Sarcomas and Gastrointestinal Malignancies
Sarcomas are a diverse group of mesenchymal tumors with over 80 histological subtypes that arise from connective tissues throughout the body. Due to their rarity and complexity, sarcomas remain understudied and represent a significant therapeutic challenge. Although approximately half of patients with high risk sarcomas develop metastatic disease after resection and radiation therapy, there are few effective systemic therapies to prevent and treat metastatic disease and no ways to select patients for adjuvant therapy after initial treatment. Gastrointestinal malignancies are among the most common cancers worldwide. Radiation therapy can improve local control of tumors such as pancreatic cancer, but there is currently no way to identify patients at risk of local versus distant relapse. We hope to use circulating tumor DNA to enable personalized therapy in patients with sarcomas and gastrointestinal malignancies. Furthermore, we aim to dissect the genetics and transcriptomics underlying the treatment response of these malignancies to design more effective therapies.
Approximately half of patients with cancer receive radiation therapy at some point during the course of their illness, and the majority of these patients are treated with curative intent. Despite the widespread use of radiation therapy, there are no validated genetic mediators of radiation resistance. As a result, radiation doses are uniformly prescribed across patients with the same type of cancer despite tremendous variability in treatment outcomes. Although radiation therapy can improve local control, long-term radiation side effects remain an issue for many cancers. We aim to better understand the genetic factors that contribute to tumor response to radiation therapy to enable personalized treatment approaches to improve outcomes and minimize toxicity.
Recent studies have highlighted the significant genetic and microenvironmental heterogeneity that can exist within human tumors. Ongoing mutation, genetic drift, and selective pressures from the tumor microenvironment drive clonal evolution that substantially impacts the response of tumors to therapy. Furthermore, strong evidence exists that therapy can select for resistant subclones that lead to progressive or recurrent disease. However, longitudinal analysis of clonal evolution under the selective pressures of therapy in humans is limited by the availability of tumor tissue from multiple time points during treatment and errors from sampling a single region within a given tumor. Because circulating tumor DNA is released from multiple tumor deposits within a patient and can be sampled repetitively from routine blood draws, it provides a unique insight into the heterogeneous genetic landscape across an individual patient’s cancer over the course of therapy. We strive to determine the effect of radiation and systemic therapies on clonal evolution to aid the development of novel treatment approaches.
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