2023
$100K Research Grant:
FGFR4 Cancer Therapy
Research Grant Summary
Project Title: A potent FGFR4-targeted antibody-drug conjugate therapy for rhabdomyosarcoma and other cancers
Principal Investigator: Meijie Tian, PhD
COG Institution: National Cancer Institute (Bethesda, MD)
Grant Amount: $100,000
The project in non-scientific terms
Children with recurrent and spread rhabdomyosarcoma have a dismal outcome, with overall survival at 20-30%. Despite decades of clinical trials, the treatment for RMS comprising chemotherapy, radiation therapy, and surgery has mainly remained the same for the last 30 years. Novel targeted therapies are desperately needed to improve outcomes for patients with high-risk diseases and reduce treatment-related toxicity. FGFR4 is a protein that is highly expressed on the surface of rhabdomyosarcoma cancer cells but at low levels in normal tissues. Our group is developing an FGFR4-targeted antibody-drug conjugate (ADC) that
can specifically kill cancer cells expressing FGFR4 while sparing normal tissue. We believe our ADC can substantially improve outcomes for patients with recurrent and spread rhabdomyosarcoma and other FGFR4-expressing cancers while reducing the side effects associated with conventional therapies.
What is the underlying issue that this project aims to solve?
Children with rhabdomyosarcoma (RMS) that has spread to other organs or has recurred despite treatment have a dismal overall survival of 20-30%. Despite decades of clinical trials, the treatment regimen for RMS comprising chemotherapy, radiation therapy, and surgery has remained largely the same for the last 30 years. Novel targeted therapies are desperately needed to improve outcomes for patients with high-risk diseases and reduce treatment-related toxicity.
Antibody-drug conjugate (ADC) is a form of immunotherapy that comprises a monoclonal antibody (mAb) conjugated to the cytotoxic payload via a chemical linker that is directed toward a target antigen expressed highly on the surface of cancer cells but at lower levels on the surface of normal tissue. This specificity
reduces systemic exposure and therefore toxicity. ADC therapy has had success in treating both hematological and solid malignancies, and 14 ADCs have been currently FDA-approved. Therefore, we aim to develop an FGFR4-targeted ADC to evaluate its anti-tumor efficacy in FGFR4 high-expressing cancers.
What are the specific aims of the research, and what steps will be taken to address them?
Our first aim is to develop an FGFR4-targeted ADC and validate its mechanisms in cell culture. This entails testing the ADC’s killing ability for different cancer tell types with varying levels of FGFR4 expression, as well as exploring the mechanisms by which the ADC facilitates the killing. Our second aim is to test the ADC’s anti-cancer efficacy in animal studies. Mice bearing tumors expressing FGFR4 will be treated with the ADC and observed for tumor shrinkage and survival. Finally, our ultimate aim is to bring the ADC to clinical trials at the NCI for patients with relapsed and refractory cancers with high FGFR4 expression.
What impact will this project have on future clinical trials and subsequent research efforts?
This study will determine the efficacy of our FGFR4-targeted ADC using different cancer cell lines in cell cultures and in animal models. Our study will provide a foundation for future clinical trials conducted in the NCI for patients with relapsed and refractory cancers that have high expression of FGFR4. Our study will
also shed light on the mechanisms of action for our FGFR4-targeted ADC.
