Antibody drug conjugates (ADCs) deliver therapeutic molecules preferentially to cancer cells compared to normal tissue. Unfortunately, ADCs penetrate poorly into most solid tumors and fail to cross the blood brain barrier, limiting utilityfor pressing needs in oncology. Our lab invented Tumor Paint, a peptide drug conjugate (PDC) that crosses the blood brain barrier and penetrates throughout brain tumors and other solid tumors. Tumor Paint, which is on track to enter clinical trials in late 2013, preferentially delivers indocyanine green (ICG) to cancer cells using a variant of CTX, a scorpion-derived knotted peptide as the targeting agent. Upon binding to cell surface Annexin II (Annexin A2) on cancer cells, CTX conjugates are rapidly internalized, which is ideal for imaging and also ideal for therapeutic delivery. Toward the goal of using knotted peptides (knottins) to deliver therapeutics to cancer cells, our team developed a platform that enables production of 10,000 peptide drug candidates in 3 weeks. We identified and overcame other major barriers to developing knotted peptides as targeting agents for cancer. We hypothesize that knottin peptides can be engineered to specifically and effectively deliver therapeutics to solid tumors.
Our Aims are to (1) Develop a clinical lead peptide-drug conjugate that preferentially delivers a radiosensitizer t brain tumors and (2) Identify a peptide drug conjugate that preferentially induces cell death in brain tumors. The significance of this work is that it creates a potentially superior alternative t ADCs for effective and safe delivery of therapeutics directly to brain tumors.

Public Health Relevance

Most cancer drugs fail to enter into the brain and are therefore not helpful to brain tumor patients. We previously discovered and developed Tumor Paint a scorpion-derived peptide that delivers fluorescent (light) molecules into brain tumors and illuminates the cancer but not normal brain. We now extend that work to create peptides that deliver potent chemotherapy or radiation sensitizing drugs specifically to brain tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Fu, Yali
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Fred Hutchinson Cancer Research Center
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Correnti, Colin E; Gewe, Mesfin M; Mehlin, Christopher et al. (2018) Screening, large-scale production and structure-based classification of cystine-dense peptides. Nat Struct Mol Biol 25:270-278
Pei, Yanxin; Liu, Kun-Wei; Wang, Jun et al. (2016) HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. Cancer Cell 29:311-323
Rosenthal, Eben L; Warram, Jason M; de Boer, Esther et al. (2016) Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report. J Nucl Med 57:144-50
Fidel, Janean; Kennedy, Katie C; Dernell, William S et al. (2015) Preclinical Validation of the Utility of BLZ-100 in Providing Fluorescence Contrast for Imaging Spontaneous Solid Tumors. Cancer Res 75:4283-91
Parrish-Novak, Julia; Holland, Eric C; Olson, James M (2015) Image-Guided Tumor Resection. Cancer J 21:206-12
Girard, Emily; Ditzler, Sally; Lee, Donghoon et al. (2015) Efficacy of cabazitaxel in mouse models of pediatric brain tumors. Neuro Oncol 17:107-15
Hubert, Christopher G; Bradley, Robert K; Ding, Yu et al. (2013) Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. Genes Dev 27:1032-45
Akcan, Muharrem; Stroud, Mark R; Hansen, Stacey J et al. (2013) Correction to Chemical Re-engineering of Chlorotoxin Improves Bioconjugation Properties for Tumor Imaging and Targeted Therapy. J Med Chem 56:9807
(2013) Correction to Chemical Re-engineering of Chlorotoxin Improves Bioconjugation Properties for Tumor Imaging and Targeted Therapy. J Med Chem 56:9807
Lee, Michelle J; Hatton, Beryl A; Villavicencio, Elisabeth H et al. (2012) Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc Natl Acad Sci U S A 109:7859-64

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