Revealing the core mechanism of a novel inhibitor for the treatment of melanoma

On April 14, the skin disease clinical translation team under the Department of Dermatology, Xiangya Hospital, Central South University, and Hunan Engineering Research Center of Skin Health and Disease published the research paper titled “Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction” in Nature Communication (IF: 11.878) with Department of Dermatology, Xiangya Hospital, Central South University as the units of the first author and the co-corresponding author, Professor Yin Mingzhu as the first author, and Professor Chen Xiang, Professor Yin Mingzhu and Professor Yan Qin (from Yale University) as co-corresponding authors.

The study reveals for the first time that NHWD-870, the independently developed novel BET inhibitor, can suppress cancer cell-macrophage interaction, providing theoretical basis for effective treatment of solid tumors represented by melanoma by suppressing the novel epigenetic target BRD4. The study finds that the inhibitor increases activity by 5-50 times compared with that of similar compounds, can effectively reverse the drug resistance of tumors, and thus is expected to double the survival time of patients with advanced melanoma. As a Class 1.1 investigational new drug co-developed with Ningbo Wenda Pharmaceutical Technology Co., Ltd., NHWD-870 will enter the phase I clinical trial with melanoma as the main indication in this July, with Professor Chen Xiang of the Dermatology Department of Xiangya Hospital as the principal investigator (PI). It is expected to become an oncology drug that targets a key genetic driver of cancers, rather than a specific type of tumor, and thus brings new hope to patients with advanced melanoma and small cell lung cancer.

Cutaneous melanoma is a malignant tumor caused by abnormal proliferation of melanocytes. It has the characteristics of strong invasiveness, easy metastasis, and easy recurrence, ranking the first in the cause of death of skin tumors. In China, the most common clinical types of cutaneous melanoma are acral melanoma and mucosal melanoma, and the rate of onset is rapidly increased by 3-5% per year. Surgery has better treatment effect for early melanoma. However, 60-70% of patients have advanced cutaneous melanoma, with the 5-year survival rate of only 5% and extremely high degree of malignancy. At present, adjuvant interferon, conventional chemotherapy and other treatments are not effective.

“When some patients with advanced cancer have ‘no drugs available’, our novel targeted drug can bring them new hope, because it can delay the cancerization or even cure of certain cancers,” said Professor Yin Mingzhu. All this is due to NHWD-870, a BET inhibitor, discovered by the clinical translation team. This inhibitor has a clinical activity that is 5-50 times higher than that of similar compounds, and can easily reach the location of solid tumors, so that it can achieve good therapeutic effect at very low concentration.

Another major innovation of this study is that it reveals a new mechanism by which NHWD-870 regulates the tumor immune microenvironment. The study shows that a large number of macrophages in melanoma tissues express PDL-1 protein (nearly 50 times higher than its expression in tumors), which is one of the main reasons for the ineffectiveness/drug resistance of PD1/PDL1 antibody therapy. Currently, the first-line melanoma targeted therapy drug BRAF inhibitor and MEK inhibitor can cause drug resistance in most patients after 3-6 months of use, whereas, NHWD-870 kills macrophages by suppressing the cancer cell--macrophage interaction, resulting in low drug resistance or even reversal of drug resistance. Therefore, the combination use of this inhibitor with PD-1/PDL-1 antibody or other targeted drugs will have a better effect. “The average survival time of the patients with advanced melanoma is about 6 months, and from our preclinical animal experiments, the survival time might be doubled, and be expected to exceed one year,” said Professor Yin Mingzhu.

Based on the characteristics of high activity and reversal of drug resistance, NHWD-870 is expected to become an oncology drug that targets a key genetic driver of cancers, rather than a specific type of tumor. This study used nine mouse models and finds that it has an effect on solid tumors such as melanoma, ovarian cancer, breast cancer, and lung small cell lung cancer.

Revealing new pathogenesis of melanoma

Recently, Professor Chen Xiang and Professor Peng Cong’s team under the Department of Dermatology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Skin Cancer and Psoriasis, and Hunan Engineering Research Center of Skin Health and Disease, has published 2 research papers in Journal of Investigative Dermatology (a top academic journal in the field of dermatology) andOncogene(an internationally renowned oncology journal) in succession, revealing a new mechanism of melanoma pathogenesis.

The research paper titled“TRAF6 activates fibroblasts to cancer-associated fibroblasts (CAFs) through FGF19 in tumor microenvironment to benefit the malignant phenotype of melanoma cells” published in Journal of Investigative Dermatologywith PhD student Guo Ye and post-doctor Zhang Xu as the co-first authors; the research paper titled “The phosphorylation of CD147 by Fyn plays a critical role for melanoma cells growth and metastasis” published in Oncogene with post doctor Zhang Xu and Professor Huang Zunnan as the co-first authors. Professor Chen Xiang and Professor Peng Cong are co-corresponding authors of the two papers, and the Department of Dermatology, Xiangya Hospital, Central South University is the first corresponding unit.

The team from the Department of Dermatology, Xiangya Hospital has long been devoted to studying the mechanism of melanoma development, and has preliminary constructed a molecular network of melanoma with CD147 and TRAF6 as nodes, providing new strategies for its treatment. In the paper published in Journal of Investigative Dermatology, the team focuses on the tumor microenvironment and melanoma, and proves for the first time the important role of TRAF6 in the melanoma tumor microenvironment, which promotes FGF19 secretion through the NF-κB signaling pathway, leading to a significant increase in plasma FGF19 levels in patients with melanoma, and induces the activation of tumor-associated fibroblasts, promotes tumor cell growth and invasion and metastasis. This study reveals the new mechanism of melanoma pathogenesis.

CD147 plays an important role in the invasion and metastasis, energy metabolism and multi-drug resistance of melanoma. It is a highly glycosylated transmembrane protein that has been researched by Professor Chen Xiang’s team for more than two decades, and its glycosylated modification is closely related to CD147 maturation, cell membrane localization and other functions. In the paper published in Oncogene, the team from the Department of Dermatology discovers for the first time that CD147 can be modified not only by glycosylation but also by phosphorylation, and that there is a cross-talk between these two modifications. Inhibition of CD147 phosphorylation level can affect the binding of CD147 to the glycosyltransferase Gnt-V, thereby reducing the CD147 glycosylation level, affecting the invasion and metastasis of melanoma cells. This study reveals the new mechanism of CD147 post-translational modification in melanin.

It is reported that the team from the Department of Dermatology, Xiangya Hospital has long been devoted to the basic research, translational research and clinical research of skin malignant tumors, especially melanoma. The team has obtained many achievements in research papers, medical big data and biological samples, multidisciplinary team (MDT) construction, and building of network hospitals of skin diseases. The team led the establishment of the Skin Tumor Research Center of the Dermatology and Venereology Branch of the Chinese Medical Association and the Skin Tumor Professional Committee of the Dermatologist Branch of the Chinese Medical Doctor Association. In 2019, it set up the Xiangya International Melanoma Research Alliance composed of top international scholars.