Abstract A110: The Identification of IGFBP-3 as a Clinically Relevant Target in the Treatment of PDAC-induced Skeletal Muscle Wasting and Testing the Efficacy of an Anti-IGFBP-3 Neutralizing Antibody
Calvin L. Cole, Zachary R. SechristAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, causes skeletal muscle wasting (SMW) in 80–85% of patients which accounts for ∼30% of patient deaths. In these patients, SMW reduces treatment tolerance and overall survival. However, no FDA-approved therapies exist. Our laboratory recently demonstrated that tumor-secreted insulin-like growth factor-binding protein 3 (IGFBP-3) is necessary and sufficient to induce SMW in murine PDAC models. Consistent with this, datasets show elevated IGFBP-3 expression in human PDAC tumors which is associated with reduced overall survival. These findings suggest that IGFBP-3 may be a promising therapeutic target. Thus, laboratory developed a novel neutralizing anti-IGFBP-3 antibody (NmAb). Here, we determine if IGFBP-3 is upregulated in the serum of patients with pancreatic cancer, evaluate the efficacy of our NmAb to attenuate SMW in a murine model of PDAC and neutralize human PDAC tumor-derived IGFBP-3, and test whether the secretion of IGFBP-3 by CAPAN-1 cells induce SMW in a xenograft mouse model.
Methods:
Serum and tumor samples from 7 patients with PDAC and 3 non-tumor bearing patients, were obtained from the URMC Biobank for IGFBP-3 ELISA and IHC analysis. Female C57BL/6 8-week-old mice (n=10) were inoculated with PDAC tumor cells and randomly assigned to treatment groups (vehicle control vs. NmAb treated (40mg/kg)). 8-week-old male and female NU/J nude mice were randomized to sham surgery or orthotopic injection of 5×105 CAPAN-1 cells (n=4/group/sex). Lean mass was assessed in all animals by dual-energy X-ray absorptiometry (DEXA). Murine C2C12 myotubes were treated with CAPAN-1 conditioned media (CM) for 24 hours and stained for myosin heavy chain to assess myotube diameter. Lastly, a chimeric anti-IGFBP-3 NmAb developed in our laboratory was added to CAPAN-1 CM to evaluate its neutralizing efficacy.
Results:
Patients with PDAC displayed significantly higher serum IGFBP-3 levels than control patients (p<0.01). In tumor-bearing patients, IGFBP-3 trended higher in stage III versus stage I–II disease (p=0.1637). IHC also showed increased IGFBP-3 protein expression in tumor vs. adjacent non-pathologic pancreas. Treatment with IGFBP-3 NmAb improved survival in treated animals compared to vehicle controls (Log-rank p<0.0001) and significantly attenuated SMW (p≤0.001). In C2C12 myotubes, CAPAN-1 CM treatment significantly reduced myotube diameter (p<0.05), which was attenuated with anti-IGFBP-3 NmAb treatment (p<0.05). Lastly, male and female NU/J mice bearing orthotopic CAPAN-1 tumors exhibited significant muscle loss beginning at week 6 versus non-tumor controls, as measured by DEXA (p<0.05).
Conclusions:
These findings suggest that serum IGFBP-3 is elevated in human PDAC patients and promotes SMW in clinically relevant in vitro and in vivo models. Moreover, our novel NmAb shows efficacy in improving survival and attenuating SMW in a murine model of PDAC. Future work will test the anti-IGFBP-3 NmAb in the CAPAN-1 xenograft model of SMW.
Citation Format:
Calvin L. Cole, Zachary R. Sechrist. The Identification of IGFBP-3 as a Clinically Relevant Target in the Treatment of PDAC-induced Skeletal Muscle Wasting and Testing the Efficacy of an Anti-IGFBP-3 Neutralizing Antibody [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A110.