University of Nebraska Medical Center

Chi Zhang, MD, PhD

Project 1

To test the hypothesis that androgen receptor (AR) is a novel target for treating GBM.

Most of the GBM tumors are diffusely infiltrative so that achieving gross tumor resection (GTR) is challenging in majority of the cases. Tumor recurrence/progression/lethality is essentially universal even after GTR. Radiation therapy thus plays a major role in treating this disease. The high content of cancer stem cells (CSCs) and the immunosuppressive tumor microenvironment (TME) in GBM have been proposed to be responsible for the resistance to treatment including radiation therapy (RT). It is necessary to identify novel therapeutic agent(s) that can pass blood-brain barrier (BBB) and enhance RT effects. Androgen receptor has been reported to be associated with CSCs in prostate cancer. Androgen deprivation therapy has been practiced for decades on prostate cancer patients that enhances radiation effects. A newer generation of drug that inhibits AR including enzalutamide is available for prostate cancer treatment and able to pass BBB. We have studied the expression pattern of AR and functions of AR in GBM tumorigenesis confirming a high frequency of AR overexpression in GBM in both genders.

Our preliminary data also support that AR could be a novel target for GBM treatment particularly for sensitizing RT effects in both cell lines and orthotopic GBM mouse models by immunomodulation in TME and systemically.

We thus propose to further study AR expression pattern in our patients’ tumor samples including lower grade gliomas aiming to develop a scoring system for the intensity and pattern of AR expression in GBM, with the assistance of our in-house pathologists, Drs. Sahara Cathhart and Jie Chen, and Dr. Michael Punsoni at Brown University. The data from our translational research in cells and in animal models leads to our current effort to conduct clinical trials for patients with recurrent and/or primary diagnosed GBM using androgen receptor antagonist currently with re-RT of the brain tumor and potentially to be combined with immunotherapeutics in the future, collaborating with Dr. Michele Aizenberg at neurosurgery and Dr. Nicole Shonka at neuro-oncology.

Project 2

To test a cell mediated drug delivery system to CNS combining brain irradiation, nanoparticles and macrophage.

We are also testing the possibility of using circulating monocyte/macrophage as a vehicle to deliver radiosensitizing drugs into the brain combining nanotechnology for drug loading into the cell vehicle and stereotactic radiation therapy to focal brain tissues for inducing CNS inflammation for chemotaxis attracting immune cells to infiltrate to certain area of the brain such as the tumor. I am also conducting clinical studies on radiation therapy for brain tumors, benign or malignant, as well as lung/breast/prostate cancers.

Project 3

To test the immune effects of metformin and a novel nanoformulation of metformin in treating GBM.

My laboratory is also conducting research on testing medications which were FDA-approved initially treating benign medical conditions or other types of cancer for their potential secondary use on treating GBM. We have conducted research on and confirmed the anti-tumor effects of metformin, a medication commonly prescribed for type II diabetic patients, in treating GBM in vitro, with and without combination with other candidate drugs that can pass blood-brain barrier.

We are now expanding the study on metformin to further explore the potential function of this drug to confirm whether its known role of converting subtypes of macrophage from M2 (pro-tumor) to M1 (anti-tumor) could be applied in treating GBM by enhancing the immunotherapy effects from PD-1/PD-L1 inhibitors. The same study will be conducted in pancreatic cancer model collaborating with Dr. Chi Lin, a radiation oncologist and the Vice Chair for Research at our department. High concentrations of metformin treated macrophage in vitro will be injected to mice carrying an orthotopic implanted GBM with/without brain RT and/or PD-L1 inhibitors for the tumor response and survivals of the animals.

In addition, we have developed, synthesized and characterized a novel nanoformulation of metformin which has been demonstrated to have much enhanced anti-tumor effects in brain tumors, lung cancer and pancreatic cancers that will be further studied in animal models in our laboratory and with our collaborators including Drs. Tanya Bronich, Svetlana Romanova and David Oupicky at Center for Drug Delivery and Nanomdicine (CDDN).

Project 4

Hypofractionated Radiation Therapy (hfRT) for Boosting the Residual Primary Lung Cancer in Combination with Anti-PD-L1 Immunotherapy After Definitive Chemoradiation Therapy for Stage III non-small cell lung cancer (NSCLC)

We are currently funded by AstraZeneca Pharm. for a phase I/II combined clinical trial testing the potential synergistic effects of combining an immunostimulatory regimen of radiation therapy with aimmune checkpoint blocker, Durvalumab. We work together with other physicians including Drs. Apar Ganti, Laxmi Buddharaju, Alissa Marr and Bhavina Sharma at Medical Oncology and Drs. Ken Zhen and Chi Lin at Radiation Oncology for conducting the trial.

Conventional RT has been known for immunosuppression for decades until recent studies suggesting immunostimulatory effects with SBRT or hfRT regimen. We thus proposed to offer patients two extra doses of RT with hfRT boosting the residual primary lung tumor that will be delivered during the phase of immunotherapy after the conventional definitive chemoradiation therapy for nonresectable stage III NSCLC. The progression-free survival of the patients from this trial will be compared with the historical data of PACIFIC studied to test for the efficacy of combining these two treatments for not only local control but also potential systemic tumor control benefit. Patients’ peripheral blood specimen will be collected for translational research purpose in our laboratory for circulating tumor DNA and miRNA and studies of surface markers in lymphocytes at different phases of the treatment to study the mechanism of treatment success/failure.