Training Group:

Molecular Signaling and Cancer Biology

Mentor / Lab:

Dr. Michael K. Wendt

Specific Research Area / Project:

Cancer Biology, Anti-metastatic Pharmacology, Drug Resistance Nodal Targeting as a Multifunctional Therapeutic Strategy in Drug Resistant Metastatic Cancer

Lab / Personal work-related websites:

Lab

Personal

Research Profile:

Cancer remains the second leading cause of death among all the diseases in the world. Although multiple therapies have benefited patients in the last two decades, many cancers are still considered incurable diseases. There are multiple barriers to cross before we conquer cancer. Among these barriers, cancer metastasis is extremely recalcitrant. For example, metastatic breast cancer (MBC) is a major clinical challenge, with five year survival rates at only ~23%. Moreover, drug resistance can happen even when the patients first response to the anti-cancer agents. Hence, there is a critical need to find drug targets and therapies against drug resistant metastatic cancer. Cancer cells are capable of developing drug resistance and metastasis via activating multiple signaling pathways. As a result, it is important to dig out key signaling nodes as therapeutic targets for drug resistant metastatic cancer and elucidate detailed mechanisms. The overall goal of my research is to fulfill the knowledge gap in understanding the functions of molecular targets in multiple oncogenic pathways. These multifunctional therapeutic targets will pave the way for new cancer therapies, including combination immunotherapies. The expected results will impact the field by producing novel cancer therapies to maximize benefits for patients.

One part of my research focuses on the role of an oncogenic phosphatase, SHP2, in drug resistant metastatic breast cancer. We used genetic depletion and two types of SHP2 inhibitors to target SHP2. The findings demonstrate that SHP2 is involved in extracellular matrix (ECM) and receptor tyrosine kinase (RTKs) signaling to promote drug resistant metastatic breast cancer. The allosteric SHP2 inhibitor, SHP099, can be combined with RTK inhibitors to delay pulmonary metastatic cancer progression. We also find that SHP2 blockade can also be combined with immune checkpoint blockade to reduce pulmonary metastasis. My research about the functions of SHP2 in T-cell activation is ongoing in the lab.

Another part of my research focuses on the role of an oncogenic deubiquitinase, UCHL1, in drug resistant metastatic cancer. We analyze the topic in both breast cancer and small cell lung cancer models. The results suggest that UCHL1 is involved in drug resistance and metastasis via facilitating RTK signaling. Research about UCHL1 inhibitors and promising combination strategies as cancer therapeutics is also ongoing.

Overall, my work is gathering evidence for multiple novel targets, which may translate to new cancer therapeutics.

About Me:

I got my bachelor's and master's degrees in pharmacy at SJTU. During the 7-year study, I was involved in the research about both mechanistic studies in breast cancer and development of biotechnology drugs. I applied to the PULSe program as I wanted to try different types of research before I decided on my career. I was first enrolled in the biotechnology training group when I joined PULSe. After the rotation, I found that I was still interested in breast cancer research, and I was impressed by the research of my current lab. Finally, I shifted to the molecular signaling and cancer biology training group, and joined the Wendt lab. I was satisfied that PULSe provided my multiple chances for the important decision in my Ph.D. career. It was a smart decision for me, which has impacted my career path in the future.

I have had a smooth and happy experience in working on my dissertation projects. The memorable experience I have had with PULSe program was the first year poster session. This was the first time I presented my research to the public. The preliminary exam at PULSe was also a unique experience around the campus. We prepare a proposal which is not related to our thesis research. I was happy that I passed the exam smoothly. I was also excited when I received a fellowship from the Purdue Center for Cancer Research in 2019. The PULSe office has always been helpful through these years. I was moved by the farewell day for Sue. Overall, the sweet memories with PULSe will always stay in my mind and be the precious fortune in my life.

I would like to start a career in the academic after finishing my PhD, and continue in cancer research. I hope that I can find a faculty position after further post-doctoral training. I want to give my experience to the next generation, and contribute more to finding better cancer therapeutics.

Awards:

• 2019 Women's Global Health Institute (WGHI) Graduate Student Poster Award (First Place)
• 2019 SIRG Graduate Research Assistantships from Purdue University Center for Cancer Research
• 2017 Purdue Graduate School Assistant Scholarship
• 2016 Purdue Graduate School’s Lynn Fellowship by Office of Interdisciplinary Graduate Programs
• 2016 Outstanding graduate of Shanghai
• 2015 Graduate National Scholarship for Masters (5% in 200 students)
• 2014 Excellent student scholarship, School of Pharmacy, SJTU
• 2013 Outstanding graduate of Shanghai Jiao Tong University
• 2013 Excellent Bachelor Thesis (Top 1% in 4000 students) of SJTU
• 2012 Bao Steel Scholarship for excellent students

Publications:

• Li Z, Wu Z, Chen H, et al. Induction of anterior gradient 2 (AGR2) plays a key role in insulin-like growth factor-1 (IGF-1)-induced breast cancer cell proliferation and migration. Medical Oncology, 2015, 32(6): 1-12.
• Li Z, Zhu Q, Hu L, Chen H, et al. Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor‐1α that enhances CoCl2-induced doxorubicin resistance in breast cancer cells. Cancer science, 2015, 106(8): 1041-1049.
• Li Z, Zhu Q, Chen H, et al. Binding of anterior gradient 2 and estrogen receptor-α: dual critical roles in enhancing fulvestrant resistance and IGF-1-induced tumorigenesis of breast cancer. Cancer Letters, 2016, 377(1):32-43
• Guo H, Chen H; Zhu Q, et al. A Humanized Monoclonal Antibody Targeting Secreted Anterior Gradient 2 Effectively Inhibits the Xenograft Tumor Growth. BBRC. 2016, 475(1): 57-63.
• Shinde A, Wilmanski T, Chen H, et al. Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer. Breast Cancer Research. 20.1 (2018): 76.
• Kim D, Sun Y, Xie D, Denton K E, Chen H, Lin H, et al. Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library. Molecules, 24.15 (2019): 2764
• Krabill A D, Chen H, Hussain S, et al. Biochemical and cellular characterization of a cyanopyrrolidine covalent Ubiquitin C‐terminal hydrolase L1 inhibitor. ChemBioChem (2019).

Presentations:

• Chen H, Zhang S, Zhang ZY, Wendt MK. 2017 Purdue’s Office of Interdisciplinary Graduate Programs (OIGP) Spring Reception. The role of SHP2 in drug resistant breast cancer.
• Chen H, Zhang S, Zhang ZY, Wendt MK. 2018 AACR Annual Meeting. Therapeutic rationale for SHP2 phosphatase inhibitors: Targeting drug resistant breast cancer via blockade of FGFR1 signaling.
• Chen H, Zhang ZY, Wendt MK. Midwest Tumor Microenvironment Meeting. The Role of SHP2 in Drug resistant and Metastatic Breast Cancer. 2019; Notre Dame University, South Bend, IN.
• Chen H, Zhang ZY, Wendt MK. WGHI’s annual Symposium. The Role of SHP2 as a Multifunctional Therapeutic Target in Drug Resistant and Metastatic Breast Cancer. 2019; Purdue University. West Lafayette, IN.

Leadership:

• 2017/04-2018/05 Travel Grant Vice Chair, Grant Review and Allocation Committee, Purdue Graduate Student Government (PGSG)