Aghi Lab Newsletter January 2017

Dear Friends and Colleagues,

As we enter the New Year, we wanted to provide you with a summary of work accomplished in Dr. Manish Aghi’s brain tumor research lab this past year as part of our annual lab newsletter. As you know, Dr. Aghi is a neurosurgeon-scientist at UCSF. We are reaching out to you due to your interest and support of Dr. Aghi and the research conducted by his team. We hope you enjoy this annual update.

Sincerely,

The Aghi Lab

AGHI LAB JANUARY 2017 NEWSLETTER

“Cancer is a noun but in the body it acts like a verb...” - Tom McLain

OVERVIEW

Manish Aghi, MD PhD, directs a research lab and operates on brain tumor patients at UCSF. His surgical practice and lab emphasize glioblastoma, an aggressive tumor resistant to current treatments, and pituitary adenomas, benign tumors that dramatically impact a patient’s quality of life upon reaching critical size. Integrating the lab and clinical practice maximizes the impact of both by studying human tissues in the lab, defining variables that maximize the impact of surgery for patients, and implementing concepts developed in the lab into clinical trials to help patients. The research team consists of eight postdoctoral fellows, students, and volunteers, several of whom have their research highlighted below.

GENE CHANGES IN PITUITARY TUMORS

The Aghi lab is defining pathways that lead to the formation of pituitary adenomas, a common benign tumor that causes symptoms due to its delicate location (right image). Garima Yagnik, a postdoctoral fellow in the lab, is working to identify DNA mutations (alterations in the tumor cells that cause unregulated growth) and polymorphisms (genetic variations in the patient that predispose to tumor development) in pituitary tumors and has identified a polymorphism in the p53 gene, which is involved in cell division and DNA repair, in patients with pituitary adenomas. These findings create hope of identifying adenoma patients whose tumors are more likely to grow over time, and to someday developing medical therapies for large pituitary adenomas.

A PROTEIN COMPLEX IN DRUG-RESISTANT GLIOBLASTOMA

Bevacizumab (avastin), a VEGF blocking antibody, cuts off the tumor blood supply and can be effective for glioblastoma but with limited response duration shown in two phase III trials. Arman Jahangiri, an MD/PhD student in the Aghi lab, has found that a protein complex between two cell receptors, c-Met and β1 integrin, forms throughout bevacizumab-resistant glioblastomas and that glioblastomas with this complex have a worse prognosis than those without. In this complex, the two receptors bind and cross-activate each other, driving the invasive resistance that limits bevacizumab treatment. In a translationally relevant finding, Arman has shown that lower bevacizumab doses can be as effective as higher doses without causing c-Met-β1 complex formation.

METABOLIC REPROGRAMMING IN DRUG-RESISTANT GLIOBLASTOMA

Before leaving the lab for medical school, previous lab managers Smita Mascharak and Ruby Kuang studied how glioblastomas adapt metabolically to the reduced availability of nutrients and oxygen that occurs after treatment with bevacizumab. We showed that glioblastoma cells that are resistant to bevacizumab increase their ability to metabolize sugar in an energy-efficient manner that is capable of working under the harsh conditions created by the drug. An indirect result of this process is increased storage of fat in resistant tumors, as shown. This observation correlates with and explains our clinical observation of bevacizumab-resistant glioblastomas being more fatty and fibrotic. Moving forward, we are studying whether inhibitors of these altered metabolic pathways combined with bevacizumab will produce a more enduring response that could hopefully be translated into the clinic. Results of this work will be published later this year in JCI Insight.

MACROPHAGES IN GLIOBLASTOMA: FRIEND OR FOE?

Macrophages are immune cells that protect against infection. Historically, macrophages were felt to play a similar role in protecting against cancer. However, recent evidence has identified two macrophage types: classic macrophages destroy tumor cells, while alternative macrophages promote tumor cell growth. Brandi Castro and Patrick Flanigan, two medical students funded by the Howard Hughes Medical Institute to work in the Aghi lab, studied mechanisms regulating the recruitment of alternative macrophages to tumors. Shown (in green) is a mouse tumor in which alternate macrophages (shown in red) are recruited to glioblastoma after bevacizumab treatment. Results of this work will be published in Oncogene. Moving forward, we are working on targeting these cells in high- and low-grade glioma.

OTHER TUMOR TYPES BEING STUDIED

An estimated 10-40% of cancer patients will develop brain metastasis, which is often met with a dismal prognosis. Ongoing work in the lab is seeking to define some of the same features described above in brain metastases so that we can work towards understanding their biology.
Meningioma is the most common primary brain tumor. We plan to study and improve molecular markers in meningioma and how they influence clinical outcomes.
We have also reported our outcomes for chordoma surgery and partnered with the Chordoma Foundation to promote patient advocacy.

FOR MORE INFORMATION

For more information about research in the Aghi Lab or how to support our efforts, visit our website at http://www.aghilab.com. To schedule a tour, please contact Joseph Neisen in the UCSF Development Office at 415-502-8309.