Methods of treating cancer harboring hemizygous loss of TP53
Provided herein are methods of treating a patient having a cancer that exhibits (i) a hemizygous loss of the TP53 gene; (ii) a hemizygous loss of the POLR2A gene; and/or (iii) a decreased level of expression of a POLR2A gene product relative to a reference (i.e., control) expression level. The methods comprise administering a therapeutically effective amount of a POLR2A inhibitor (e.g., a nucleic acid that inhibits the expression of a POLR2A protein, an amatoxin, alpha-amanitin, or alpha-amanitin conjugated to a cell targeting moiety, such as an EpCAM antibody) to a patient having or determined to have (i) a hemizygous loss of the TP53 gene; (ii) a hemizygous loss of the POLR2A gene; and/or (iii) a decreased level of expression of a POLR2A gene product relative to a reference (i.e., control) level.
1. A method of treating a patient having cancer comprising:
(a) selecting a patient determined to have cancer cells comprising (i) a hemizygous loss of the TP53 gene; (ii) a hemizygous loss of the POLR2A gene; or (iii) a decreased level of expression of a POLR2A gene product relative to a reference level; and
(b) administering a therapeutically effective amount of POLR2A inhibitor to the patient, wherein the POLR2A inhibitor comprises an amatoxin, and wherein the amatoxin is conjugated to an antibody that specifically binds to a tumor-associated antigen.
2. The method of claim 1 , wherein the amatoxin is alpha-amanitin.
3. The method of claim 1 , wherein the POLR2A gene product is an mRNA.
4. The method of claim 1 , wherein the POLR2A gene product is a protein.
5. The method of claim 1 , wherein the reference expression level is an expression level in non-cancerous cells.
6. The method of claim 1 , wherein the cancer cells have been determined to exhibit a hemizygous loss of the TP53 gene.
7. The method of claim 1 , wherein the cancer cells have been determine to exhibit a hemizygous loss of the POLR2A gene.
8. The method of claim 1 , wherein the patient has cancer cells that exhibit a decreased level of expression of a POLR2A gene product relative to a reference expression level.
9. The method of claim 1 , wherein the cancer cells are lung cancer, brain cancer, breast cancer, liver cancer, ovarian cancer, colorectal cancer, prostate cancer, or pancreatic cancer cells.
10. The method of claim 1 , wherein the cancer cells are metastatic, recurrent, or multi-drug resistant.
11. The method of claim 1 , further comprising administering at least a second anticancer therapeutic.
12. The method of claim 11 , wherein the second anticancer therapeutic is a chemotherapeutic agent.
13. The method of claim 12 , wherein the chemotherapeutic agent is 5-fluorouracil, oxaliplatin, or SN-38.
14. The method of claim 1 , wherein the patient is a human.
15. The method of claim 1 , wherein the patient is a non-human mammal.
16. The method of claim 1 , wherein the patient has previously undergone at least one round of anti-cancer therapy.