Photo of Bin Zheng,  PhD

Bin Zheng, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-9958


bin.zheng@cbrc2.mgh.harvard.edu

Bin Zheng, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Associate Professor, Dermatology, Harvard Medical School
  • Associate Investigator, Dermatology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

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 (clinicaltrials.gov. 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-induced immune suppression and evasion of immune elimination. Importantly, MDSCs have been suggested to contribute to resistance to various cancer therapies in melanoma, including to anti-CTLA-4 and anti-PD-1 blockade. Hence, targeting MDSCs presents an attractive approach to modulate tumor immunity to improve current cancer immunotherapies.

➣ 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.

Publications

Powered by Harvard Catalyst
  • Zhao H, Swanson KD, Zheng B. Therapeutic Repurposing of Biguanides in Cancer. Trends Cancer 2021. PubMed
  • Zhou Q, Kim SH, Pérez-Lorenzo R, Liu C, Huang M, Dotto GP, Zheng B, Wu X. Phenformin promotes keratinocyte differentiation via the calcineurin/NFAT pathway. J Invest Dermatol 2020. PubMed
  • Yu J, Yan J, Guo Q, Chi Z, Tang B, Zheng B, Yu J, Yin T, Cheng Z, Wu X, Yu H, Dai J, Sheng X, Si L, Cui C, Bai X, Mao L, Lian B, Wang X, Yan X, Li S, Zhou L, Flaherty KT, Guo J, Kong Y. Genetic Aberrations in the CDK4 Pathway Are Associated with Innate Resistance to PD-1 Blockade in Chinese Patients with Non-Cutaneous Melanoma. Clin Cancer Res 2019. PubMed
  • Zhao H, Zheng B. Dual Targeting of Autophagy and MEK in KRAS Mutant Cancer. Trends Cancer 2019; 5:327-329. PubMed
  • Li S, Lavagnino Z, Lemacon D, Kong L, Ustione A, Ng X, Zhang Y, Wang Y, Zheng B, Piwnica-Worms H, Vindigni A, Piston DW, You Z. Ca-Stimulated AMPK-Dependent Phosphorylation of Exo1 Protects Stressed Replication Forks from Aberrant Resection. Mol Cell 2019. PubMed
  • Strub T, Ghiraldini FG, Carcamo S, Li M, Wroblewska A, Singh R, Goldberg MS, Hasson D, Wang Z, Gallagher SJ, Hersey P, Ma'ayan A, Long GV, Scolyer RA, Brown B, Zheng B, Bernstein E. SIRT6 haploinsufficiency induces BRAF melanoma cell resistance to MAPK inhibitors via IGF signalling. Nat Commun 2018; 9:3440. PubMed
  • Kim SH, Li M, Trousil S, Zhang Y, Pasca di Magliano M, Swanson KD, Zheng B. Phenformin Inhibits Myeloid-Derived Suppressor Cells and Enhances the Anti-Tumor Activity of PD-1 Blockade in Melanoma. J Invest Dermatol 2017. PubMed
  • Casimiro MC, Di Sante G, Di Rocco A, Loro E, Pupo C, Pestell TG, Bisetto S, Velasco-Velázquez MA, Jiao X, Li Z, Kusminski CM, Seifert EL, Wang C, Ly D, Zheng B, Shen CH, Scherer PE, Pestell RG. Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis. Cancer Res 2017; 77:3391-3405. PubMed
  • Waldhart AN, Dykstra H, Peck AS, Boguslawski EA, Madaj ZB, Wen J, Veldkamp K, Hollowell M, Zheng B, Cantley LC, McGraw TE, Wu N. Phosphorylation of TXNIP by AKT Mediates Acute Influx of Glucose in Response to Insulin. Cell Rep 2017; 19:2005-2013. PubMed
  • Trousil S, Chen S, Mu C, Shaw FM, Yao Z, Ran Y, Shakuntala T, Merghoub T, Manstein D, Rosen N, Cantley LC, Zippin JH, Zheng B. Phenformin enhances the efficacy of ERK inhibition in NF1-mutant melanoma. J Invest Dermatol 2017. PubMed
  • Wu L, Zhou B, Oshiro-Rapley N, Li M, Paulo JA, Webster CM, Mou F, Kacergis MC, Talkowski ME, Carr CE, Gygi SP, Zheng B, Soukas AA. An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. Cell 2016; 167:1705-1718.e13. PubMed
  • Shen CH, Kim SH, Trousil S, Frederick DT, Piris A, Yuan P, Cai L, Gu L, Li M, Lee JH, Mitra D, Fisher DE, Sullivan RJ, Flaherty KT, Zheng B. Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nat Med 2016. PubMed
  • DeRan M, Yang J, Shen CH, Peters EC, Fitamant J, Chan P, Hsieh M, Zhu S, Asara JM, Zheng B, Bardeesy N, Liu J, Wu X. Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep 2014; 9:495-503. PubMed
  • Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B. Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A 2013. PubMed
  • Shen CH, Yuan P, Perez-Lorenzo R, Zhang Y, Lee SX, Ou Y, Asara JM, Cantley LC, Zheng B. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell 2013. PubMed
  • Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen CH, Wen J, Asara J, McGraw TE, Kahn BB, Cantley LC. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell 2013; 49:1167-75. PubMed
  • Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab 2012; 16:104-12. PubMed
  • Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13:376-88. PubMed
  • Zheng B,Jeong JH,Asara JM,Yuan YY,Granter SR,Chin L,Cantley LC. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 2009; 33:237-47. PubMed
Hide