New Awards Support Discovery of Novel Cancer Drugs
Four Columbia University faculty members have been selected as winners of the inaugural 2023 Irving Cancer Drug Discovery Program (ICDDP) Award. The ICDDP, which debuted in February as part of the Herbert Irving Comprehensive Cancer Center (HICCC), was established to help faculty accelerate cancer research discoveries and advancements made in their labs to the clinic. Beginning in July 2023, each awardee will receive a $100,000 to $200,000 grant annually for 1 to 2 years to fund research personnel and supplies.
The recipients of the ICDDP award are: Jordan S. Orange, MD, PhD, chair of pediatrics at Columbia University Vagelos College of Physicians and Surgeons (VP&S); Michael M. Shen, PhD, Arthur J. Antenucci professor of genetics, urology, and systems biology at VP&S; Peter D. Canoll, MD, PhD, professor of pathology and cell biology at Columbia University Irving Medical Center (CUIMC); and Swarnali Acharyya, PhD, Herbert Irving assistant professor of pathology and cell biology at VP&S.
Led by Director Tannishtha Reya, PhD, the ICDDP is designed to provide critical infrastructure and support to enable the development of key scientific discoveries into new approaches for the diagnosis and treatment of cancers. The program will support a range of projects, including the development of diverse therapeutic modalities such as small molecules, antibodies (biologics), and cell therapies, as well as the development of new computational, diagnostic, and drug delivery technologies.
All ICDDP awardees are also invited to audit a future Life Science Lab to Market Accelerator Bootcamp, a multi-session course designed to give academic investigators an overview of early development aspects of therapeutic design and commercialization. The Bootcamp is offered as part of the Accelerating Cancer Therapeutics program and typically runs from January to May each year.
The Winning Projects:
"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, professor of medicine
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, professor of neurological surgery; Brent Stockwell, PhD, professor of biological sciences; Peter A. Sims, PhD, associate professor of systems biology; Osama Al Dalahmah, MD, PhD, professor of pathology and cell biology
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.
"Developing the first targeted therapy against cancer cachexia"
Lead Investigator: Swarnali Acharyya, PhD
Co-Investigator: Henry M. Colecraft, PhD, professor of physiology and cellular biophysics, and pharmacology
Nearly 80% of patients with advanced cancer experience a debilitating, irreversible muscle wasting syndrome known as cachexia. Cancer patients with cachexia become too weak to tolerate the required dose on anti-cancer therapies and die prematurely from cardiac and respiratory failure due to weak cardiac and diaphragm muscles. Currently, there are no FDA approved therapies to reduce or prevent cachexia. Recent studies from Acharyya’s laboratory identify a protein called Zip14 as a novel mediator of cachexia in metastatic cancer. Based on these findings, Acharyya and her colleagues propose the use of anti-Zip14 monoclonal antibodies to inhibit Zip14 function as a therapeutic strategy to prevent cachexia.