# Unravel the role of CD276 and determine efficacy of CD276-targeted therapy on Merkel cell carcinoma progression and metastasis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2023 · —

## Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin with a dismal five-year
survival rate of less than 18% in advanced disease and a mortality rate 3-times higher than melanoma. MCC
disproportionately and predominantly affects Caucasian males older than 65, who are well represented among
Veterans, and more than 5000 new MCC cases have been diagnosed among Veterans. Hence, MCC has a
growing impact on Veterans’ health and VA healthcare system. Notwithstanding the approval of immunotherapy,
treating metastatic MCC remains a challenge. Thus, we are compelled to seek novel therapies to overcome
resistance, or to serve as definitive treatments for MCC patients who are ineligible for immunotherapy due to
comorbidities.
 In this proposal, we will collaborate with VA Medical Centers encountering most Veteran MCC patients to
define the role of B7-H3 (encoded by CD276) in MCC patient survival in a large cohort of Veteran patients.
Moreover, we will determine the efficacy of CD276-targeted therapy, as its overexpression has been associated
with poor outcome in a myriad of advanced human cancer including MCC. Our collaborator, Dr. St. Croix at the
National Cancer Institute, has developed a novel antibody-drug conjugate (ADC, m276-SL-PBD), which couples
CD276 antibody with a cytotoxic DNA-binding agent PBD. Notably, m276-SL-PBD confers robust anti-tumor
activities and long-term durability in a range of preclinical models, including our MCC cell line-derived xenograft
(CDX) models (preliminary data leading to this proposal). Remarkably, m276-SL-PBD effectively prevents
resistance by directly eradicating heterogenous cancer cells including cancer stem cells, tumor vasculatures
and tumor stromal cells, where CD276 upregulation is endowed. Therefore, we postulate that m276-SL-PBD is
a superior anti-MCC drug with sustainable response, underscoring a novel therapeutic advance in MCC.
 To overcome barriers, we have successfully established unique and robust models for MCC preclinical
studies including multiple primary MCC cell lines, CDX, and patient tumor-derived xenograft (PDX) models with
reconstituted human immune system. To simulate clinical scenario, we have first established human metastatic
MCC cell lines with propensity for spontaneous visceral dissemination after subcutaneous inoculation in mice.
Due to its finite resource, we will utilize single mouse testing (SMT)-base PDX trial strategies that are
increasingly used to better capture inter-tumor heterogeneity and generate highly clinically relevant preclinical
evidence. The cost-effectiveness of SMT-based studies allow to encompass a large cohort of patient tumors
and evaluate heterogeneous drug effects across patients, which is of particular importance in rare cancer
preclinical studies including MCC.
 Hence leveraging our singularly powerful patient MCC-derived models, we are ideally positioned to pursue
proposed studies: 1) to determine safety, therapeutic efficacy, and direc...

## Key facts

- **NIH application ID:** 10584403
- **Project number:** 1I01CX002497-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Ling Gao
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10584403

## Citation

> US National Institutes of Health, RePORTER application 10584403, Unravel the role of CD276 and determine efficacy of CD276-targeted therapy on Merkel cell carcinoma progression and metastasis (1I01CX002497-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10584403. Licensed CC0.

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