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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA135491-06
Application #
8762325
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2008-07-01
Project End
2019-08-31
Budget Start
2014-09-19
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$396,000
Indirect Cost
$171,000
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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