Combined therapy of 4′-thio-5-aza-2′-deoxycytidine and Venetoclax
The present invention relates to the combination therapy of 4′-thio-5-aza-2′-deoxycytidine (Aza-T-dCyd), a multi-target inhibitor including a DNMT1 inhibitor, and Venetoclax, an inhibitor of BCL-2, which mediates apoptosis.
1 . A pharmaceutical composition for treating a solid tumor selected from the group consisting of colon cancer, bladder cancer, ovarian cancer, and lung cancer, or a hematologic cancer selected from the group consisting of MDS, AML, ALL, and CMML, comprising a 4′-thio-5-aza-2′-deoxycytidine drug and a venetoclax drug.
2 . A kit for treating a solid tumor selected from the group consisting of colon cancer, bladder cancer, ovarian cancer, and lung cancer, or a hematologic cancer selected from the group consisting of MDS, AML, ALL, and CMML, comprising a 4′-thio-5-aza-2′-deoxycytidine drug and a venetoclax drug.
3 . A method of treating a solid tumor selected from the group consisting of colon cancer, bladder cancer, ovarian cancer, and lung cancer, or a hematologic cancer selected from the group consisting of MDS, AML, ALL, and CMML, the method comprising administering to a subject in need thereof a 4′-thio-5-aza-2′-deoxycytidine drug and a venetoclax drug.
4 . The method according to claim 3 , wherein the 4′-thio-5-aza-2′-deoxycytidine drug and the venetoclax drug are co-administered in the same formulation or in different formulations.
5 . The method according to claim 3 , wherein the 4′-thio-5-aza-2′-deoxycytidine drug and the venetoclax drug are administered to the subject via the same route or different routes.
6 . The method according to claim 3 , wherein the 4′-thio-5-aza-2′-deoxycytidine drug and the venetoclax drug are administered to the subject as parenteral or oral administration.
7 . The method according to claim 3 , wherein the 4′-thio-5-aza-2′-deoxycytidine drug and the venetoclax drug are administered simultaneously or sequentially.
8 . The method according to claim 3 , wherein the 4′-thio-5-aza-2′-deoxycytidine drug is administered at 8 mg/day or more and less than 32 mg/day.
9 . The method according to claim 3 , the 4′-thio-5-aza-2′-deoxycytidine drug is administered at a dose of 25% to 75% of the maximum tolerated dose.
10 . The method according to claim 3 , wherein the 4′-thio-5-aza-2′-deoxycytidine drug reduces DNMT1 protein or inhibits DNMT1 in a concentration-dependent manner.
11 . The method according to claim 3 , wherein the 4′-thio-5-aza-2′-deoxycytidine drug is administered at a high dose that prevents the mechanisms of resistance development from overactivating base excision repair (BER), one of the methods of DNA damage repair.
12 . The method according to claim 3 , wherein the subject meets one or more of the following criteria:
(i) who has developed resistance to a DNMT1 inhibitor; who has accumulated altered epigenetic DNA methylation patterns in cancer cells relative to normal cells;
(ii) who has been informed of or diagnosed with a poor prognosis or potential for resistance to DNMT1 inhibitors; who has been diagnosed with an elevated level of lineage commitment master transcription factors selected from the group consisting of CEBP/alpha, Pu.1 and GATA factors, while expression of CEBP/epsilon or late developmental stage transcription factors remains low due to hypermethylation of each gene, relative to normal individuals;
(iii) who has a known or diagnosed risk of developing nucleoside metabolism resistance when receiving nucleoside-based anticancer agents;
(iv) who is a candidate for platinum-based anticancer agents; who have developed or are likely to develop resistance to platinum-based anticancer agents; and
(v) who is epigenetically silenced for tumor suppressor genes and/or SLFN11 relative to normal individuals.
13 . The method according to claim 3 , wherein the drug 4′-thio-5-aza-2′-deoxycytidine is administered as a targeted anti-cancer agent at or above a standard dosage of a DNMT1 inhibitor to a patient in need thereof who is limited in the standard dosage of a DNMT1 inhibitor as a standard therapy due to the fact that the DNMT1 inhibitor damages, thereby damaging normal tissue as well as cancer cells.
14 . The method according to claim 3 , wherein the subject is:
a patient diagnosed with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphocytic leukemia (ALL),
a patient with platinum-resistant recurrent end-stage ovarian cancer,
a patient with platinum-resistant metastatic bladder cancer,
a patient with metastatic bladder cancer,
a patient with p53 mutated bladder cancer or hypermethylated SLFN11 bladder cancer, which are specific biomarkers to be treated, or
a patient diagnosed with stage III or IV ovarian cancer.
15 . The method according to claim 3 , wherein the subject is:
a patient with chronic myelomonocytic leukemia (CML),
a patient with T-cell acute lymphoblastic leukemia (T-ALL),
a patient with chronic lymphocytic leukemia (CLL),
a high-risk patient with genomic abnormalities,
a patient with relapsed secondary AML (sAML),
a patient with treatment-related AML (t-AML) due to prior therapy, or
a drug-resistant/refractory patient.