Optimization of the therapy targeting aggressive cancers by the D-VC drug combination developed in Kazakhstan.
The action of the drug is based on targeted chemotherapy. Our studies have shown that the stereoisomer of vitamin C (D-VC) is more effective and less toxic. The second component of the drug, ATO, enhances oxidative stress and leads to a cytotoxic effect selectively in cancer cells. A developed drug combination induces a cytotoxic oxidative stress in cancer cells mediated by the active uptake of glucose by these cells. Initially, the program was focused on suppressing malignant KRAS mutant cancers, which are known to actively consume glucose, but it is a common feature of many malignant cancers. Determining the types of cancers most sensitive to the combination of ATO and D-VC will be an important goal of this project and the genomic profiling of tumors will be most informative. Tumors are highly heterogeneous and identifying the most critical driver mutations will be instrumental in defining the types of cancers During clinical trials, a genomic profiling will determine the malignant types of cancer that are most sensitive to the ATO/D-VC drug combination. Optimization of target therapy of aggressive cancer types by complex treatment with D-VC developed in Kazakhstan
Creation of a new drug with a mechanism of induced glucose-dependent cytotoxic oxidative stress in cancer cells and development of an optimal regimen of antitumor therapy based on the use of its highest possible doses.
- New method of pharmacotherapy of KRAS – mutant types of cancer will be developed;
- The most tolerable and safe doses of D-VC and ATO will determined as a result of preclinical studies.
- clinical studies of the tolerability and safety (phase 1) of maximally tolerated high doses of D-VC with arsenic trioxide (ATO), justification of the optimal therapeutic dose regimen will conducted.
- The pharmacokinetics of D-VC will evaluated.
- Genomic profiling of tumors will performed to evaluate cancer types highly sensitive to glucose-dependent oxidative drug.
- An assessment of the effectiveness and safety (phase 2) of a new variant of antitumor therapy for KRAS-mutant types of cancer with the maximum tolerated doses of the studied drugs will carried out.
- The effectiveness of long-term results of therapy with glucose-dependent oxidative drugs D-VC and arsenic trioxide (ATO) will be evaluated (reduction of tumor volume and survival within 1 year).
- regulatory and technical documentation will be prepared for the licensing procedures for conducting phase 3 clinical trials and registration of a medicinal product (multicenter study).
- New dosage form D-VC will be developed, providing increased stability and commercial attractiveness.
Clinical trials (KazIOR, Almaty)
Phase I involved 10 patients with colorectal cancer to evaluate safety. The doses used were D-VC — 0.6 g/kg, ATO — 0.15 mg/kg. The phase remains open for other patient enrollments with other solid tumors.
Phase II included patients with colorectal and pancreatic cancer with KRAS mutations. The goal is to evaluate the effectiveness of D-VC and ATO therapy in previously established doses. 6 patients were included and it is planned to include up to 20 patients.
Preclinical studies are determining the maximum tolerated dose of ATO to increase the effectiveness of therapy. The effectiveness of the drugs has been confirmed in xenograft models. The tests are being conducted in the pharmacological testing laboratory of NDDA (National Center for Expertise of Medicines, Almaty).