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Updated: Apr 15, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study
Renata Pasqualini1,2, Randall E Millikan1,2, Dawn R Christianson1,2
1David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Background:
Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature.
Methods:
The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer.
Results:
BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine.
Conclusions:
These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients.
Insights
Researchers developed bone metastasis-targeting peptidomimetic-11 (BMTP-11) for targeting interleukin-11 receptor alpha (IL-11Rα) in cancer. Clinical trials showed BMTP-11 localized to tumors and induced apoptosis, establishing it as a targeted drug candidate.
Area of Science:
- Oncology
- Pharmacology
- Vascular Biology
Background:
- Tumor vasculature presents attractive targets for ligand-directed drug discovery.
- Systematic mapping of human endothelial receptors (
- vascular zip codes
- ) within tumors has been performed using direct peptide library selection in cancer patients.
- A ligand-binding motif to interleukin-11 receptor alpha (IL-11Rα) was previously identified in the human vasculature.
Purpose of the Study:
- To develop a ligand-directed, peptidomimetic drug (BMTP-11) for IL-11Rα-based human tumor vascular targeting.
- To evaluate the efficacy, toxicity, and pharmacokinetics of BMTP-11 in preclinical models and early-phase clinical trials.
- To establish BMTP-11 as a targeted drug candidate for metastatic, castrate-resistant prostate cancer.
Main Methods:
- Generation of BMTP-11, a peptidomimetic drug targeting IL-11Rα.
- Preclinical evaluation in prostate cancer xenograft models, including drug localization, apoptosis induction, and pharmacokinetic/pharmacodynamic analyses.
- Formal GLP toxicity studies in rodents and nonhuman primates.
- A single-institution, open-label, first-in-man clinical trial (NCT00872157) in patients with metastatic, castrate-resistant prostate cancer.
Main Results:
- BMTP-11 demonstrated preclinical promise and was advanced to clinical development.
- Biopsy-verified localization of BMTP-11 to bone marrow tumors was confirmed in patients.
- Drug-induced apoptosis was observed in all treated patients.
- The maximum tolerated dose was identified as 20-30 mg/m(2) on a weekly schedule.
- Dose-dependent, reversible nephrotoxicity was identified as the dose-limiting toxicity.
Conclusions:
- Biologic endpoints confirm BMTP-11's potential as a targeted drug candidate for metastatic, castrate-resistant prostate cancer.
- Functional tumor vascular ligand-receptor targeting systems can be identified through direct combinatorial selection of peptide libraries in cancer patients.
