revolutionizing care in some BCL-2 expressing hematological cancers, is an obvious therapeutic solution to mSS. In addition there are now dozens of venetoclax-based combination therapies in clinical trials in hematological cancers attributing to…  Read More »

Desmoplastic small round cell tumor (DSRCT) is a rare, highly-aggressive soft-tissue sarcoma with an overall five-year survival rate of less than 30%. Next generation sequencing (NGS) has given cancer researchers unprecedented access to the cancer genome, revealing targetable mutations, predictors of treatment response, and deepening our understanding of the genetic underpinnings of tumor development and progression. However, no large-scale genomic analysis of DSRCT has ever been performed, likely partially due to the difficulty in obtaining large numbers of primary tumor samples and partially due to lack of funding for such a rare disease. Because Memorial Sloan Kettering Cancer Center (MSK)…  Read More »

Is immune checkpoint inhibition the solution for angiosarcoma patients? Genetic and immune profiles of angiosarcoma subtypes will lead to novel insights for the design of individualized immune checkpoint-based therapy for AS patients. Angiosarcomas are rare and aggressive tumors that arise from the vascular endothelium. Despite all therapeutic efforts, the prognosis for angiosarcoma patients is very poor with a 5-year survival of only 30-40%, urging the need for novel therapeutic approaches for these patients. Angiosarcomas can present anywhere in the body and can either develop spontaneously (primary angiosarcomas) or due to previous radiotherapy, chronic lymphedema, or exposure to UV radiation (secondary…  Read More »

A therapy preventing the emergence of lung metastasis in adolescents with osteosarcoma could save more than 70% of the lives currently lost to this disease. This would represent the most significant improvement in outcome for osteosarcoma since the advent of chemotherapy in the 1960s. The primary cause for treatment failure in metastatic osteosarcoma is the emergence of resistance. Metastatic recurrence commonly follows a pattern of initial response to treatment followed by late development of metastatic lesions, often years after completion of therapy. Metastatic recurrences are inherently resistant to chemotherapy. Our lab has determined that tumor-derived IL6 and CXCL8 are critical…  Read More »

Ewings sarcoma is a rare type of cancerous tumor that grows in bones or the soft tissue around the bones, such as cartilage or the nerves. It usually affects children and young adults between the ages of 10 to 19. Ewings sarcoma affects about 250 children and young adults every year in the United States and shows up slightly more often in males. The incidence of Ewing sarcoma has remained unchanged for 30 years. The incidence for all ages is one case per 1 million people in the United States. In patients aged 10 to 19 years, the incidence is…  Read More »

Liposarcomas are the most common histologies of soft tissue sarcomas. Although the most common subtypes of liposarcoma, well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS), often coexist, their clinical behavior and prognosis differ dramatically. Efficacious and well tolerated systemic treatment options for both subtypes are lacking with few advances made over preceding decades. Development of novel therapies is, in part, constrained by our limited understanding of liposarcoma pathogenesis. Whole exome sequencing has shown that mutation rates are modest in coding regions of WDLPS and DDLPS genomes, with few recurrently mutated genes across series and no significant differences between histologies to explain…  Read More »

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. RMS can be divided in two main histopathological subtypes: alveolar (ARMS), mainly characterized by chromosomal translocations resulting in the oncogenic fusion transcription factors (PAX3- or PAX7-FOXO1); and embryonal (ERMS) characterized by a more heterogeneous genomic profile associated with activation of various tumor-promoting signaling pathways and/or loss of tumor surveillance. Alveolar RMS is the most aggressive subtype, associated with frequent metastasis at the time of diagnosis and limited response to treatment, resulting in poor survival rates, emphasizing the need to develop…  Read More »

Most soft tissue sarcomas (STS) remain incurable in the metastatic setting with traditional chemotherapy. Immune checkpoint inhibitors (ICIs), including antibodies to PD-1/PD-L1 and CTLA-4, act by reversing tumor-mediated suppression of T cells. While these drugs have dramatically improved outcomes in many solid tumors, ICIs are effective in less than 20% of STS patients. Recent studies have shown that sarcoma patients who do not achieve benefit with ICIs have few T cells infiltrating the tumor tissue, and low expression of immune-related genes. One potential explanation is that due to the low mutational burden in many STS, antigen-presenting cells do not recognize…  Read More »

Children with metastatic bone cancer have a poor prognosis, with an overall survival rate of less than 30%. Stanford investigators developed a new drug, monoclonal antibodies against the cancer cell marker CD47 (CD mAb), which activates specific immune cells (macrophages) in osteosarcomas to attack and eliminate cancer cells. Preclinical efficacy studies of CD47 mAb in animal models have been finalized and a phase I clinical trial will be initiated at Stanford in 2020. Since osteosarcomas will not decrease in size in response to CD47 mAb therapy, at least not in the immediate post-treatment phase, we need to develop new imaging…  Read More »

Long-read sequencing (LRS) technologies permit to continuously read individual DNA/RNA molecules over long stretches of DNA (>10kb), thus providing unparalleled information to resolve complex structural variants (SVs), the repertoire of RNA isoforms and gene fusions at single-haplotype resolution, and infer methylation profiles. Despite these advantages, LRS has not been applied to analyse sarcoma genomes yet, in which complex SVs undetectable by Illumina sequencing and mediating gene fusion formation and oncogene amplification abound, as we have recently shown (Cortes-Ciriano et al., Nature Genetics, In press). In this project, we will perform long-read whole-genome and transcriptome sequencing, as well as methylation profiling,…  Read More »

Liposarcomas (LPS) are classified in three principal subtypes: pleomorphic, myxoid/round cell and well-differentiated/de-differentiated (WD/DD); each of them with different clinical behavior, treatment sensitivity and underlying biology. WD/DD LPS comprises approximately 40% of LPS and most commonly arise in the retroperitoneum. Surgical resection is the primary management strategy for localized retroperitoneal LPS, but most patients experience local or metastatic disease progression within 5 years of diagnosis. The role of adjuvant therapy is not well established, and only a quarter of patients receive neoadjuvant or adjuvant radiotherapy (RT). Given challenges with local recurrence and metastatic disease in LPS, development of novel therapies…  Read More »

In the study of cellular mechanisms that are out of control in cancer, noncoding RNAs(ncRNAs) are becoming increasingly important: these are transcripts that do not code for proteins, but which frequently play regulatory roles by fine-tuning the function of other molecules with very relevant roles in the appearance and/or development of the tumor. Although the ncRNAs of the small type are generally very well characterized and their roles as pro- or anti-carcinogenic agents are well known, long ncRNAs, due to its great specificity and variety of action, are less understood. In our group, we have developed a series of techniques…  Read More »

Sarcomas are rare, life-threatening, malignant tumors affecting soft, visceral, and bone tissues. Due to their high heterogeneity (more than 60 subtypes), many sarcomas lack effective therapies. Incidence is 50-60 new cases/year per million. 20% are metastatic at diagnosis and 40% of localized cases will develop metastases. For locally advanced or metastatic disease, few curative options might be offered. In metastatic setting, complete responses to chemotherapy are very rare and median of survival is around 1 year. Most cytotoxic chemotherapies have reached a ceiling in efficacy. Median PFS in first line is 3.5-5 months. Few new drugs have been approved in…  Read More »

While the introduction of the combination of intensive chemotherapy and multi-modal While the use of chemotherapy, surgery and irradiation have improved outcomes in Ewing sarcoma (ES), such about 70% of patients are cure, progress has plateaued for over three decades and there have been essentially no new advances. Furthermore, for patients with metastatic disease at diagnosis, or those who have relapsed after initial therapy, the five-year disease-free survival is 20-30%. These realities highlight a major unmet clinical need for sarcoma patients. The overarching hypothesis of this proposal is that drug-priming can unmask Ewing sarcoma cells to become more sensitive to…  Read More »

While the introduction of the combination of intensive chemotherapy and multi-modal While the use of chemotherapy, surgery and irradiation have improved outcomes in Ewing sarcoma (ES), such about 70% of patients are cure, progress has plateaued for over three decades and there have been essentially no new advances. Furthermore, for patients with metastatic disease at diagnosis, or those who have relapsed after initial therapy, the five-year disease-free survival is 20-30%. These realities highlight a major unmet clinical need for sarcoma patients. The overarching hypothesis of this proposal is that drug-priming can unmask Ewing sarcoma cells to become more sensitive to…  Read More »