Introduction

The present invention relates to a new molecular therapeutic approach that allows reversing the resistance to chemotherapeutic agents based on conventional cytostatics, such as cisplatin, which represents the standard of care for many solid and hematological tumors. The proposed technology also allows containing the toxicity of chemotherapeutic agents through a selective and safe molecular approach.

Technical features

Cisplatin has been shown to require a specific molecular mechanism, involving IkB-alpha from NFkB, to trigger cell death. The molecules involved in this mechanism are sometimes subject to genetic alterations, which make the cells resistant to chemotherapy. Using various in silico approaches, 230 million compounds from the ZINC database were analyzed and four compounds were identified capable of interacting with the proteins involved in this molecular mechanism to reverse resistance and thus make cells sensitive to chemotherapeutics. In vivo studies of the identified compounds allowed to obtain optimal responses on the tumor, without presenting toxicity for the patient.

The toxicity of chemotherapy is one of the main limitations of this type of treatment, which sometimes contraindicates the treatment or causes significant toxic effects to the patient. Acting on the molecular mechanism with the identified compounds allows to contain the toxicity of the chemotherapy because, by maximizing the response, allowing to use a lower dose of chemotherapy than the standard one.

Possible Applications

• Use of the two molecules already selected for the treatment of metastatic solid tumors, in combination with conventional cytostatics;
• Use of the two molecules already selected for the treatment of hematological cancers (such as some forms of lymphoma), in combination with conventional cytostatics;
• Drug repositioning: identification of a clinically tested drug able to interact with the molecules involved with the identified mechanism.

Advantages

• Increased response to conventional cytostatics, such as cisplatin;
• Reduction of cytostatics doses and consequent containment of toxicity due to treatment with chemotherapeutic agents.