Game Changers

Haian Fu

Fu leads a research program that is the primary driver of discovery and evaluation of novel therapeutic options for cancer patients at Winship. Fu, PhD, is associate dean for innovation and international strategies, professor and chair of the Department of Pharmacology and Chemical Biology, and professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. At Winship, Fu holds the Winship Partner in Research Endowed Chair and is leader of the Discovery and Developmental Therapeutics Program and director of the Emory Chemical Biology Discovery Center.

Q. What insights has your team contributed to molecular target-based cancer drug discovery, biomedical technology and clinical trials for therapeutic development?

A. Currently, most targeted cancer therapeutics act on dysregulated enzymes in cancer, such as protein kinases, to block their cancer-causing catalytic functions. However, most cancer driver genes encode non-enzymes, such as adaptor proteins, which have no targeted therapies, leaving a large population of patients with limited treatment options.

We focus on cancer-associated protein-protein interactions (PPI) that both enzymes and non-enzymes utilize to transmit oncogenic signals in cancer. While most cancer drugs act on an individual target molecule, the PPI-targeted approach aims to perturb the interface between two proteins to block the transmission of cancer-driving signals. The PPI targets were historically regarded as highly challenging and undruggable.

Our effort has led to the discovery of a landscape of neo-interactions encompassing both oncogenic and tumor suppressor mutations, offering a fertile ground for genomics-directed therapeutic exploitation. These firstin-class mutation-directed PPI modulators are expected to accelerate the development of patient tumor-specific precision medicine.

Q. Please explain how patients benefit from this research?

A. Our approach to disable or modify tumor mutation-created neoPPIs and hypoPPIs aims to develop a new generation of anticancer agents that can be tailored specifically to patients with a particular mutation that does not exist in a healthy individual. We hope that this strategy will transform our way of treating patients by targeting the oncogenic mutation-driven cancer-causing programs with precision.

Chrystal Paulos

Paulos' research aims to develop novel T cell–based therapies for patients with melanoma. Her research team has contributed significant insight into how to mount T cell memory responses to tumors. Paulos, PhD, is an associate professor in the Department of Surgery and the Department of Microbiology and Immunology at Emory University School of Medicine.

Q. What insights has your team contributed toward understanding how to mount T cell memory responses to tumors?

A. We discovered that specially selected immune T cells that contain the novel anti–tumor CD4 marker, when given back to patients directly, cause tumors to shrink and can orchestrate other immune cells in the patient's body to prevent tumor relapse.

Q. How do patients benefit from this research?

A. Harnessing immunity to tumors via checkpoint blockade or adoptive T cell transfer therapy has revolutionized medicine. All NCI-designated cancer centers provide their patients with some form of immunotherapy. While this has been impactful for many patients, there is still room for improvement, as not everyone benefits. Even if a patient does respond to immunotherapy, sometimes this benefit is not long-lasting. We think that if we can bolster effective memory T cell responses via our approach, we may be able to further augment PD-1 or cell-based immunotherapies with our clinical team.

Sumin Kang

Kang's research centers on using translational and preclinical studies to better understand the protein kinase signaling as well as metabolic reprogramming in tumorigenesis and tumor metastasis. Kang, PhD, is associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and director of Winship's Basic and Translational Science Division of HMO. Kang's work is supported with competitive peer-reviewed federal grants, including NIH R01s for pro-metastatic and cisplatin-resistant signaling of RSK2 and MAST1 in cancer.

Q. In what ways would you describe your research as "changing the game" in cancer treatment?

A. The main cause of cancer death is not the primary tumor but the recurrence of metastatic disease that follows cancer therapies. We are focusing on identifying a novel critical factor that leads to tumor recurrence. We look at cancer recurrence as a complex process rather than a single factor– driven disease. Therefore, we use integrated metabolomics, proteomics and transcriptomics to detect genes, transcripts, proteins and metabolites, and to better understand cancer in an unbiased manner.

We not only put effort into understanding the underlying mechanisms of new networks in tumor recurrence but also into the identification of specific and effective small molecule inhibitors to target these novel factors. We validate them in preclinical settings, which in the long run will contribute to overcoming cancer recurrence that is mediated by therapy resistance and metastatic switch.

Q. How do patients benefit from your research?

A. A correct understanding of how current drugs work and how cancers evade therapy will help patients receive optimal and right drug combinations that work best for their diseases. For instance, we found that a kinase called MAST1, which drives cancer cells to become resistant to cisplatin-based chemotherapy, and glucocorticoids, which are often used together with cisplatin as supportive care, facilitated MAST1 induction. Based on this finding, we suggest that MAST1 inhibition may be considered when patients receive glucocorticoids together with cisplatin.

Douglas K. Graham

Graham focuses clinically in pediatric leukemia and is a National Institutes of Health–funded investigator with an active laboratory focusing on developing novel therapeutics for pediatric cancer, recently validating MerTK as a novel cancer agent in multiple cancer types. In particular, his lab studies the MerTK and Axl pathways in pediatric leukemia and non-small cell lung cancer. His research team has helped develop a first-in-class small molecule inhibitor against MerTK, and this cancer drug is being tested at Emory in clinical trials. Graham, MD, PhD, is professor of pediatrics and chief of the Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta. He holds the William G. Woods Chair and is the division chief of pediatric hematology/oncology/BMT at Emory University.

Q. What role has your lab played in developing potential new "game-changing" treatments?

A. Our research team has worked to identify and validate a new cancer target, MerTK. When this receptor tyrosine kinase is abnormally activated, cancer cells do not respond well to therapy. However, we have helped develop a new cancer drug that can turn off this cancer protein and make cancer cells die, particularly when combined with other treatments. We have also discovered that our new drug turns on the patient’s immune system in a manner that further fights cancer cell growth. Our research group is particularly excited that the cancer drug is completing initial testing in human solid tumor cancer trials and the early data warranted further testing in follow-up studies. Recently, three additional clinical trials testing the efficacy of this cancer drug at Emory, as well as other sites in the US and internationally, have opened.

Q. How does your research benefit pediatric patients?

A. The initial clinical trial focused on testing this drug in adult cancer patients with solid tumors who have not responded well to other cancer treatments. The more recent trials have focused on evaluating the benefit of this drug in lung cancer. We will soon open a trial at Winship and at the Children's Healthcare of Atlanta to determine the benefit of this new cancer drug in patients with acute lymphoblastic leukemia and acute myeloid leukemia. This leukemia trial will enable adults and pediatric patients (ages 12 and up) to be enrolled in the study. A future trial is also planned to expand the availability of this drug to children with leukemia who are below the age of 12.