Compositions and methods of treatment of drug resistant cancers

摘要

Time-staggered inhibition of EGFR, in combination with DNA damaging agents, is a useful therapeutic strategy for treating cancers, particularly drug resistant cancers such as a subset of triple-negative tumors, particularly those with high basal levels of phosphorylated EGFR. The staggered therapy was also demonstrated to be applicable to other types of tumors, especially lung cancers, which contain either high levels of phosphorylated wild-type EGFR or mutations within EGFR itself. EGFR inhibition dramatically sensitizes cancer cells to DNA damage if the drugs are given sequentially, but not simultaneously. The first drug must be administered in a dosage and for a period of time sufficient for the dynamic network rewiring of an oncogenic signature maintained by active EGFR signaling to unmask an apoptotic process that involves activation of caspase-8.

主权项

1. A method for treating a cancer in a subject in need thereof, wherein the cancer is resistant to a DNA-damaging chemotherapeutic agent, the method comprising:
administering to the patient an effective amount of a pharmaceutical composition comprising a liposome in a pharmaceutically effective excipient, wherein the liposome includes an aqueous interior layer and a lipophilic exterior layer, the lipophilic exterior layer including a hydrophobic inhibitor of an EGFR pathway, and the aqueous interior layer including a hydrophilic DNA-damaging chemotherapeutic agent, wherein the pharmaceutical composition further comprises a controlled release excipient, and wherein a therapeutically effective amount of the EGFR inhibitor is released at the time of administration, and a therapeutically effective amount of the DNA damaging agent is released at least four hours later.