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Jianneng Li

Archibald Assistant Professor

Archibald Assistant Professor
Office
271 Galvin Life Science Center/Freimann Life Science Center
Notre Dame, IN 46556
Email
jli33@nd.edu

Website

Research Interests:

Drugs are inherently “dirty”!!! Including so-called targeted therapies. While designed for specificity, most FDA-approved small molecules and biologics interact with multiple proteins, pathways, and cellular contexts beyond their primary targets. These off-target and network effects can contribute to both therapeutic benefit and toxicity, underscoring the importance of identifying new targets and gaining a deeper understanding of existing clinical drugs. These efforts are extremely important because they address complementary needs in advancing medicine. Discovering new targets can lead to innovative treatments for diseases that lack effective therapies, helping to fill gaps in clinical care. At the same time, improving our understanding of how current drugs work, such as their mechanisms of action, resistance pathways, and off-target effects, can enhance their clinical efficacy, enable the development of combinatorial therapies, minimize side effects, and guide their optimal use in personalized medicine. Together, these efforts ensure that research not only drives innovation but also maximizes the benefit of existing therapies for patients. Currently, many drugs are FDA-approved and widely used in clinics to treat prostate cancer, such as abiraterone (targeting androgen synthesis), enzalutamide (targeting AR (androgen receptor)), and PARP inhibitors (olaparib, rucaparib, and talazoparib, targeting DNA repair). Our previous work (Nature, 2015) reveals that, other than its principal target (CYP17A1, a rate-limiting enzyme involved in androgen synthesis), abiraterone and its metabolites possess other targets in prostate cancer tumors, including 3β-HSD1 (another rate-limiting enzyme involved in androgen synthesis) and AR, which makes the drug have a multilayer function to tackle prostate cancer. Another of our works (Science Translational Medicine, 2021) has also demonstrated that rucaparib (a PARP inhibitor) can reverse enzalutamide resistance in prostate cancer through an off-target effect that suppresses H6PD activity. All these intriguing and unexpected findings raise an important question: whether other clinical drugs, such as enzalutamide and other PARP inhibitors, also have additional targets that enhance their effectiveness in prostate cancer treatment. Right now, we have three promising projects ongoing to interrogate the question.

Another very exciting topic we are working on is bipolar androgen therapy (BAT, AKA SPA, supraphysiological androgen) in prostate cancer treatment. Although most efforts in developing treatment strategies to tackle prostate cancer focus on inhibiting AR signaling, with treatments such as abiraterone and enzalutamide, abundant emerging evidence in both preclinical models and patients suggests that SPA treatment can cause regression of prostate cancer via cell-cycle arrest, DNA damage, etc., making SPA an alternative strategy for treating prostate cancer patients. However, SPA profoundly disrupts endocrine and cardiovascular homeostasis, leading to hypertension, fluid retention, thromboembolic risk, and metabolic abnormalities, which collectively restrict BAT to carefully selected patients and preclude its broader use. Moreover, despite promising clinical responses, resistance to BAT emerges in a substantial subset of prostate cancer patients, limiting the durability of benefit and posing a significant challenge in routine clinical practice. Therefore, treatment strategies that circumvent the systemic toxicity and resistance of SPT remain unmet needs. Currently, two projects with very strong preliminary data are underway to address unmet needs.

To achieve the aims in our projects, we are collaborating with worldwide laboratories and integrating all the resources from the state-of-art research core facilities in Notre Dame and other institutes, utilizing a variety of cutting-edge approaches, such as CRISPR/Cas9 knockout and activation screening, genome editing, live cell imagine, AI assistant prediction of protein-protein and protein-drug bindings, small molecule library screening etc..

Our research program is highly translational, driven by clinically derived observations and unanswered questions in patient care. By integrating clinical insight with mechanistic investigation, we seek to generate discoveries that are immediately relevant to therapeutic decision-making and future clinical testing.

Biography:

  • Archibald Assistant Professor, Department of Biological Sciences, University of Notre Dame, IN 2023
  • Member, Harper Cancer Research Institute (HCRI); Member, Warren Family Center for Drug Discovery, University of Notre Dame, IN 2023
  •  Associate Member, Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Cancer Center (NCI-designated comprehensive cancer center), IN 2023
  • Research Associate, Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, OH 2021-2023
  • Postdoctoral fellow, Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, OH (Mentor: Nima Sharifi) 2013-2021
  • Ph.D. (Biophysics), Fudan University, Shanghai, China (Mentor: Kang Sun) 2008-2013
  • B.S. (Biological Sciences), Shanghai Ocean University, Shanghai, China 2004-2008

Selected Publications:

Primary Research Areas:

Cancer
Cellular and Molecular Biology
Development and Regeneration
Genetics and Genomics

Research Specialties:

Cancer Biology
Endocrinology
Steroid Metabolism
Function and Signal of Steroid Receptors
Prostate Cancer
Steroid Related Cancers

View all of Publications: https://www.ncbi.nlm.nih.gov/myncbi/jianneng.li.1/bibliography/public/