Peyton High

All Publications

• LGR5: from stem cell marker to therapeutic target. Trends in cancer High, P. C., Cappellino, M. G., Blackburn, T. A., Carmon, K. S. 2026; 12 (6): 495-509

  Abstract

  Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is an established marker of normal and cancer stemlike cells. LGR5 has been implicated in promoting cancer cell plasticity that drives tumorigenesis, metastasis, and therapeutic resistance. LGR5 rapidly and constitutively internalizes and potentiates Wnt (Wingless/Int-1)/β-catenin and adhesion signaling pathways, though its precise mechanisms and interacting partners remain unresolved. An improved understanding of LGR5 signaling may provide invaluable insight into its intricate and important functions in cancer progression. Moreover, several LGR5-targeting therapies, including peptibody- and antibody-drug conjugates and bispecific antibodies, are showing promising efficacy and tolerability in colorectal cancer and other tumor types. This review discusses the cancer-related functions of LGR5 and explores the preclinical and clinical approaches to therapeutically target this enigmatic protein.

  View details for DOI 10.1016/j.trecan.2026.02.006

  View details for PubMedID 41942305

  View details for PubMedCentralID PMC13060024

• Bispecific antibody-drug conjugates targeting EGFR and LGR5 exert potent antitumor activity in colorectal cancer models BioRxiv High, P. C., Cappellino, M. G., Sullivan, S. P., Blackburn, T. A., Guernsey-Biddle, C., Liang, Z., Carmon, K. S. 2026

  View details for DOI 10.64898/2026.06.22.733843

• Antibody-drug conjugate combination therapy targeting LGR5 and MET with different payloads enhances efficacy in preclinical colorectal cancer models BioRxiv Subramanian, S., High, P. C., Guernsey-Biddle, C., Cappellino, M. G., Liang, Z., Aldana, A. M., Li, L., Pan, S., Carmon, K. S. 2026

  View details for DOI 10.64898/2026.07.18.739355

• Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models. Cell reports. Medicine High, P. C., Liang, Z., Guernsey-Biddle, C., Subramanian, S., Shyu, Y. M., Aldana, A. M., Toh, Y., Carmon, K. S. 2025; 6 (10): 102363

  Abstract

  Colorectal cancer (CRC) remains the second-leading cause of cancer-associated deaths, indicating an urgent need for improved therapeutic options. We previously generated antibody-drug conjugates (ADCs) targeting the cancer stem-like cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). However, tumor relapse due to LGR5 downregulation and suboptimal payload selection warrants strategies to improve ADC efficacy. Here, we report that cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody indicated for RASWT metastatic CRC, augments LGR5 expression independent of RAS/PIK3CA mutation status and promotes EGFR-LGR5 interactions. Furthermore, we describe the development of LGR5 ADCs incorporating a camptothecin-derived payload that is well tolerated and significantly inhibits tumor growth. Importantly, cetuximab in combination with LGR5 ADCs results in enhanced tumor inhibition or regression versus single-agent treatment and extends survival in RASMUT patient-derived xenografts. These findings support growing evidence that ADC combination therapies may be more effective than monotherapies and suggest a broader clinical use for cetuximab in treating RASMUT CRC.

  View details for DOI 10.1016/j.xcrm.2025.102363

  View details for PubMedID 40972582

  View details for PubMedCentralID PMC12629807

• Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Antitumor Activity in Colorectal Cancer. Cancer research Jacob, J., Anami, Y., High, P. C., Liang, Z., Subramanian, S., Ghosh, S. C., AghaAmiri, S., Guernsey-Biddle, C., Tran, H., Rowe, J., Azhdarinia, A., Tsuchikama, K., Carmon, K. S. 2025; 85 (5): 973-986

  Abstract

  As colorectal cancer remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wild-type (WT) and mutant colorectal cancer, with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG mAb, H231, which had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of zirconium-89-labeled H231, with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and the cytotoxicity of EREG ADCs was assessed in a panel of colorectal cancer cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing colorectal cancer cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed that EREG ADCs were well tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in colorectal cancer cell line and patient-derived xenograft models. These data suggest that EREG is a promising target for the development of ADCs for treating colorectal cancer and other cancer types that express high levels of EREG. Although the efficacy of clinically approved anti-EGFR mAbs is largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and WT patients, thus improving existing treatment options. Significance: EREG-targeting antibody-drug conjugates demonstrate acceptable safety and robust therapeutic efficacy in RAS mutant and wild-type colorectal cancer, suggesting their potential as an alternative to EGFR-targeted therapy to benefit a broader patient population.

  View details for DOI 10.1158/0008-5472.CAN-24-0798

  View details for PubMedID 39693606

  View details for PubMedCentralID PMC11875910

• Exploring the Potential of Epiregulin and Amphiregulin as Prognostic, Predictive, and Therapeutic Targets in Colorectal Cancer. Onco Guernsey-Biddle, C., High, P., Carmon, K. S. 2024; 4 (4): 257-274

  Abstract

  The epidermal growth factor receptor (EGFR) plays a critical role in regulating essential cellular processes that are frequently hijacked to promote cancer. In colorectal cancer (CRC) in particular, the EGFR signaling pathway is frequently hyperactivated via receptor and/or ligand overexpression and downstream oncogenic mutations. Current EGFR-targeted therapies for metastatic CRC (mCRC) include the monoclonal antibodies (mAbs) cetuximab and panitumumab. However, intrinsic and acquired resistance to EGFR-targeted mAbs are commonly observed. Thus, additional biomarkers are necessary to better understand patient sensitivity to EGFR-targeted therapies. Furthermore, therapeutic targeting of alternative EGFR pathway components may serve as one mechanism to overcome EGFR-targeted mAb resistance. In this review, we discuss the mounting evidence supporting EGFR ligands epiregulin (EREG) and amphiregulin (AREG), which are overexpressed in CRC with potential key roles in tumor progression, as predictive biomarkers for EGFR-targeted therapy sensitivity as well as mediators of therapy resistance; though further studies are necessary to validate the prognostic roles and mechanisms by which these ligands contribute to resistance. Additionally, we review recent advances towards therapeutic targeting of EREG and AREG in cancer through the development and use of EREG- and AREG-targeted monoclonal antibodies (mAbs) as well as antibody-drug conjugates (ADCs). We conclude with a discussion on the roadblocks to clinical implementation of EREG and AREG as biomarkers as well as approaches to enhance efficacy of current EREG- and AREG-targeted strategies.

  View details for DOI 10.3390/onco4040019

  View details for PubMedID 40727266

  View details for PubMedCentralID PMC12302966

• Demographics- and Performance-Based Differences in STEM Students' Entrepreneurial Mindsets JOURNAL OF CHEMICAL EDUCATION High, P., Dajani, J., Ainapurapu, S., Alagic, A. 2024; 101 (10): 4234-4241

  View details for DOI 10.1021/acs.jchemed.4c00544

  View details for Web of Science ID 001302029900001

• The Evolving Paradigm of Antibody-Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases. Pharmaceutics High, P., Guernsey, C., Subramanian, S., Jacob, J., Carmon, K. S. 2024; 16 (7)

  Abstract

  Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody-drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs.

  View details for DOI 10.3390/pharmaceutics16070890

  View details for PubMedID 39065587

  View details for PubMedCentralID PMC11279420

• G protein-coupled receptor-targeting antibody-drug conjugates: Current status and future directions. Cancer letters High, P., Carmon, K. S. 2023; 564: 216191

  Abstract

  In recent years, antibody-drug conjugates (ADCs) have emerged as promising anti-cancer therapeutic agents with several having already received market approval for the treatment of solid tumor and hematological malignancies. As ADC technology continues to improve and the range of indications treatable by ADCs increases, the repertoire of target antigens has expanded and will undoubtedly continue to grow. G protein-coupled receptors (GPCRs) are well-characterized therapeutic targets implicated in many human pathologies, including cancer, and represent a promising emerging target of ADCs. In this review, we will discuss the past and present therapeutic targeting of GPCRs and describe ADCs as therapeutic modalities. Moreover, we will summarize the status of existing preclinical and clinical GPCR-targeted ADCs and address the potential of GPCRs as novel targets for future ADC development.

  View details for DOI 10.1016/j.canlet.2023.216191

  View details for PubMedID 37100113

  View details for PubMedCentralID PMC11270908

• "Design a Sensor": Implementation of Entrepreneurial-Minded Learning in Undergraduate General Chemistry JOURNAL OF CHEMICAL EDUCATION High, P., Alagic, A. 2023; 100 (4): 1557-1563

  View details for DOI 10.1021/acs.jchemed.3c00057

  View details for Web of Science ID 000955001300001