Bin Zheng, Ph.D.

Associate Professor of Dermatology
Harvard Medical School
Associate Investigator
Cutaneous Biology Research Center, Mass General Research Institute
PhD UC San Diego 2002
3d genome organization; ampk; bladder cancer; braf; cancer cell metabolism; cancer epigenetics; cancer immunotherapy; cohesin complex; ctcf; drug resistance; genes tumor suppressor; immune checkpoint blockade; immunometabolism; io; mdsc; mek/erk pathway; melanoma; metabolic heterogeneity; metabolic signaling; metformin; pd-1; phenformin; stag2; targeted therapies

Our laboratory is working to decipher the molecular alterations in metabolic regulation and signal transduction that drives cancer, with a focus on melanoma. Our goal is to translate these findings into personalized targeted and immunotherapies, contributing to finding cures for melanoma.

Approximately half of all cutaneous melanomas harbor a mutation in BRAF (BRAF V600E) that drives cancer growth by constitutively activating downstream MEK/ERK signaling. The “addiction” of melanomas harboring this mutation has stimulated the development of BRAF inhibitors (BRAFi), including Vemurafenib and Dabrafenib. These BRAFi show great clinical benefit in malignant melanoma with BRAF V600E mutations in the initial phase of treatment. However, the vast majority of the responsive patients treated with these inhibitors develop resistance and relapse during the course of treatment. In addition to BRAF-targeted therapy, another recent groundbreaking approach in melanoma treatment involves targeting the immune checkpoints that counter melanoma’s intrinsically high immunogenicity. Biological drugs that target PD-1 or PD-L1 have shown significant clinical benefit in melanoma patients and have produced a high degree of durable responses, However, these outcomes are only achieved in a subset of patients. Therefore, overcoming BRAFi resistance and improving the response rates of immune checkpoint blockade therapies and represent two of the greatest challenges facing this field. The central goal of our research is to address these outstanding problems by gaining a better understanding of metabolic programming and signal transduction in melanoma and translate these basic research findings into better strategies for melanoma prevention, diagnosis and treatment. Preclinical work from our laboratory on a central metabolic regulator, AMP activated protein kinase (AMPK) and repurposing of phenformin, a previously approved diabetes drug,  provided the basis for a Phase I clinical trial evaluating phenformin with the dabrafenib BRAF inhibitor and trametinib MEK inhibitor combination in patients with BRAF mutant melanoma ( NCT03026517).

We have been working on the following specific projects:

  • Metabolic regulation of tumor immunity.  We are pursuing the characterization of  the metabolic vulnerabilities of myeloid-derived suppressor cells (MDSCs). MDSC is a major immune cell type that contributes to tumor-inducedimmune suppression and evasion of immune elimination. Importantly, MDSCs havebeen suggested to contribute to resistance to various cancer therapies in melanoma, including to anti-CTLA-4 and anti-PD-1 blockade. Hence, targeting immunometabolism of MDSCs presents anattractive approach to modulate tumor immunity to improve current cancerimmunotherapies.
  • Roles of AMPK at the interface of metabolism and cancer.  We have an interest in understanding the role of AMPK in melanoma tumor development and progression.  We are investigating downstream metabolic targets of AMPK in melanoma cells. In addition, we are characterizing the role of AMPK in modulating the function of MDSCs in the tumor microenvironment.  
  • Repurposing phenformin for cancer therapy.  We continue to elucidate the mechanism of action for the anti-tumor activities of phenformin, and to facilitate the translational studies on repurposing phenformin for cancer prevention and treatment.  
  • Metabolic rewiring and BRAFi resistance.  We are exploring metabolic changes that occur during the development of BRAFi resistance in melanoma and characterizing metabolic vulnerabilities that can be targeted to overcome BRAFi resistance in melanoma. These efforts may lead to better combinatory therapeutic strategies in melanoma. 
  • Metabolic heterogeneity in melanoma.  Intratumor phenotypic heterogeneity has been shown to influence drug resistance and metastasis. In melanoma, a slow-cycling subpopulation of cells that is marked by expression of the H3K4 histone lysine demethylase KDM5B has previously been identified. We are therefore characterizing KDM5B-dependent metabolic heterogeneity in melanoma and explore its therapeutic implications. 
  • Alterations of 3D genome organization in melanoma.  Mammalian genomes are folded in a highly organized fashion within the nucleus. The cohesin complex participates in the required 3D organization that regulates gene expression through generating and maintaining DNA loops. We recently discovered that loss of the tumor suppressor STAG2, which encodes a core subunit of the cohesin complex,  as a novel mechanism of resistance to BRAF pathway inhibition in melanoma. We are currently characterizing direct targets of STAG2 in melanoma through various cutting edge epigenomic approaches, which will provide insights into how STAG2 contributes to malignant phenotypes in cancer.






Research lab website Publications
Cutaneous Biology Research Center
CNY-Building #149
149 13th Street
Charlestown, MA 02129