Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal tissue cancers, with over 50 histological sub-types. Regardless of type, virtually all STS are treated the same; i.e. with doxorubicin (DOX) followed by resection, if possible. More than 20% of STS are non-resectable and, of those that are, more than 20% recur. For non-resectable or recurring patients, median survival is a dismal 18 months. Perhaps because of its rarity, no new front-line agents have been developed for STS in decades. Among newer agents being developed for STS, TH-302 is showing exceptional promise. TH-302 is an alkylating pro-drug that is activated only in regions of severe hypoxia, and is currently in a phas III trial in combination with DOX in unresectable STS. The primary endpoint of this trial is overal survival with a secondary endpoint of objective radiological response with RECIST 1.1. RECIST responses rarely correlate with survival responses in soft tissue sarcomas, however. The purpose of this work is to develop MR imaging biomarkers that can predict response to DOX and/or TH-302, with the overarching hypothesis that distinct MRI-defined sub-regions of tumors will have differential responses to these agents. Because these sub-regions are defined by their distinct physiology illuminated by combining multiple MR scans, we have termed these as distinct habitats. Because TH-302 is active only in hypoxia, and hypoxia should be represented by a specific habitat, we specifically hypothesize that imaging of the hypoxic habitat can be used to predict and monitor responses to TH-302. The hypoxia habitat is classified as having low perfusion and high cell density. In contrast, the DOX-responsive habitat should be well perfused (yielding higher drug concentrations) and have high cell density (with more drug targets). This represents a conceptual advance as such habitats may provide a common predictive biomarker across the multiple histological sub-types of STS for patient stratification and therapeutic decision support. The approach will follow on preliminary work, wherein delineated habitats were quantitatively identified across multiple histological types and grades of STS by combining T1, contrast- enhanced T1, and T2 STIR MR images. The current proposal is entirely pre-clinical, with the expectation that findings herein can be rapidly translated to clinial care. Preclinical work is justified in that there is greater flexibility to interrogate a wider porfolio of MRI pulse sequences and treatment strategies that can be related to underlying histology and molecular profiling.
Aim 1 will quantitatively compare MR-visible habitats to histology and molecular profiles of xenotransplanted tumors.
Aim 2 will test the hypothesis that tumors with different habitat profiles will be differentially responsive to DOX and/or TH-302.
In Aim 3, we wil investigate the effects of metabolic perturbations to affect the hypoxic habitat and thus improve response to TH-302. At the end of this study, we will have developed a new set of MR imaging biomarkers for predicting and monitoring response in this heterogeneous group of diseases, with the expectation that these finding will inform a follow-on study in the clinic.
Sarcomas are cancers of connective tissue and are fundamentally different from carcinomas, such as lung, breast, prostate or pancreatic cancers. Sarcomas are more prevalent in children, and there are over 50 sub-types known. There is a real problem because, at the molecular level, they are as different from each other as they are from the carcinomas, yet they are all treated the same. In this proposal, we hypothesize that commonality among sarcomas can be found in their physiology. Importantly, these physiologies can be targeted with specific drugs and, even more important, these physiologies can be imaged with MRI. We call these physiologies 'habitats' because multiple different physiological environments can co-exist within a single tumor, and they are defined by their MRI-measurable blood supply and cell density. For this proposal, we will target our therapies against areas with high cell density, because that's where the cancer cells are. Within these areas, if the habitat has an abundant blood supply, we will use doxorubicin, a standard chemotherapy agent that relies on an adequate blood supply to work. If the blood supply is lacking, we will target those areas with a new class of drugs that are active in oxygen-poor environments; the so-called hypoxia activated pro-drugs (HAPs). Thus, by imaging the habitats, we can we propose to use imaging to determine what kind of drugs, and in what order, sarcoma patients should receive.
| Napel, Sandy; Mu, Wei; Jardim-Perassi, Bruna V et al. (2018) Quantitative imaging of cancer in the postgenomic era: Radio(geno)mics, deep learning, and habitats. Cancer 124:4633-4649 |
| Avnet, Sofia; Di Pompo, Gemma; Chano, Tokuhiro et al. (2017) Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-?B activation. Int J Cancer 140:1331-1345 |
| Gillies, Robert J; Kinahan, Paul E; Hricak, Hedvig (2016) Radiomics: Images Are More than Pictures, They Are Data. Radiology 278:563-77 |
