Manish Aghi, MD PhD, directs a research lab and operates on brain tumor patients at UCSF. His surgical practice and lab emphasize (1) glioblastoma, an aggressive primary brain tumor resistant to current treatments; (2) metastases of malignant cancers that spread to the brain from other organs; and (3) pituitary adenomas, benign tumors that dramatically impact a patient’s quality of life upon reaching critical size. The primary focus of the lab is the microenvironment of these tumors, recognizing that many cancer treatments fail because they do not recognize cancer for what it is, a dynamic organ with complex interplay between tumor cells and their microenvironment. Integrating Dr. Aghi's lab and clinical practice maximizes the impact of both by studying human tissues in the lab and implementing concepts developed in the lab into clinical trials to help patients. The 8 to 12-person research team consists of postdoctoral fellows, students, and volunteers, several of whom have their research highlighted below.

The poor prognosis of glioblastoma (GBM) reflects the capacity of GBM cells to supplement proliferative programs with pro-tumoral interactions with the microenvironment, including invasion, angiogenesis, and immunosuppression. There is a need to simultaneously target these processes, as, at the microscopic level, these processes can be temporally, mutually exclusive phenotypes that toggle back and forth. A single molecule with the ability to impact all of these processes therefore has the potential for a far greater anticancer effect than conventional agents limited to one mechanism of action. Towards that end, UCSF neurosurgery resident Michael Safaee has developed intriguing data revealing the previously underappreciated importance of CD97 in driving these processes in GBM. Mike then established a collaboration between the Aghi lab and Planet Biotechnology, a company that developed DAF-Fc, a small molecule targeting CD97 in GBM. Through an NIH Small Business Innovation Research (SBIR) grant awarded to the Aghi lab and Planet Biotechnology and an F32 postdoctoral fellowship awarded to Dr. Safaee, preclinical evaluation of this treatment is underway in the hopes of eventually going to a clinical trial.

Ankush Chandra, a recent Howard Hughes Medical Institute (HHMI) research fellow in the Aghi lab investigated bevacizumab resistance earlier during its evolution and found that transcription factor Zeb1 mediated the phenotypic changes found in these resistant tumors. Ankush is currently evaluating the naturally occurring honokiol as a means of prolonging responsiveness to bevacizumab in glioblastoma.

Glioblastoma (GBM) originates from stem cells that are difficult to treat due to their heterogeneity. Our lab has recently identified two unique cell types that reside near GBM stem cells and support the stem cells: cancer-associated fibroblasts (CAFs) and tumor-associated neutrophils (TANs). Jonathan Rick, a UCSF medical student funded by a Howard Hughes Medical Institute (HHMI) fellowship, showed that stem cells recruit CAFs from the circulation into GBM via platelet-derived growth factor (PDGF) secretion. Garima Yagnik, Aghi lab postdoctoral fellow, and Sumedh Shah, a medical student in the Aghi lab funded by an HHMI fellowship, showed that TANs support GBM stem cells via osteopontin secretion. Defining these pathways may enable disruption of the stem cell niche in GBM.

Glioblastomas create a tumor microenvironment that is very T-cell depleted. Jordan Spatz, PhD, a postdoctoral fellow and current UCSF medical student in the Aghi lab, is developing a novel gene therapy approach to address this issue by delivering four immunomodulatory genes to glioblastoma.

Work by postdoctoral fellow Garima Yagnik and former UCSF neurosurgery resident Martin Rutkowski in the Aghi lab has shown that pituitary adenoma growth is controlled by tumor cytokines that regulate the tumor-associated macrophages (TAMs). They found that, at some point, small pituitary adenomas enter a growth phase in which tumor-secreted monocyte chemoattractant protein-1 (MCP-1) attracts monocytes out of the circulation which then differentiate into TAMs and are polarized into M2 pro-tumoral macrophages that cause pituitary adenoma cells to secrete EZH2 and S100A9, which promote adenoma proliferation and invasion, respectively. Over time, adenoma cells secrete GM-CSF which changes TAMs to an M1 anti-tumoral subtype that slows adenoma growth, causing the adenoma to enter a quiescent phase. These findings may someday enable immunomodulatory approaches to treat pituitary adenomas that are refractory to standard treatments.

Aside from the basic science work described above, physician-scientist members of our team published the following clinical studies in 2018: