Increasing evidence points to the active roles tumor stroma and host cells play in supporting cancer survival and resistance to treatment. The situation is more pronounced in the metastatic setting, where traditional therapeutic approaches targeting tumor cells are initially beneficial but often give way to the development of resistance or relapse. Recent studies suggest that targets within the genetically stable tumor microenvironment may provide more durable therapeutic opportunities to overcome therapy resistance, but weaponizing these targets against cancer cells requires new insight into how tumor-stroma...

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Increasing evidence points to the active roles that tumor stroma and host cells play in supporting cancer survival and resistance to treatment. The situation is more pronounced in the metastatic setting, where traditional therapeutic approaches targeting tumor cells are initially beneficial but often give way to the development of resistance or relapse. Recent studies suggest that targets within the genetically stable tumor microenvironment may provide more durable therapeutic opportunities to overcome therapy resistance, but weaponizing these targets against cancer cells requires new insight into how tumor-stromal cell interactions change over time. I propose to develop a novel imaging platform to understand the dynamic changes in the tumor microenvironment in response to treatment. The research will also uncover new approaches to selectively disrupt the physically interacting cancer-stromal cell population with the goal of mobilizing immune cells and enhance chemoimmunotherapy. Through precision prodrug delivery to tumors, release, and locoregional activation, the research will also aim to minimize systemic and off-target toxicity. Although the approach proposed here is applicable to all solid tumors, I will focus on metastatic breast cancer, an incurable form of breast cancer giving rise to >90% of all breast cancer deaths. Within the scope of the above goals, I propose to: (1) Develop a novel prodrug strategy to deliver and locally activate prodrugs to overcome the toxic effects of chemotherapeutics; (2) Develop a method to simultaneously target and deplete cancer and key protumor host cells to improve chemoimmunotherapy; and (3) Develop a method to selectively target and disrupt physically interacting cancer-protumor host cells to determine drug target efficacy and improve treatment response.

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