This proposal advances the first-in-class synthesis and biological evaluation of protein-drug conjugates that feature engineered proteins (called betabodies) that target the lipid phosphatidylserine (PS). PS is in the inside part (inner leaflet) of the membrane that surrounds normal cells, but in cancer cells and cells lining tumor blood vessels, PS is flipped and exposed on the outside of the cell. In addition, PS exposed on cancer cells helps to suppress the immune response that fights cancer. Specific protein antibodies that attach to PS have demonstrated the ability to delay tumor growth in multiple mouse models of cancer. Betabodies also bind to PS, but since they are smaller than antib...

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This proposal advances the first-in-class synthesis and biological evaluation of protein-drug conjugates that feature engineered proteins (called betabodies) that target the lipid phosphatidylserine (PS). PS is in the inside part (inner leaflet) of the membrane that surrounds normal cells, but in cancer cells and cells lining tumor blood vessels, PS is flipped and exposed on the outside of the cell. In addition, PS exposed on cancer cells helps to suppress the immune response that fights cancer. Specific protein antibodies that attach to PS have demonstrated the ability to delay tumor growth in multiple mouse models of cancer. Betabodies also bind to PS, but since they are smaller than antibodies, they show better penetration of tumors such as pancreatic and lung. Exposed PS provides an exquisite opportunity for selective targeting of tumors. In this innovative proposal, very potent small-molecule anticancer drugs (KGP18 and KGP156) discovered in our labs will be attached to betabodies (provided by Dr. Rolf Brekken, UTSW) to form betabody-drug conjugates (BDCs) through a chemical linker that can be cut by enzymes that are secreted by cancer cells. KGP18 and KGP156 work by two mechanisms: 1) they are extremely cytotoxic to cancer cells, and 2) they damage tumor blood vessels leading to massive tumor cell death while leaving normal blood vessels unaffected. Our hypothesis is that these drug-linkers and BDCs will demonstrate high selectivity for tumor vasculature and tumor cells. The workplan includes: 1) synthesis of drug-linker constructs; 2) evaluation to make sure that enzymes secreted by cancer cells can cut the linkers and release the drugs; 3) synthesis of betabody drug conjugates (BDCs); 4) evaluation of BDCs to ensure binding to PS and cytotoxicity to cancer cells. These proof-of-concept studies will guide future translational advancement of BDCs for the treatment of breast, pancreatic and lung cancers.

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