Dr. Manish Aghi, MD, Ph.D., directs a research lab and operates on brain tumor patients at UCSF. His surgical practice and lab emphasize (1) glioblastoma (GBM), an aggressive brain tumor resistant to current treatments; (2) metastases of cancers that spread to the brain from other organs; (3) pituitary adenomas, benign tumors that dramatically impact a patient’s quality of life upon reaching critical size; and (4) medulloblastoma, a devastating pediatric brain tumor. The lab's primary focus 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 a complex interplay between tumor cells and their microenvironment. Integrating Dr. Aghi's lab and clinical practice maximizes the impact of studying human tissues in the lab and implementing concepts from the lab into clinical trials to help patients.

The COVID-19 pandemic made 2020 a challenging year.  After scaling down our operations in the spring, we resumed research with social distancing and transitioning our in person meetings to review data to an online format during which our 12-person research team of postdoctoral fellows, students, and volunteers gathered to discuss the research highlighted below.

The poor prognosis of GBM caries is largely due to cellular invasion, 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 need for constant growth and proliferation, invasive GBM cells undergo significant metabolic reprogramming. Joseph Garcia, a UCSF medical student funded by an NIH diversity supplement in the Aghi lab, is using  a series of system-wide unbiased screens to determine the specific metabolic alterations that occur in GBM’s most invasive cells. Following the screens, our team will probe for specific mechanisms using targeted assays. By understanding the metabolic factors that drive tumor invasion, we hope to identify novel therapeutic targets for GBM. 

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 notoriously immunosuppressed, with a dearth of anti-tumor processes occurring in the tumor microenvironment. MYCN-amplified Group 3 medulloblastoma is particularly aggressive, with a devastating prognosis. Using a murine model of MYCN-amplified Group 3 medulloblastoma, we seek to uncover and reverse the MYCN-induced chemokine abnormalities in medulloblastoma to drive immune cells towards the tumor site. Of particular interest is restoring tumor expression of CXCL10, though several other cytokines are also under investigation. We are also working on upregulating MHC-I expression on tumor cells to enhance T-cell mediated tumor-killing. EZH2 inhibition is a clinically promising option that we are focusing on and pathways involving MYCN, interferon-gamma, TNF-alpha, and NF-kB. 

Ultimately, we hope to enhance T-cell migration, invasion, and tumor-killing, while upregulating MHC-I expression on tumor cells to initiate a robust immune response to these devastating tumors. This project was initiated by Aghi lab postdoc and UCSF neurosurgery resident Taemin Oh and is now being continued by UCSF medical student and yearlong research fellow Ryan Phelps.

Research by Aghi lab postdoc and  UCSF neurosurgery resident Michael Safaee with assistance from Sabraj Gill, an Aghi Lab research associate, revealed that CD97 is highly expressed in glioblastoma and may have roles in tumor invasion, angiogenesis, immune cell suppression, and immune evasion. Michael and Sabraj are targeting the gene with CRISPR interference to study CD97's role in tumor invasiveness, angiogenesis, tumor cell metabolism, and regulation of immune cell populations in glioblastoma. Proximity-dependent biotinylation labeling is being used to characterize the extracellular binding partners of CD97 in vivo. The lab is also studying an Fc fusion protein targeting CD97 as a potential therapeutic in collaboration with industry.

Breast cancer is the most common malignancy in women in the United States, and brain metastases in these patients are associated with poor prognosis. Immunoediting is a critical component of metastatic tumor cell elimination, and tumor clones that develop immune-escape mechanisms are associated with progression and metastatic dissemination. Ramin Morshed, an Aghi lab postdoc and UCSF Neurosurgery resident, is currently working with syngeneic mouse models of metastatic breast cancer to identify genetic changes in brain metastatic cancer cells that lead to immune system evasion. By identifying perturbations in gene expression, antigen presentation, and immune cell infiltrate into breast cancer brain metastases, immune escape mechanisms and potential novel targets for immunotherapy may be identified.

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. UCSF medical student Matheus Perreira published a study showing the efficacy and safety of transsphenoidal surgery for elderly patients with pituitary adenomas.  This study was published in Neurosurgical Focus.
2. UCSF medical student Alex Haddad published a study finding that null cell pituitary adenomas were more aggressive than gonadotroph pituitary adenomas in 1166 cases from UCSF. This study was published in Neurosurgical Focus.
3. Former Aghi lab Howard Hughes research fellow Ankush Chandra published a study of glioblastoma in the elderly and found that outcomes were independent of tumor location in a large cohort of patients from the publicly available SEER database. This study was published in World Neurosurgery.