Current Projects

"Generation of anti-PAG monoclonal antibodies to treat solid malignancies"

Every year, 400,000 cancer patients in the US receive treatment with anti-PD-1 antibodies, a type of immunotherapy that releases a brake on the anticancer actions of T cells. However, only about 25% of patients respond well. Seeking to improve outcomes, the Mor lab discovered a new protein called PAG that acts as a checkpoint on T cells, limiting their cancer-killing actions. When PAG is absent, the PD-1 pathway is blocked, making T cells more effective against cancer cells. In lab experiments, T cells without PAG showed stronger ability to kill cancer cells, and mice without PAG had slower-growing tumors. The Mor group created antibodies against PAG by immunizing mice and selecting the best ones that can block tumor growth in animal models by boosting anti-cancer T cell activity. Now, they plan to expand their collection of PAG antibodies, improve their effectiveness, and test them in models that mimic human biology before taking them to clinical trials.

"Optimizing Cell Therapy for Solid Tumors by Hardwiring Cytotoxic Cell Lytic Granule Dispersion via Genome Wide and Small Molecule Screens"

Lead Investigator: Jordan S. Orange, MD, PhD

Cell therapy is a transformative intervention for curing leukemia, demonstrating how cytotoxic cells of the immune system can be harnessed to treat cancer. Despite there being an FDA-approved cell therapy product and many ongoing clinical trials, there has yet to be a true success in using cell therapy for treating solid tumors. Decades of investigation in Orange’s laboratory has proven that cytotoxic cells are specialized for a one-at-a-time killing approach that is easily overwhelmed and suppressed by the solid tumor environment. Now, he plans to find an irreversible small molecule that can be added to therapy cells before they are infused into a patient to make them permanently kill multi-directionally after being triggered by a tumor cell.

"Development of Small Molecule Inhibitors of NSD2"

Lead Investigator: Michael M. Shen, PhD

Co-Investigator: Donald Landry, MD, PhD

Prostate cancer represents the second leading cause of cancer death in American men. Although next-generation inhibitors of androgen receptor signaling, such as enzalutamide, have extended overall survival of advanced prostate cancer, the disease inevitably recurs due to the emergence of aggressive forms of castration-resistant prostate cancer, including neuroendocrine prostate cancer (NEPC), which is an aggressive lethal variant that lacks effective treatments. Shen’s laboratory has shown that a histone methyltransferase enzyme called NSD2 is up-regulated in NEPC, and that its inhibition results in loss of neuroendocrine differentiation and restoration of enzalutamide sensitivity. He will use medicinal chemistry approaches to develop novel small molecule derivatives of an existing small molecule that targets NSD2, in order to identify compounds with improved inhibitory properties that can be developed as new treatments.

“Advancing a New Ferroptosis Inducing Drug (VP224) to Clinical Trial for GBM”

Lead Investigator: Peter D. Canoll, MD, PhD

Co-Investigators: Jeffrey N. Bruce, MD; Brent Stockwell, PhD; Peter A. Sims, PhD; Osama Al Dalahmah, MD, PhD

Currently available treatments for glioblastoma (GBM) have very limited efficacy, in part due to quiescent glioma cells that are resistant to standard forms of chemotherapy. Prior studies have shown that an inhibitor enzyme of glutathione peroxidase 4 (GPX4) called RSL3 can induce ferroptotic cell death of quiescent or dormant GBM cells in slices of GBM generated from patient surgical samples, and that combining RSL3 with the topoisomerase inhibitor Topotecan, a chemotherapeutic drug that effectively kills proliferating glioma cells, can significantly prolong survival in a mouse model of GBM. The Stockwell lab has recently developed a newer GPX4 inhibitor, VP224, with superior pharmacokinetic properties. After verifying the efficacy of VP224 in a mouse model of GBM, Canoll and his colleagues plan to perform safety studies in preparation for a future clinical trial.

"Treatment of STK11-Deficient Non-Small Cell Lung Cancer"

Lead Investigator: Benjamin Izar, MD, PhD

Non-small cell lung cancer (NSCLC) is one of the most common and deadliest cancers worldwide. Patients with NSCLC that lacks a critical gene called STK11 face an especially poor outlook. These tumors often prove resistant to current immunotherapies, leaving patients with few effective treatment options. To address this pressing need, Dr. Benjamin Izar and his team are pioneering a new approach to combat STK11-deficient NSCLC by uncovering a previously unknown genomic vulnerability in these tumors.

Through cutting-edge research, Dr. Izar’s team has gained important insights into how cancer cells adapt to a feature known as chromosomal instability (CIN). These findings have led to the discovery of a promising new drug target, which the team will investigate further in this project, aiming to develop a novel therapeutic strategy to fight these aggressive cancers.

If successful, this work could lay the foundation for a completely new class of immunotherapy for patients with STK11-deficient NSCLC and other cancers with high chromosomal instability. This breakthrough has the potential to significantly improve outcomes for patients who currently have few options, offering hope for more effective and personalized treatments in the future.