The American Association for Cancer Research (AACR) recently recognized the NETRF-funded research of Ali Azhdarinia, PhD, of the University of Texas Health Science Center at Houston, at their virtual grant awards event on May 11, 2021. Dr. Azhdarinia is investigating image-guided precision medicine to treat NETs in the gastrointestinal tract and pancreas that are resistant to chemotherapy.
Dr. Azhdarinia leads the Theranostics Laboratory in the Center for Precision Biomedicine at the Brown Foundation Institute of Molecular Medicine at the UT Health Science Center at Houston. His image-based laboratory primarily focuses on developing bioconjugates, a technique that chemically links two molecules together. By designing and synthesizing innovative bioconjugates that can target and bind to NETs he can provide surgeons – in real time – tumor imaging information, but also use them to potentially deliver a “cytotoxic payload” that can kill the tumors.
The idea for this awarded research evolved from discussions at a NETRF meeting in 2018 with Daniel Halperin, MD, from M.D. Anderson Cancer Center. “Dr. Halperin helped me understand what the clinical problem was – chemotherapy isn’t typically indicated for most types of neuroendocrine cancers of the gastrointestinal tract and pancreas, especially grade 1, grade 2 tumors,” Dr. Azhdarinia says. However, there was evidence that patients with these types of tumors showed some response to the chemotherapy drug, temozolomide, particularly those patients with pancreatic NETs. This partial response to the treatment was due to the activity of an enzyme (called MGMT) found in these organs that inhibits the drug’s action. Because the pancreas had less MGMT than the gastrointestinal tract, the drug worked better on pancreatic NETs. Unfortunately, raising the dose of the drug to overcome MGMT inhibition had toxic effects on normal cells of the body, thus limiting its effectiveness.
Dr. Azhdarinia’s funded research project hypothesized that there may be a way to increase the tumor-killing effects of temozolomide, and overcome the inhibitory effects of MGMT, while avoiding its toxic effects on normal cells. This is where his bioconjugate plays a critical role. By targeting and binding temozolomide specifically to NET cells the bioconjugate could effectively concentrate the drug’s cell-killing effects on the tumor, while sparing non-binding, normal cells of the body. In his studies, he will see if he can pump enough temozolomide bioconjugate into a tumor to exhaust MGMT’s inhibitory process while avoiding normal cell toxicity.
“There are two things we hope to accomplish,” Dr. Azhdarinia says. “First, that patients with pancreatic NETs can continue to receive this treatment – in an even safer way, without added toxicity. Second, that patients who have carcinoid tumors can now have this as a new therapeutic option because it can overcome that enzyme-mediated resistance.”
Currently, Dr. Azhdarinia has completed developing the drug conjugate and demonstrated that it can specifically bind and enter tumor cells in cell culture to kill them. Without NETRF funding support, Dr. Azhdarinia says his research would still be at the chemistry stage of investigation rather than at the point of transitioning his research into in vivo studies. He is both optimistic and excited to begin moving his line of investigation into therapy studies in the coming months.