Targeting the biological underpinnings of pulmonary metastasis in osteosarcoma
Osteosarcoma is a bone tumor that affects children during their growth spurt. Treatment is difficult and has not improved in almost four decades. Most of the kids who die from osteosarcoma succumb to complications of lung metastasis. Therapies that prevent or treat metastatic disease may be the most impactful innovation that we could bring these children. There are currently three primary challenges that prevent us from improving outcomes in these patients: First, we know what the most common genetic changes in osteosarcoma are, but we know little about how these changes create cancer. The defining feature of osteosarcoma genomes is simply widespread rearrangement of chromosomes (like DNA going through a blender). Parsing the changes that result from this chaos has been difficult because all current sequencing strategies map experimental sequences onto a normal human genome, not the deeply rearranged osteosarcoma genome. As such, it becomes impossible to identify the real relationship between any two parts of the genome. Second, we understand little about the steps that drive the development of metastatic lesions. We know that each metastatic lesion is filled with a complex arrangement of highly abnormal immune and lung cells alongside tumor cells, which often look quite different one from another. However, we do not understand the process that transforms a single tumor cell stuck in the lung into this complex metastatic organ. Third, when we and others have identified potential drivers of metastasis, they are usually not druggable, negating any potential impact those discoveries might have on patients.
Project Update 2024:
During Year 2 of the award, we have made significant progress in each of our aims. We have assembled a draft genome assembly of a human osteosarcoma cell line and have built and optimized computational methods for further analysis of the rearranged DNA seen in osteosarcoma. We have mapped the critical genes that regulate cell lineage in a subset of osteosarcoma tumors and have noted regulatory differences between primary and lung metastatic lesions. We have identified the changes that occur in the tumor microenvironment of lung metastasis and the spatial context in which tumor cells, immune and other cells exist. We have generated data on the changes that occur in lung metastasis upon treatment with single and combination agents. We have also succeeded in generating a large number of data sets on primary and metastatic tumors that will provide a wealth of information on the biology of metastatic osteosarcoma and which will be freely available for other researchers. We have assessed a panel of CDK12/13 degraders and inhibitors against various targets including CDK12/13 as well as CDK11 and have identified a potential new target, CDC5L. Together, our efforts, backed by regular interactions between members of our team, continue to enable our goal to identify the mechanisms that drive lung metastasis in osteosarcoma and to generate treatment strategies to disrupt these processes.
Project Goals:
Our proposal will address each of these challenges. To unravel the effects that widespread genetic rearrangements have on malignant behavior, we will build reference genomes specific to each tumor. With these tumor-specific references, we will map out all the new connections formed by those rearrangements so that we can determine how each genetic switch becomes re-wired. With these “genetic wiring diagrams” in hand, we can begin to discover they ways that this caner-specific re-wiring drives malignant behavior like metastasis. To uncover the processes that drive the development of metastatic lesions, we will employ a combination of cutting-edge techniques that allow us to watch metastases develop cell-by-cell, observing changes in gene expression across the genome, from single disseminated tumor cells to complex metastatic lesions, being sensitive to the unique genetic wiring of each tumor. To overcome the challenges of druggability, we will leverage a newer technology, pioneered by members of our research team, to develop drugs that utilize things like “molecular glues” designed to stick to specific proteins, tagging them with signals that engage the recycling machinery of the cell, eliminating the protein by degrading it (reducing the protein to its nutrient parts). Beginning with a target that we have already identified, and expanding to new targets as we learn more about the genetic re-wiring and mechanisms of metastasis, we will produce a new generation of metastasis-targeting candidate drugs. Successful prosecution of this plan could transform the therapeutic approach to patients with metastatic osteosarcoma and beyond.
