May 2023 Sarcoma Research Update

In honor of Sarcoma Awareness Month, we wanted to share MSK’s most recent sarcoma research update!

 May 2023 Sarcoma Research Update

MSK leads the world in the area of molecular oncology: identifying the specific genetic mutation that causes an individual’s cancer, and then fighting the cancer by targeting this mutation. Also called precision or personalized medicine, this approach has completely transformed the way cancer is understood and subsequently treated. Its full potential is still being realized, but early evidence is tremendously exciting to the international oncology research community.

The advent of precision medicine has been particularly impactful on the study of soft tissue sarcoma—a rare group of cancers that start in the tissues between the organs, such as the fat, muscles, nerves, tendons, and blood and lymph vessels. A diagnosis of metastatic sarcoma portends a poor prognosis (overall survival 17-20 months). With > 70 biologically distinct diseases, sarcoma requires broad reaching research programs that span medical and scientific disciplines and therapeutic and technological fields to meet the diverse needs of patients with this often medically neglected disease. In this regard, Dr. Tap oversees the clinical, translational, and basic science components of the MSK Sarcoma Medical Oncology Program, now one of the largest in the world with 14 medical oncologists, 12K annual outpatient visits, ~ 40 open clinical trials, and over 100 supportive research and clinical staff members. Together, this world-class team has established unique programs and collaborations that have changed international treatment paradigms. In 2019-20 alone, nine novel agents have been approved or are on a strong regulatory track in sarcoma, an unprecedented success. The MSK Sarcoma Program led 7 of these efforts and was involved in all 9.

The Impact of Sarcoma

While the incidence rates for many forms of cancer are steadily declining, the number of people found to have sarcoma has gone up in recent years. With nearly 20,000 cases diagnosed in the United States, sarcoma represents about one percent of all cancer diagnoses in adults and 15 percent in children and adolescents. Because sarcoma most frequently afflicts young people, the disease costs more life years than many of the more-common cancers. This is compounded by the fact that the often complex and diverse biopsychosocial needs of adolescents and young adults with cancer are poorly understood and often ignored. This has led to poorer outcomes for patients with cancer aged 15-39 in disease matched cohorts. In fact, sarcoma was the impetus for the development of AYA@MSK, a comprehensive center developed under the co-direction of Dr. Tap and Glade-Bender (pediatric oncology) that is beginning to revolutionize holistic and longitudinal medical care for AYA patients with cancer. In sum, these are challenging cancers that require comprehensive and innovative efforts to identify and appropriately apply new therapies and clinical strategies to help people with sarcoma live longer, healthier, and happier lives.

Comprehensive Programs

Our ability at MSK to affect the care of our patients on a global level is often based on the development of comprehensive, inclusive, and collaborative program project areas. For example, we have built one of the largest sarcoma immunology programs in the world, which focuses on T cell activity, engineered T cells/chimeric antigen receptors, oncolytic viruses, macrophage biology, and understanding and modulating the mesenchymal immune microenvironment. Our initial analyses of PD-L1 expression and tumor-infiltrating lymphocytes advanced understanding of the sarcoma immune microenvironment and lead to one of the first major clinical trials in sarcoma, nivolumab +/- ipilimumab. Since, we have run ~20 novel clinical trials exploring various aspects of immune manipulation in sarcoma. These trials are identifying active treatments for the various sarcoma subtypes including dedifferentiated liposarcoma and broadening our understanding of the mesenchymal immune environment, response predictors, mechanisms to augment immune recognition/trafficking, and how to overcome immune escape. We have developed a large tissue and genomic database that is now allowing us to identify predictive biomarkers and exploring novel combinations of checkpoint inhibitors with CDK4 inhibitors (CDK4i), chemotherapy, VEGF-based tyrosine kinase inhibitors, DNA damage response inhibitors, and novel CAR T cells.

Molecular Oncology

At MSK, another area of strength is in molecular oncology: where we identify genetic drivers that cause a person’s cancer, and then fight the disease by targeting these specific mutations. Also called precision or personalized medicine, this approach has completely transformed the way cancer is understood and managed by bridging scientific and clinical observations and advances. Dr. Tap and his colleagues have made major advancements in bringing personalized medicine to their patients. They have leveraged a technology invented here—called MSK-IMPACT—to characterize, on a genomic level, the tumors of more than 3000 sarcoma patients. Through rapid sequencing, MSK-IMPACT looks for any of the 500+ genetic mutations known to play a role in cancer.

We have developed expansive initiatives using genomic techniques to identify and target actionable abnormalities in single sarcoma subtypes (N Engl J Med 2018). These initiatives have informed larger efforts that are changing treatment paradigms in rare diseases. Our team led a novel drug developmental strategy of pexidartinib in tenosynovial giant cell tumors (TGCT). Our bench-to-bedside approach (N Engl J Med 2015) prompted a pivotal international phase 3 Study that led to FDA approval of pexidartinib (Lancet 2019) as a first in-class drug for this rare disease. The trial included novel imaging modalities and TGCT-specific patient reported outcome measures, setting standards for drug development and care in this disease. This process has been mirrored in other sarcoma subtypes, e.g. sorafenib in desmoid tumors (N Engl J Med 2018), a program that was developed and led by our team members which similarly shaped treatment and research paradigms in this disease.

Dedifferentiated Liposarcoma

Our work has fundamentally advanced the understanding of treatment-induced senesence and the application of CDK4 inhibitors in cancer and resulted in the inclusion of palbociclib in the NCCN guidelines for dedifferentiated liposarcoma. Through correlative and laboratory studies, we gained significant insight into CDK4i mechanisms of action/resistance and defined a new understanding of senesence after growth arrest. The project has also identified ATRX phosphorylation and CDH18 expression as possible predictive biomarkers of response to CDK4 inhibitors. MSK’s sarcoma team is now one of the largest referral centers for liposarcoma anywhere and is working on the next generation of CDK4 inhibitors, now leading a randomized national pivotal trial of abemaciclib in dedifferentiated liposarcoma and spearheading the research and development strategy for MDM2 inhibitors also in dedifferentiated liposarcoma. In addition, MSK has shown efficacy of immunotherapy in dedifferentiated liposarcoma in their clinical research. This has allowed for a large collaborative effort between our immunotherapy and molecularly targeted programs to better understand how and in whom to offer this therapy while we pursue combinations of immunotherapy and CDK4 inhibitors, the latter we have shown to trigger an inflammatory response in dedifferentiated liposarcoma when they induce senescence.