Sunday, April 28, 2024
4/28/2024
The most prevalent primary brain tumor, glioblastoma, ranks among the most lethal of human cancers. The brain tumor microenvironment (TME) is thought to play a critical role during tumor development and treatment resistance. Unlike many other solid tumors, the glioblastoma TME is dominated by macrophages and microglia— collectively known as tumor-associated macrophages (TAMs). TAMs are plastic in nature and can polarize toward pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the brain tumor microenvironment, which fosters tumor development, contributes to tumor aggressiveness, and impedes the therapeutic effect of various treatment regimens. Through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state to enhance anti- tumor immunity. The promise of TAM-targeted therapy has not yet been realized, due in part to a limited understanding of the molecular mechanisms underlying TAM behavior and function. My postdoctoral work has elucidated novel mechanisms that govern the polarization of TAMs in the glioblastoma TME. Notably, my preliminary data suggests that targeting the CARD9/BCL10/MALT1 (CBM) signaling complex represents a promising therapeutic approach to shifting the glioblastoma TAM phenotype to favor anti-tumor immunity. The overall objectives of this application are to determine the molecular mechanisms that regulate TAM immunoreactivity in glioblastoma and to utilize this information to inform the development of new and effective therapeutic interventions to improve treatment outcomes. My central hypothesis is that CBM activation within TAMs is required for glioblastoma-induced TAM polarization toward an immunosuppressive phenotype and this CBM-dependent TAM polarization facilitates tumor growth, progression, and resistance to therapy. I first propose to elucidate the molecular mechanisms by which glioblastoma cells communicate with TAMs to drive CBM activation (Aim 1). Second, I will evaluate how CBM activity within TAMs influences TAM function (Aim 2). Finally, during the R00 phase of this proposal I will investigate how inhibiting the CARD9-CBM complex in TAMs in vivo affects glioblastoma tumor progression and responsiveness to standard therapies (Aim 3). Collectively, these studies will advance our understanding of the mechanisms governing the brain tumor immune microenvironment of glioblastoma and inform the development of new approaches to manipulating this immune microenvironment to improve treatment outcomes for glioblastoma. During the mentored K99 phase of this award, I will greatly benefit from the expert mentoring world-class research resources available at the University of Pittsburgh and the UPMC Hillman Cancer Center. Completing the proposed project will allow me to build a strong scientific foundation and then lead an innovative research program as an independent investigator. Overall, the K99/R00 award will be an indispensable support for my timely transition to a successful career as a multifaceted, cross-disciplinary investigator in neuro-oncology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
