Dr. Manish Aghi, MD, Ph.D., directs a research lab and operates on brain tumor patients at UCSF. The lab's primary focus is the microenvironment of brain tumors, recognizing that many cancer treatments fail because they do not recognize cancer for what it is, a dynamic organ with a complex interplay between tumor cells and their microenvironment. 

In 2021, the Aghi Lab continued to adapt to the challenges from the COVID-19 pandemic. After a year of virtual discussions and social distancing protocols, we resumed research and  in-person meetings at full capacity, with the work of our research team of postdoctoral fellows, students, and volunteers  highlighted below.

Immunotherapy, which stimulates an immune response against the tumor, has been revolutionary in the treatment of some malignancies, but, unfortunately, clinical trials exploring immunotherapies for GBM have been disappointing to date. This failure has been attributed to GBM’s low mutational burden and systemic and local immune dysfunction. To improve these therapies, a more comprehensive understanding of molecular determinants of GBM's responsiveness to immunotherapy is needed. The emergence of CRISPR-Cas technology has enabled high-throughout, genome-wide genetic screens, such as in vivo ‘‘cell fitness screens” under different treatment conditions to identify ‘‘context-specific’’ genes governing treatment resistance. Under funding from the Neurosurgery Research Education Foundation (NREF), UCSF Neurosurgery resident Jacob Young is utilizing an in vivo genome-wide CRISPR screen in the setting of syngeneic tumors treated with immunotherapy to reveal immune-sensitizing candidate genes. 

While successful in other cancers, immunotherapy has been ineffective for GBM. In addition to its immunosuppressive environment, GBM T cells become rapidly exhausted, greatly reducing their cytotoxic capabilities. The Aghi Lab is working to elucidate the role of one these markers, CD39, with the use of specially bred CD39 knockout mice. CD39 has yet to be rigorously tested in GBM. Western Michigan University medical student Allison Zheng is investigating its role in the GBM microenvironment via studies in cultured cells and mice. These studies hope to clarify how CD39 affects T-cell function, and its potential role in T cell exhaustion.

The poor prognosis GBM caries is largely due to its invasive capacity, which enables escape from resection and drives inevitable recurrence. Numerous factors have been proposed as the primary driving forces behind GBM’s ability to invade adjacent tissues, including shifts in its cellular metabolism. To satisfy the energy demands required to grow and invade, cancer cells undergo significant metabolic reprogramming. Funded by a diversity supplement to an Aghi Lab R01, UCSF medical student Joseph Garcia has utilized system wide high-throughput screens to identify the transsulfuration pathway, which protects cells against oxidative stress, as being up regulated in invasive GBM cells. The Aghi Lab is currently investigating how this pathway facilitates invasion using targeted assays and inhibiting transsulfuration pathway enzymes to mitigate tumor cell invasion

Medulloblastoma is an aggressive brain tumor that predominantly impacts children. Current treatments can be toxic and neurologically devastating. As such, immunotherapies are promising alternatives. These tumors are immunosuppressed, with a dearth of anti-tumor processes occurring in the tumor microenvironment. MYCN-amplified Group 3 medulloblastoma carries a particularly devastating prognosis. Using a mouse model, we seek to reverse MYCN-induced chemokine abnormalities in medulloblastoma to drive immune cells towards the tumor. Of particular interest is restoring tumor expression of CXCL9 & CXCL10 to recruit CD4+ and CD8+ T-cells. We have also upregulated MHC-I expression on tumor cells to 'uncloak' the tumor and enhance T-cell mediated tumor-killing through simultaneous MYCN & EZH2 inhibition.  This project was initiated by Aghi lab postdoc and UCSF neurosurgery resident Taemin Oh and is now being concluded by UCSF medical student and yearlong research fellow Ryan Phelps.

Research by Aghi lab postdoc and  UCSF neurosurgery resident Michael Safaee with assistance from medical student Elaina Wang, Aghi Lab Junior Specialist Sabraj Gill, and medical student Allison Zheng revealed that CD97 is highly expressed in glioblastoma and may have roles in tumor invasion, angiogenesis, immune cell suppression, and immune evasion. In a paper accepted for publication in Scientific Reports, the team targeted CD97 with CRISPR interference to study CD97's role in tumor invasiveness, angiogenesis, tumor cell metabolism, and regulation of immune cell populations in glioblastoma. They also studied an Fc fusion protein targeting CD97 as a potential therapeutic in collaboration with an industry partner.

Aside from the basic science work described above, physician-scientist members of our team published several clinical studies in 2020, two of which are highlighted below:

1. Medical student Meeki Lad published a study showing that graduating neurosurgery residents accumulate over six times as many spinal cases in their training as compared to orthopaedic residents.  This study was published in Journal of Neurosurgery: Spine.
2. Medical student Eric Chalif published a study detailing how giant pituitary adenomas greater than 4cm in diameter have better outcomes at high-volume facilities compared to low-volume facilities. This study was published in Journal of Neurosurgery.
3. Aghi Lab alumni and current neurosurgery resident Rushikesh Joshi published a study in Journal of Neurosurgery identifying risk factors for postoperative diabetes insipidus after over 1000 pituitary surgeries at UCSF.