Drug Discovery

Department of Surgery faculty see firsthand a critical need: Medications that offer longer durable efficacy, less resistance to the conditions they treat and fewer side effects. Our surgeon-scientists bring a valuable perspective to drug discovery and development through many initiatives. These include identifying new drug targets and natural substances that have a therapeutic effect as well as developing new compounds. Research in the Department spans basic science investigations to understand mechanisms of action to preclinical and clinical testing.

Research in the Department has generated many discoveries and an extensive track record of high-quality, high-impact publications. Our work is leading to more efficacious ways to treat many of the conditions and diseases that impact our patients' lives.

Cancer-Drug Development

Work by our faculty takes many therapeutic approaches to a wide range of cancer types. In pancreatic cancer, faculty are working on novel strategies, including new interleukin-22 (IL-22) inhibitors and other immunomodulators targeting signaling and inflammatory pathways in this deadly type of cancer. Other efforts have led to the development of targeted HSP90 (heat shock protein 90) inhibitors in multiple cancer models, including head and neck squamous cell, colorectal, adrenal and thyroid cancers and melanoma. To address particularly aggressive forms of neuroblastoma, faculty have discovered certain DNA repair pathways that contribute to treatment resistance, providing new and highly promising therapeutic targets for our pediatric patients. Additional investigations focus on novel therapeutics against the initiation and progression of lung, esophageal and many other types of cancer. Some of these approaches include natural substances, such as those found in the longleaf ground cherry and black raspberry.  

Drug discovery work on the inhibition of PD-1 (programmed cell death protein 1) in cancer immunotherapy has become a mainstay of immunotherapy treatment today against melanoma, other skin cancers and many other types of cancer as well. Additional drug delivery efforts aim to treat locally advanced cancers with sustained release formulations of withanolides from the groundcherry plant, Physalis longifolia, through two patented nanoscale delivery systems. This work will soon be moving into clinical trials. 

Diabetes & Obesity 

University of Michigan investigators are developing novel stem-cell-based therapeutics to improve the dysfunctional lipid metabolism seen in obesity and diabetes. Faculty also use the models of obesity and diabetes developed in our laboratories to test novel pharmacologic agents for pharmaceutical industry collaborators.

Regenerative Medicine

Faculty have made breakthrough discoveries leading to new ways to improve healing and regeneration of irradiated bone. They also are identifying new targets in the inflammatory process in order to prevent heterotopic ossification, the debilitating growth of bone in soft tissues following severe burns and other trauma.

Our regenerative medicine research has led to development of a novel, implantable formulation of deferoxamine and hyaluronic acid that can significantly improve bone regeneration. When used prophylactically it also has been shown to help protect bone from the harmful effects of radiation. This work will lead to new options for our patients with craniofacial deformities and radiation-related bone injuries as well as those who have undergone radiotherapy for breast cancer.

Trauma and Critical Care 

Research in the area of trauma and critical care is leading to new drug targets and therapies for life-threatening injuries. Therapeutic strategies include use of inhibitors of hypoxia-inducible factors (HIF) and toll-like receptor-3 (TLR-3) to thwart the progression of lung contusion to systemic inflammatory illness. We are home to one of the first research teams to hypothesize that immune-modulating drugs might benefit patients with sepsis. This work has led to preclinical and clinical investigations of several immunomodulators — with promising results for improved sepsis outcomes. Other Department of Surgery laboratories are investigating the effectiveness and optimal dosing of valproic acid to address uncontrolled bleeding, traumatic brain injury, myocardial infarction and sepsis — both in civilian life and combat situations.

Our trauma and critical care faculty were the first to identify proinflammatory pathways activated by conventional resuscitation strategies using crystalloid fluids. Findings have helped change resuscitation protocols, particularly in combat situations, to include the histone deacetylase inhibitor valproic acid. This has been shown to lengthen the survival window and minimize tissue damage following traumatic brain injury. The hemorrhage control dressing developed by our faculty is now standard issue in armed service first aid kits. In addition, we're further investigating other targeted histone deacetylase inhibitors for patient-, organ-, and injury-specific uses. Eighteen HDACs have been identified to date, each aimed at distinct therapeutic targets.

Vascular Disease

Faculty research on vascular disease is pointing to new ways to treat deep vein thrombosis, pulmonary embolism and post-thrombotic syndrome. Of particular interest are selectin inhibitors rather than conventional blood-thinning agents. Based on their lab discoveries, other faculty investigators are focused on novel therapeutic options for diabetic wound healing and diabetic ulcers. 

Vascular disease research has led to the discovery of the role of the Ly6C^Hi macrophage as a key cause of persistent inflammation in diabetic wound healing, guiding us to a novel, potentially life- and limb-saving therapeutic target. 

Team-based science drives our work. Among many other efforts, we are proud to be part of a large collaboration focused on pancreatic cancer therapies with investigators from Pathology, Pharmacology and many other basic science departments. We also work closely with Michigan Drug Discovery, a University-wide initiative to speed the translation process, as well as with Pharmaceutical Chemistry and Medicinal Chemistry investigators. In collaboration with several pharmaceutical companies, our laboratories have many clinical trials underway to test existing agents for new indications, combinations and formulations. Additionally, we have launched the country's first academic surgical department clinical research organization, an innovative approach to create new and meaningful relationships with industry partners. By working with some of our surgical laboratories, industry collaborators benefit from the use of unique models and other preclinical opportunities to help move novel agents and technologies closer to clinical impact.