We hypothesize that our novel antisense DNA derivatives will be potent and specific therapeutics for breast, ovarian, and pancreatic cancer. Breast cancer will attack ~175,000 US women, and ovarian cancer ~25,000 US women, in 2000. The oncogene ERBB2 is amplified and overexpressed in over 30% of early and advanced stage mammary tumors, as well as ovarian malignancies. Pancreatic cancer will attack ~30,000 US men and women in 2000 and is fatal in virtually all patients. Most pancreatic tumors display K‑RAS oncogenes with 12th or 13th codon mutations, as do some ovarian tumors. Oligonucleotide therapeutics offer powerful tools for intervention against activated oncogenes in malignant cells. We will use them to ablate ERBB2 overexpression and tumor growth in breast cancer and ovarian cancer, and K‑RAS expression and tumor growth in ovarian and pancreatic cancer. Both oncogenes are activated in a broad spectrum of malignancies. Our previous NCDDG, collaborating with DTP/DCTD/NCI, yielded two unexpectedly powerful phosphorothioate lead sequences, NSC690185 against ERBB2, and NSC690187 against K‑RAS.
Our new NCDDG will analyze the mechanism of action of the leads, and test the hypothesis that more potent sequences and more potent derivatives may be discovered, permitting efficacy against disseminated malignancies. We will seek more susceptible mRNA targets, and synthesize several novel DNA derivatives of the lead sequences to find optimized leads with maximum potency against human tumor xenografts in immunocompromised mice. For each lead sequence, we will synthesize and test the potency of steric blocking peptide nucleic acid (PNA)-peptide conjugates, and RNase H-active 2’-O-methyl RNA/DNA/2’-O-methyl RNA phosphorothioate chimeras, a/b/a-anomeric DNA chimeras, DNA borane phosphonates, DNA-dendrimer conjugates, and DNA-peptide conjugates. Oligonucleotide mode(s) of action will be analyzed critically. The DNA derivatives will be administered parenterally and orally. Pharmacokinetics and toxicology will be assessed for the most potent oligonucleotide derivatives. Clinical and pharmaceutical partners will be identified to carry the lead compounds from this preclinical project forward to Phase I clinical trials.