About

Xianxin Hua, M.D., Ph.D., is a Professor of Cancer Biology at the University of Pennsylvania's Perelman School of Medicine. He is a member of several research institutes including the Institute of Diabetes, Obesity, and Metabolism (IDOM), the Center for Liver and Digestive Diseases, the Center for Targeted Therapeutics and Translational Nanomedicine (CT3N), and the Institute of Translational Medicine and Therapeutics (ITMAT). Dr. Hua's research focuses on elucidating the molecular mechanisms by which the tumor suppressor and scaffold protein Menin regulates normal cells and cancers, particularly in the context of epigenetic regulation of gene transcription, beta cell signaling, and proliferation. His work investigates how the Menin pathway influences pancreatic beta cells, neuroendocrine tumors (NETs), colorectal cancer (CRC), and a subset of acute myeloid leukemia (AML). He has developed innovative platforms such as the Sequential Tumor-selected Antibody and antigen-Retrieval (STAR) platform to isolate tumor-specific nanobodies and is actively developing novel immunotherapies, including chimeric antigen receptor (CAR) T cells, to target NETs and AML. Dr. Hua's research employs a wide range of approaches including protein and cell engineering, synthetic biology, bioinformatics, gene editing, immunology, and immunotherapy, aiming to provide new insights into epigenetic regulation and to develop more effective treatments for these cancers.

Research topics

• Biology
• Cancer research
• Cell biology
• Internal medicine
• Chemistry

Selected publications

• Sa1294 MENIN SELECTIVELY PROMOTES COLORECTAL TUMORIGENESIS IN FAMILIAL ADENOMATOUS POLYPOSIS BUT NOT COLITIS-ASSOCIATED COLORECTAL CANCER

  Gastroenterology · 2026-05-01

  article
  PublisherDOI

• Sa1294 MENIN SELECTIVELY PROMOTES COLORECTAL TUMORIGENESIS IN FAMILIAL ADENOMATOUS POLYPOSIS BUT NOT COLITIS-ASSOCIATED COLORECTAL CANCER

  Gastrointestinal Endoscopy · 2026-05-01

  article
  PublisherDOI

• DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition

  Leukemia · 2025-03-27 · 3 citations

  articleOpen access

  Unbiased kinome-wide CRISPR screening identified DYRK1A as a potential therapeutic target in KMT2A-rearranged (KMT2A-R) B-acute lymphoblastic leukemia (ALL). Mechanistically, we demonstrate that DYRK1A is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human KMT2A-R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing KMT2A-R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased KMT2A-R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in KMT2A-R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.

  PublisherOA PDFDOI

• Data from Nanobody-Directed CEA-Targeting CAR T Cells Eliminate Gastrointestinal Cancer Xenografts

  2025-08-01

  preprintOpen accessSenior author

  <div>Abstract<p>Gastrointestinal cancers (GIC), including gastric cancers and colorectal cancers, are among the leading causes of cancer-related deaths worldwide. Metastatic gastric cancers and colorectal cancers often develop resistance or fail to respond to current therapies. Adoptive T-cell immunotherapy, especially with T cells expressing chimeric antigen receptors (CAR) targeting CD19, has revolutionized leukemia treatment. However, the development of CAR T-cell therapy for GICs is still in progress. In this study, we used a sequentially tumor-selected antibody and antigen retrieval system to isolate a nanobody that directs CAR T cells to attack gastrointestinal tumor cells in preclinical mouse models. The nanobody VHHB30 specifically binds to the N-terminal (nonglycosylated) domain of carcinoembryonic antigens (CEA). The resulting VHHB30-CAR T cells (CEACAR T cells) exhibited cytotoxicity against both colorectal cancer and gastric cancer cell lines <i>in vitro</i> in a CEA-dependent manner. Moreover, third-generation CEACAR T cells showed enhanced antitumor activity compared with second-generation CEACAR T cells. Furthermore, <i>in vivo</i> studies demonstrated that the CEACAR T cells eradicated various colorectal and gastric tumor xenografts in preclinical mouse models, highlighting a promising approach for CAR T-cell therapy development in GICs through unbiased <i>in vivo</i> selection of potent VHH binders.</p></div>

  PublisherDOI

• Nanobody-Directed CEA-Targeting CAR T Cells Eliminate Gastrointestinal Cancer Xenografts

  Cancer Immunology Research · 2025-05-29 · 5 citations

  articleSenior author

  Gastrointestinal cancers (GIC), including gastric cancers and colorectal cancers, are among the leading causes of cancer-related deaths worldwide. Metastatic gastric cancers and colorectal cancers often develop resistance or fail to respond to current therapies. Adoptive T-cell immunotherapy, especially with T cells expressing chimeric antigen receptors (CAR) targeting CD19, has revolutionized leukemia treatment. However, the development of CAR T-cell therapy for GICs is still in progress. In this study, we used a sequentially tumor-selected antibody and antigen retrieval system to isolate a nanobody that directs CAR T cells to attack gastrointestinal tumor cells in preclinical mouse models. The nanobody VHHB30 specifically binds to the N-terminal (nonglycosylated) domain of carcinoembryonic antigens (CEA). The resulting VHHB30-CAR T cells (CEACAR T cells) exhibited cytotoxicity against both colorectal cancer and gastric cancer cell lines in vitro in a CEA-dependent manner. Moreover, third-generation CEACAR T cells showed enhanced antitumor activity compared with second-generation CEACAR T cells. Furthermore, in vivo studies demonstrated that the CEACAR T cells eradicated various colorectal and gastric tumor xenografts in preclinical mouse models, highlighting a promising approach for CAR T-cell therapy development in GICs through unbiased in vivo selection of potent VHH binders.

  PublisherDOI

• Supplemental Figure 2 from Nanobody-Directed CEA-Targeting CAR T Cells Eliminate Gastrointestinal Cancer Xenografts

  2025-08-01

  preprintOpen accessSenior author

  <p>Supplemental Figure 2. Proliferation and of VHHB30 3rd Generation CAR T Cells in Co-Culture with NB4/NB4CEA Tumor Cells. A. The CAR positivity of VHHB30 third-generation CAR T-cells. B. Total CD3 positive T cells increased 7days after co-culture with VHHHB30 third-generation CAR T-cells while not much in comparison to co-culture with NB4 wild type. C, D. The UTD and CAR T-cells proliferating in coculture with target NB4CEA tumor cells, while the cells decreased in other groups indicating the antigen-dependent stimulation effect of the immune synapse between CAR T-cells and its target. E. NB4CEA tumor cell numbers as a CD33 positive cell population decreased in co-culture with VHHHB30 third-generation CAR T-cells after day 2 indicating the cytotoxicity effect of VHHHB30 third-generation CAR T-cells.</p>

  PublisherDOI

• Sa1212: MENIN PROMOTES COLONIC ADENOMA FORMATION IN MOUSE MODELS OF FAMILIAL ADENOMATOUS POLYPOSIS

  Gastroenterology · 2025-05-01

  article
  PublisherDOI

• Supplemental Figure 1 from Nanobody-Directed CEA-Targeting CAR T Cells Eliminate Gastrointestinal Cancer Xenografts

  2025-08-01

  preprintOpen accessSenior author

  <p>Supplemental Figure 1. The nucleotide sequence (A) and amino acid residue sequence (B) of nanobody VHHB30.</p>

  PublisherDOI

• Supplemental Table 1 from Nanobody-Directed CEA-Targeting CAR T Cells Eliminate Gastrointestinal Cancer Xenografts

  2025-08-01

  preprintOpen accessSenior author

  <p>Supplemental Table 1: Overview of Clinical Trials Investigating CEA-Targeted CAR T-cell Therapies in CEA-Positive Gastrointestinal and Solid Tumors</p>

  PublisherDOI

• <i>KMT2A</i>-Rearranged ALL Requires DYRK1A for Regulation of ERK Signaling and Cell Proliferation

  Blood · 2024-11-05

  articleOpen access

  Background: B-acute lymphoblastic leukemia (ALL) is the most common childhood cancer and is driven primarily by oncogenic chromosomal rearrangements and gene fusions. While overall survival rates are nearly 90% in children and about 40% in adults with good- and intermediate-risk ALL subtypes, clinical outcomes of patients with high-risk ALL subtypes, including KMT2A-rearranged (KMT2A-R), are significantly lower, posing an urgent need to develop novel therapeutic strategies for these patient populations. Results: To identify targetable kinases and potential precision medicine approaches in KMT2A-R ALL, we conducted domain-specific kinome-wide CRISPR screens and found the serine/threonine kinase DYRK1A essential for KMT2A-R ALL proliferation. The Cancer Dependency MAP suggests DYRK1A is non-essential for normal tissues, indicating a potential therapeutic window. RT-PCR and Western blot analyses showed increased DYRK1A expression levels in KMT2A-R ALL cell lines and patient-derived xenograft (PDX) samples compared to other leukemia subtypes, suggesting direct regulation by the KMT2A-fusion oncogene. Meta-analysis of ChIP-seq data confirmed direct binding of the KMT2A-fusion protein to the DYRK1A promoter. Inhibition of menin, a tumor suppressor protein that forms a complex with the KMT2A-fusion protein, reduced DYRK1A expression at RNA and protein levels and prevented the binding of the KMT2A-fusion protein to the DYRK1A promoter, validating the direct regulation of DYRK1A by the KMT2A-fusion oncogene. To test the consequence of direct pharmacologic inhibition of DYRK1A using EHT1610 and harmine, we treated multiple KMT2A-R ALL cell lines and PDX models, validating potent inhibition of leukemia cell growth without inducing apoptosis. Furthermore, we detected potent upregulation of MYC and hyperphosphorylation of ERK. Premature ERK signaling activation in developing B cells is known to induce cell cycle arrest as a protective mechanism to prevent the development of autoimmune diseases. We hypothesized that DYRK1A inhibitor-induced ERK hyperactivation leads to cell cycle arrest in KMT2A-R ALL via a similar mechanism. Supporting our hypothesis, combining DYRK1A inhibitors with the MEK inhibitor trametinib rescued KMT2A-R ALL cell proliferation, validating that ERK hyperactivation is the main driver of DYRK1A inhibitor-mediated cell cycle arrest. Interestingly, although DYRK1A inhibition mainly affected cell proliferation, we detected a potent increase in the pro-apoptotic molecule BIM. BIM is inactivated by the anti-apoptotic molecule BCL2, which was also slightly increased after DYRK1A inhibition, indicating that DYRK1A inhibitors could also sensitize KMT2A-R ALL cells to BCL2 inhibition (e.g., venetoclax). In support of our hypothesis, combined treatment with DYRK1A inhibitors and venetoclax synergistically killed KMT2A-R ALL cells in vitro. Given the poor pharmacodynamics and severe toxicity of EHT1610 and harmine, we synthesized a new DYRK1A inhibitor, GNF2133, and tested its activity in vitro against KMT2A-R ALL cell lines and in vivo +/- venetoclax in KMT2A-R ALL PDX models. Importantly, both GNF2133 and venetoclax were well tolerated in xenograft mice, and combination inhibitor therapy resulted in superior inhibition of in vivo leukemia proliferation and long-term animal survival. Conclusion: Our results identify DYRK1A as a critical regulator of ERK signaling in KMT2A-R ALL. DYRK1A inhibition leads to BIM accumulation, sensitizing cells to BCL2 inhibition by venetoclax in vitro and in vivo and resulting in therapeutic benefit in preclinical PDX models that is highly translatable to the clinic.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01CA113962

  NIH · $1.4M · 2012

• NIH Grant R01DK085121

  NIH · $1.4M · 2015

• NIH Grant R01CA100912

  NIH · $1.4M · 2011

• NIH Grant K01CA078592

  NIH · $625k · 2003

• Beta Cell Regeneration by an Epigenetic Pathway

  NIH · $1.4M · 2013–2018

Frequent coauthors

• Zijie Feng

  Second Affiliated Hospital of Xi'an Jiaotong University

  148 shared

• Smita Matkar

  104 shared

• Robert W. Schnepp

  102 shared

• Xin He

  94 shared

• Haoren Wang

  University of California, San Diego

  92 shared

• Austin Thiel

  89 shared

• Buddha Gurung

  Century Therapeutics (United States)

  85 shared

• Bryson W. Katona

  University of Pennsylvania

  82 shared

Labs

• Xianxin Hua LabPI

Education

• Ph.D, Department of Molecular Genetics

  The University of Texas Southwestern Medical Center at Dallas

  1995

• M.S., Medical Sciences

  Hubei Medical College

  1986

• M.D.

  Hubei Medical College

  1983

Awards & honors

• Member, Institute of Diabetes, Obesity, and Metabolism (IDOM…
• Member, Center for Liver and Digestive Diseases, University…
• Member, Center for Targeted Therapeutics and Translational N…
• Member, Institute of Translational Medicine and Therapeutics…
• Investigator, Abramson Family Cancer Research Institute