Targeting gene amplification in cancer using triplex formation as a therapeutic strategy
Disclosed herein are methods and agents for the treatment of cancer using p53-independent apoptosis to reduce the number of p53-depleted or p53-mutated cancer cells that have amplified HER2 gene. Also disclosed herein are methods and agents for the treatment of HER2-positive cancer in individuals with Li-Fraumeni Syndrome.
1 . A method of inducing DNA damage in cancer cells, the method comprising contacting the cancer cells with a first triplex forming oligonucleotide (TFO) and a second TFO, wherein:
(a) the cancer cells comprise an amplified HER2 gene that comprises a first polypurine target site and a second polypurine target site that is different from the first polypurine target site,
(b) the first TFO is complementary to and hybridizes to the first polypurine target site in the amplified HER2 gene, and the second TFO is complementary to and hybridizes to the second polypurine target site in the amplified HER2 gene, and
(c) hybridization of the first TFO to the first polypurine target site and the second TFO to the second polypurine target site in the amplified HER2 gene induces DNA damage in the cancer cells.
2 . The method of claim 1 , wherein the cancer cells are mammalian cancer cells.
3 . The method of claim 1 , wherein the cancer cells are human cells.
4 . The method of claim 1 , wherein each of the first and the second TFO has a length of 13 nucleotides to 30 nucleotides.
5 . The method of claim 4 , wherein each of the first and second TFO is in a delivery vehicle or is conjugated to a delivery vehicle.
6 . The method of claim 5 , wherein the delivery vehicle is a nanoparticle.
7 . The method of claim 1 , wherein each of the first and second TFO has backbone modifications.
8 . The method of claim 7 , wherein the backbone modifications include phosphorothioates, phosphorodithioates, methylphosphonates, phosphoramidates, boranophosphate oligos, polyamides, methylene(methylimino) linkages, morpholino oligos, or some combination thereof.
9 . The method of claim 1 , wherein the cancer cells are renal cell carcinoma cells, lung cancer cells, colon cancer cells, colon carcinoma cells, ovarian cancer cells, breast cancer cells, colorectal cancer cells, gastric cancer cells, endometrial cancer cells, brain cancer cells, cells of sarcoma of soft tissue or bone, bone cancer cells, adrenal tumor cells, leukemia cells, pancreatic cancer cells, bladder cancer cells, or hepatocellular carcinoma cells.