Chinese researchers and physicians are being increasingly recognized for their significant contributions to advancing biomedical research, including cancer research, in China and around the world. To facilitate and strengthen collaboration among cancer researchers and physicians in the United States and China, the US Chinese Anti-Cancer Association (USCACA) and the US National Foundation for Cancer Research (NFCR) have established the USCACA-NFCR Scholar Exchange and Fellowship Program in basic, translational, and clinical studies. The goal of this joint scholar program is to recognize and reward research excellence by Chinese cancer researchers. Recipients are honored with the USCACA-NFCR Scholar Excellence Award for their achievements in cancer research performed while they were in the United States, as well as contributions to eradicating human cancers after their return to China.
Since November 2010, five young Chinese researchers and physicians have been recognized with this prestigious Award. In this special issue of the Chinese Journal of Cancer, we, together with editor of the journal, Dr. Yi-Xin Zeng and the board of editors, are proud to introduce these five outstanding young investigators as follows.
· Dr. Yong Gao, Affiliated East Hospital, Tongji University, Shanghai (2010)
· Dr. Ji-Long Yang, Tianjin Medical University Cancer Hospital and Institute, Tianjin (2010)
· Dr. Pei-Rong Ding, Sun Yat-sen University Cancer Center, Guangzhou (2011)
· Dr. Min Huang, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (2011)
· Dr. Ying-Mei Wang, Tianjin Medical University General Hospital, Tianjin (2011)
We have invited these awardees to contribute a short essay that summarizes their research achievements. As illustrated in their essays, these outstanding young scholars have received excellent training from their mentors in the United States and made impressive discoveries in demonstrating molecular mechanisms underlying the cause and progression of human cancers and in searching for new approaches that could improve treatments for cancer patients.
USCACA is a not-for-profit professional organization founded in 2009(http://www.uscaca.org). With members from academia, industry and government, USCACA facilitates collaborations among cancer researchers and physicians in the United States and China. Our current focus is on expediting novel cancer drug development by fostering clinical trial networks, sharing best practices and knowledge of clinical trial, and providing education and training opportunities. USCACA collaborates with the Chinese Anti-Cancer Association (CACA), the Chinese Society for Clinical Oncology, and other professional associations. Our mandate is to improve cancer treatment through research, education, and collaboration.
NFCR is a leading US cancer research charity(http://www.nfcr.org). Since 1973, NFCR has provided over $288 million to fund cancer research and public education relating to cancer prevention, early diagnosis, and the newest treatment options in the United States, Europe, and Asia. As early as in 1982, NFCR started a cancer research and international training program in China. Today, NFCR directly funds innovative research projects in universities and research institutes in China, provides clinical training opportunities for physicians from major Chinese hospitals through its US-based Institute for clinical research excellence, and sponsors high level cancer research conferences to promote international collaboration.
In recent years, NFCR has focused on developing the Tissue Bank Consortium in Asia (TBCA) that is truly a partnership with Chinese university hospitals, Chinese government agencies, the US National Cancer Institute (NCI) and major multi-national pharmaceutical companies. TBCA provides an important international platform that promotes global standardization in biospecimen collection, storage, and quality control, and through its peer-review process, assures that tumor tissue samples and associated clinical data are made available for highly meritorious research purposes. NFCR is committed to research for cures for all types of cancer.
The common goal of USCACA and NFCA is to expedite novel cancer drug development by stimulating the translation of laboratory discoveries into novel cancer treatments, fostering collaborations in clinical cancer drug development, and sharing best practices and knowledge between China and the United States. The USCACA-NFCR Scholar Exchange and Fellowship Program provides a unique opportunity for young Chinese scholars who have an interest in advancing their basic, translational, and clinical knowledge and skills, and in establishing long-term collaborations with leading scientists in the United States who can support their continued work and future success in China.
Dr. Yong Gao is the current Director and professor at the Department of Oncology, Shanghai East Hospital, Tongji University. Dr. Gao graduated from Shanghai Second Military University in 1987 and then worked as an oncologist in Shanghai Changzheng Hospital for 15 years. In 2007, he joined Dr. Su-Yun Huang's laboratory as a visiting associate professor at the Department of Neurosurgery, the University of Texas M. D. Anderson Cancer Center, Houston, Texas in the United States. His research projects focused on targeted treatment of pancreatic cancer.
Pancreatic cancer is currently the fourth leading cause of cancer-related deaths worldwide. A full understanding of the cellular and molecular mechanisms in the development and progression of pancreatic cancer is crucial for identifying new targets of effective treatment modalities for this deadly disease. Previous studies have demonstrated that Sp1 overexpression plays an important role in regulating the expression of vascular endothelial growth factor (VEGF) and tumor angiogenesis in pancreatic cancer. Dr. Gao demonstrated that treatment with combination of mithramycin A and tolfenamic acid promoted degradation of Sp1 protein and synergistically enhanced their antitumor activity against pancreatic cancer. The underlying mechanism of mithramycin A's inhibition involves a reversible interaction with double-stranded DNA with GC-base specificity and selective regulation of transcription of genes with GC-rich promoter sequences.
In a separate project, Dr. Gao demonstrated that treatment with combination of mithramycin A and betulinic acid can also suppress pancreatic cancer growth, angiogenesis, and invasion. In xenograft mouse models of human pancreatic cancer, treatment with betulinic acid and mithramycin A displayed a dose-dependent antitumor activity. This effective combination produced less discernible side effects than did the effective doses of gemcitabine, another common clinical chemotherapeutic agent. Betulinic acid combined with mithramycin A synergistically inhibited proliferation and invasion of pancreatic cancer cells as well as tumor angiogenesis. Mechanistically, treatment with combination of betulinic acid and mithramycin A significantly inhibited Sp1 recruitment onto the Sp1 and the VEGF gene promoters, leading to a robust inhibition of transcription of Sp1 and VEGF and down-regulation of expression of Sp1 and VEGF protein. These data show that Sp1 is an important target of both betulinic acid and mithramycin A and their combination treatment enhanced therapeutic effects on human pancreatic cancer.
In 2009, Dr. Gao returned to China and was appointed as the Director of the Department of Oncology at the Shanghai East Hospital. He continues to work on targeted treatment of pancreatic cancer that is funded by the National Science Foundation of China. In addition, as an attending oncologist, Dr. Gao treats over 100 cancer patients every month at his hospital.
Dr. Ji-Long Yang, currently an associate professor in Surgical Oncology at the Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, received his bachelor degree in Clinical Medicine from the Henan Medical University in 2000, master degree in Pathology from the Zhengzhou University in 2003, and Ph.D. degree in Oncology from the Fudan University Cancer Hospital in 2006. Subsequently, Dr. Yang joined the faculty of Tianjin Medical University Cancer Institute and Hospital, where he performed both surgery and basic sarcoma research. He was selected as the New Century Talent of Tianjin Medical University in 2009.
In July 2009, Dr. Yang joined Dr. Wei Zhang's laboratory at the University of Texas M. D. Anderson Cancer Center (MDACC) for postdoctoral training. While at MDACC, he had an opportunity to work with a multi-disciplinary team including sarcoma oncologist Dr. Jonathan Trent and sarcoma surgeon Dr. Raphael Pollock on research projects involving gastrointestinal stromal tumor (GIST), leiomyosarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (MPNST). Dr. Yang discovered that the WWOX gene, a tumor suppressor gene, is frequently deleted or under-expressed in osteosarcoma, whereas the APEX1 gene is often amplified and over-expressed and the expression of APEX1 is a significant prognostic predictor for osteosarcomas. Using integrated array comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) analyses, Dr. Yang and his colleagues also discovered genetic amplification of vascular endothelial growth factor (VEGF) pathway genes and validated the VEGF-A gene amplification in human osteosarcoma. Using several proteomic technologies including reverse-phase protein lysate array and tissue microarray coupled with transcriptome analysis, Dr. Yang reported a novel phenomenon that there is a mesenchymal-to-epithelial reverting transition (MErT) in leiomyosarcoma. He provided evidence that this process is regulated by slug and that this MErT process is clinically important. He also contributed to several other projects and co-authored two papers about GIST genomics. Additionally, he functionally determined insulin-like growth factor 1 receptor (IGF1R) pathway as a primary target for treatment. Because of his outstanding work, Dr. Yang was selected as a recipient of the 2010 Connie & Jim Walter Fellowship in Sarcoma Research at MDACC and the USCACA Scholar Award in 2010.
In July 2010, Dr. Yang returned to the Tianjin Medical University Cancer Hospital and Institute to continue his career as a clinician scientist. In addition to being a surgeon, Dr. Yang continues to research on the molecular basis of sarcoma and melanoma in collaboration with his colleagues in Tianjin (China), Houston (USA), and Tampere (Finland). Dr. Yang's researches are currently funded by the Natural Science Foundation of China, the Liddy Shriver Initiatives for Sarcoma (USA), the Tianjin Natural Science Foundation, the Tianjin Education Commission, the Tianjin Medical University, and the Tianjin Medical University Cancer Institute & Hospital. Dr. Yang's achievements demonstrate a potential for excellence and contribution to sarcoma research and treatment.
During Dr. Pei-Rong Ding's research fellowship at the Memorial Sloan-Kettering Cancer Center, he worked with Drs. W. Douglas Wong and Martin R. Weiser. His work mainly focused on a translational research project aiming at identifying the mechanism of resistance to chemotherapy/chemoradiotherapy. In the project, they analyzed the molecular profiles of rectal cancer with a goal of discerning the association of molecular changes with response to preoperative chemoradiotherapy. Meanwhile, he actively proposed and carried out several clinical research projects aiming at optimizing the surveillance strategies for colorectal cancer. One such research project involved identifying the pattern of recurrence of locally advanced rectal cancer treated with preoperative chemoradiotherapy. Predictive models of recurrence would lead to risk-adaptive follow-up strategies for high-risk and low-risk patients to avoid exposing low-risk patients to unnecessary treatment toxicities and to save health care resources in the meantime. He also conducted research to identify prognostic significance of lymphovascular invasion as an independent predictor of recurrence for all stages of diseases. Furthermore, he contributed to a retrospective analysis reviewing treatment of synchronous rectal cancer and liver metastases to identify the role of chemoradiotherapy in this population of patients, and to determine whether chemoradiotherapy is beneficial in treating patients with stage IV diseases.
His research “Patterns of recurrence in rectal cancer treated with neoadjuvant chemoradiotherapy and TME” was featured as a plenary presentation at the New York Society for Colon and Rectal Surgeon Residents' Night in 2010, attracting broad interest and active discussions at the meeting. Abstracts based on his work, “Patterns of recurrence in rectal cancer treated with neoadjuvant chemoradiotherapy and TME” and “Predictors of site-specific recurrence following combined modality therapy for locally advanced rectal cancer” were presented at the prestigious annual meeting of the American Society of Clinical Oncology (ASCO) in 2010.
While Dr. Ding was in New York city, he also took part in basic research in Dr. Zhe-Sheng Chen's laboratory at St. John's University. His research “The phosphodiesterase-5 (PDE-5) inhibitor vardenafil is a potent inhibitor of ABCB1/P-glycoprotein transporter” was published. This study was designed to determine the reversal mechanisms of vardenafil and tadalafil on ABC transporters-mediated multiple drug resistance in cancer cells. The study revealed that the PDE-5 inhibitor, vardenafil, reverses ABCB1-mediated multidrug resistance (MDR) by directly blocking the function of ABCB1 as a drug efflux pump without affecting the expression of the transporter.
After returning to the Sun Yat-sen University Cancer Center, Dr. Ding mainly focuses on clinical trials with a goal of optimizing the effect of preoperative chemoradiotherapy on rectal cancer. Meanwhile, he also conducts translational research exploring the epigenetic changes in induction of epithelial-to-mesenchymal transition in colon cancer cells and the underlying mechanisms. Some of his research results were published in Cancer, Journal of Gastrointestinal Surgery, International Journal of Colorectal Diseases, Tumor Biology, and Biomarkers.
Dr. Min Huang received her Ph.D. training under the supervision of Prof. Jian Ding at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, where she developed her initial interests in DNA damage response. After graduation, Dr. Huang did her postdoctoral research in Dr. Alan D'Andrea's laboratory at Dana-Farber Cancer Institute, Harvard Medical School and focused on the molecular mechanisms of DNA damage response triggered by DNA interstrand cross-links (ICL), the most dangerous DNA lesions with covalent bonds connecting DNA double strands.
DNA lesions, such as those caused by ionizing radiation and ultraviolet light, block replication fork progression and activate subsequent checkpoint response. Due to the uncoupling of minichromosome maintenance (MCM) helicase and DNA polymerase, the stalled replication forks generate the local accumulation of long stretches of single-stranded DNA (ssDNA), which are then rapidly coated by the replication protein A (RPA). Indeed, such an intermediate structure has been thought essential for the initiation of checkpoint signaling. However, distant from other types of DNA damages, ICL-blocked replication forks fail to generate ssDNA, which raises a question, namely, how ICL-activated checkpoint signaling is initiated. To address this challenge, Dr. Huang and her collaborators revealed that the DNA-binding activity of FAAP24 medicates the binding of FANCM/FAAP24 complex to ICL lesions, where the complex facilitates the subsequent recruitment of RPA. FANCM/FAAP24-dependent RPA recruitment is required for efficient ATR-mediated checkpoint activation. This work solved a long-existing puzzle by demonstrating how DNA cross-linking damage activates the checkpoint machinery.
Another critical unanswered question in ICL-induced DNA response is what are the molecules responsible for recognizing ICL and initiating the Fanconi anemia (FA) repair pathway, the primary mechanism by which cells detoxify ICL lesions. Current evidence suggests that the FA pathway initiates DNA damage recognition by the FANCM complex. However, genetic inactivation of FANCM causes only a partial defect in the FA pathway activation, suggesting the existence of redundant DNA damage sensors. To address this question, Dr. Huang performed a siRNA screening and revealed that the MutS complexes (MutSα and MutSβ), previously known only participating in the correction of mismatched DNA, function as redundant FA DNA damage sensors. Dr. Huang's work reveals the unanticipated cross-talks between two repair pathways that were previously thought to be distinct. It also suggests potential therapeutic strategies for targeting tumors harboring these defects of these two pathways.
After finishing her postdoctoral training, Dr. Huang returned to China and joined Shanghai Institute of Materia Medica, Chinese Academy of Sciences, as an assistant professor. She continues to her researches in DNA damage response as well as applying her expertise to cancer research and anticancer agent development. She has recently identified the first small molecular inhibitor disrupting the function of FA repair pathway through targeting the USP1/UAF1 complex. Dr. Huang has established herself in the DNA damage response field and expanded her research interests from basic mechanism study to translational anticancer research. Her work has been published in high-impact biological journals including Molecular Cell, Developmental Cell, Natural Structural & Molecular Biology, Clinical Cancer Research, and Molecular Cancer Therapeutics.
Dr. Ying-Mei Wang, currently at the Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, received her bachelor degree in Clinical Medicine from the Tianjin Medical University in 2002, master degree in Gynecology Oncology from the Tianjin Medical University in 2006, and Ph.D. degree in Gynecology Oncology from the Tianjin Medical University in 2010. Her Ph.D. research was awarded with an Excellent PhD Graduate Award from the Tianjin Medical University.
In October 2008, sponsored by a China Education Council Fellowship, Dr. Wang joined Dr. Wei Zhang's laboratory at the University of Texas M. D. Anderson Cancer Center (MDACC) as an exchange Ph.D. student. Dr Wang's research projects focused on the role of a newly characterized gene, MIIP, that codes for a migration and invasion inhibitory protein (MIIP) in endometrial cancer. She uncovered the actin stress fiber cytoskeleton system as a target for MIIP's inhibition of endometrial cancer cell migration. Specifically, she demonstrated that MIIP inhibited RhoA activity which in turn suppressed cell tail retraction and Rac1 activity, leading to blockage of iamllipodia formation for cell movement. Using integrated array comparative genomic hybridization (aCGH), Dr. Wang and her colleagues discovered genetic alterations in endometrial cancer cell lines. The results from the genomic studies have successfully resulted in a Developmental Grant under the M. D. Anderson's Uterine SPORE program. Her studies led to other three first-author publications in Molecular Cancer, International Journal of Gynecological Cancer, and Current Protein & Peptide Science. Additionally, Dr. Wang contributed significantly to several other projects and co-authored a number of publications.
In October 2010, Dr. Wang returned to the Tianjin Medical University General Hospital to continue her career as a clinician scientist. In addition to being a surgeon, Dr. Wang continues to research on the molecular basis of endometrial cancer in collaboration with Dr. Zhang's group at MDACC. She won the first prize in research competition at the Tianjin Medical University in December 2010. She is the principal investigator of a provincial research project and a co-investigator in three projects funded by the National Natural Science Foundation of China. Dr. Wang's long-term career goal is to conduct gynecologic tumors research that will impact clinical treatment.
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