Synthetic manipulation of engineered perivascular niches

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ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Glioblastoma (GBM) is the most common and lethal form of brain cancer. Standard of care is surgical resection followed by treatment with the alkylating agent temozolomide (TMZ) and radiotherapy. Resection removes the tumor bulk, and TMZ provides some benefit to many patients. The parent Cancer Tissue Engineering Collaborative project (R01 CA256481) is developing a tissue engineering approach to accelerate the evaluation of new anticancer compounds that overcome TMZ resistance. We are developing tissue engineered models of the perivascular niches (PVNs) that extend from the tumor into the surrounding parenchyma and which are believed to play a dominant role in invasion, recurrence, TMZ resistance, and poor survival. Our efforts focus on developing an engineered PVN biomaterial, investigating pathophysiological processes driving GBM invasion and TMZ resistance, and accelerating evaluation of novel TMZ derivatives that target GBM regardless of MGMT status. The objective of this NOT-CA-23-045 NOSI Administrative Supplement is to support a new collaborative initiative to incorporate synthetic gene circuits into our engineered PVN models. Current tissue engineering brain vascular models lack orthogonal, regulatable control over the growth and maturation of the perivascular niche. The ability to enact independent, quantitative control over PVN growth and maturation would represent a significant advance and would enable us to deeply examine reciprocal interactions within the PVN that may yield novel therapeutic targets to improve outcomes. To realize this objective, we propose a new collaborative effort to with Dr. Ahmad Khalil (Boston University) to apply his laboratory’s genome-orthogonal synthetic zinc finger transcriptional regulator (synZiFTR) technology to enable drug-regulated, orthogonal control over PVN growth vs. maturation in the perivascular niche models under development by this project. To do this, we will regulate growth and maturation of a synthetic engineered perivascular niche (Aim S1). We will subsequently benchmark patterns of TMZ resistance and invasion in response to synthetic vasculature (Aim S2). This proposed supplement will support a collaborative team to develop a new yet complementary capability to integrate advanced tissue engineering and synthetic biology toolsets to provide regulatable control over brain perivascular niche models. Collaboratively, we will establish human synthetic tissue constructs as an important new tool to investigate reciprocal GBM-PVN signaling within the brain tumor microenvironment. Such capabilities are essential for investigating patterns of GBM cell drug resistance, invasion, and vascular remodeling necessary for improving patient outcomes.