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Published on: March 9, 2019
Unbiased Selection of Peptide-Peptoid Hybrids Specific for Lung Cancer Compared to Normal Lung Epithelial Cells
Jaya M Matharage1, John D Minna1, Rolf A Brekken1
1Advanced Imaging Research Center, ‡Simmons Comprehensive Cancer Center, §Hamon Center for Therapeutic Oncology Research, ∥Departments of Biochemistry, ⊥Pharmacology, #Internal Medicine, and ▽Surgery, University of Texas Southwestern Medical Center , 5323 Harry Hines Blvd., Dallas, Texas 75390, United States.
Abstract:
To develop widely applicable diagnostic and potentially therapeutic approaches overcoming protein heterogeneity in human cancer, we have developed a technology to unbiasedly select high specificity compound(s) that bind any biomolecule (e.g., proteins, lipids, carbohydrates) presented on the cancer cell surface but not on normal cells. We utilized a peptidomimetic based on-bead two-color (OBTC) combinatorial cell screen that can detect differences between two cell surfaces at high accuracy by looking for beads (where each bead in the library had one peptide-peptoid hybrid on the surface) that only bound cancer but not normal cells. We screened a library of 393 216 compounds targeting HCC4017 lung adenocarcinoma cells (labeled in red) in the presence of HBEC30KT normal bronchial epithelial cells (labeled in green) derived from the same tissue of the same patient. This screen identified a peptide-peptoid hybrid called PPS1 which displayed high specific binding for HCC4017 cancer cells over HBEC30KT cells. Specificity was validated through on-bead, ELISA-like and magnetic bead pulldown studies, while a scrambled version of PPS1 did not show any binding. Of interest, the simple dimeric version (PPS1D1) displayed cytotoxic activity on HCC4017 cells, but not on normal HBEC30KT cells. PPS1D1 also strongly accumulated in HCC4017 lung cancer xenografts in mice over control constructs. We conclude that such combinatorial screens using tumor and normal cells from the same patient have significant potential to develop new reagents for cancer biology, diagnosis, and potentially therapy.
Insights
Researchers developed a new screening technology to find compounds targeting cancer cells. A compound called PPS1D1 showed specific cancer cell binding and cytotoxic activity, offering potential for cancer diagnosis and therapy.
Area of Science:
- Oncology
- Biotechnology
- Chemical Biology
Background:
- Cancer cells exhibit unique surface biomolecules that can be targeted for diagnosis and therapy.
- Existing methods struggle with the heterogeneity of cancer cell surface markers.
- Developing highly specific compounds against cancer cells is crucial for effective treatment.
Purpose of the Study:
- To develop a technology for unbiased selection of specific compounds targeting cancer cell surface biomolecules.
- To identify novel compounds with diagnostic and therapeutic potential for human cancers.
- To overcome challenges posed by protein heterogeneity in cancer.
Main Methods:
- Utilized a peptidomimetic based on-bead two-color (OBTC) combinatorial cell screen.
- Screened a library of 393,216 compounds against lung adenocarcinoma (HCC4017) and normal bronchial epithelial cells (HBEC30KT) from the same patient.
- Validated compound specificity using on-bead, ELISA-like, and magnetic bead pulldown assays.
Main Results:
- Identified a peptide-peptoid hybrid, PPS1, with high specificity for HCC4017 cancer cells.
- A dimeric version, PPS1D1, demonstrated cytotoxic activity against HCC4017 cells but not normal cells.
- PPS1D1 showed significant accumulation in HCC4017 lung cancer xenografts in mice.
Conclusions:
- Combinatorial screening using patient-derived tumor and normal cells is effective for developing cancer-specific reagents.
- The identified PPS1D1 compound holds promise for cancer diagnosis and therapy.
- This technology offers a versatile approach to target cancer cell surface biomolecules.
