Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability

Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.

Cost-utility analysis of sintilimab combined with chemotherapy in first-line treatment of advanced or recurrent non-small cell lung cancer / 中国药房

OBJECTIVE From the perspective o f China ’s h ealth service system ，to ev aluate the cost-effectiveness of sintilimab combined with chemotherapy in the first-line treatment of advanced or recurrent non-small cell lung cancer （NSCLC），so as to provide reference for the selection of clinical medication plan and medical and health decision-making. METHODS Based on the ORIENT-11 study data ，a partitioned survival model was established ，and the model period was 21 days to simulate the death of 99％ of the patients. Using quality-adjusted life years （QALY）as an output indicator ，the cost-effectiveness of sintilimab combined with chemotherapy （trial group ）versus chemotherapy alone （control group ）in the first-line treatment of advanced or recurrent NSCLC was evaluated. Cost and utility were discounted using 5％ discount rate ；sensitivity analysis and scenario analysis were used to verify the robustness of the underlying analysis results. RESULTS Under the premise that 3 times of the per capita gross domestic product （GDP）of China in 2020 was used as the threshold of willingness-to-pay （WTP），the patients in the trial group obtained more utility （0.482 QALY）and also spent nearly twice as much as the control group. The incremental cost-effectiveness ratio（ICER）was 334 974.41 yuan/QALY. Univariate sensitivity analysis showed that progression-free survival status utility value ， pemetrexed price ，utility discount rate ，cost discount rate and sintilimab price had a greater impact on ICER. The results of probability sensitivity analysis showed that when the WTP threshold was 3 times of China ’s per capita GDP in 2020，the probability of the trial group ’s plan being cost-effective was 6.5％. The results of the scenario analysis verified the robustness of the underlying analysis results. CONCLUSIONS On the premise of taking 3 times of China ’s per capita GDP in 2020 as the WTP threshold ， sintilimab combined with chemotherapy is not cost-effective for first-line treatment of advanced or recurrent NSCLC compared with chemotherapy alone.

Pharmacoeconomic evaluation of additional use of daratumumab in the treatment of transplant-ineligible newly diagnosed multiple myeloma / 中国药房

OBJECTIVE To evaluate the econ omical efficiency of daratumumab combined with lenalidomide and dexamethasone （D-Rd） regimen versus lenalidomide and dexamethasone （Rd） regimen alone in the treatment of transplant- ineligible newly diagnosed multiple myeloma （TNE-NDMM）. METHODS From the perspective of China ’s health system ，a partitioned survival model with three health states of progression free survival ，disease progression and death was established by using the published MAIA test data and relevant literature data. The model cycle was 28 days and the simulation time limit was 20 years. The incremental cost-effectiveness ratio （ICER）was calculated using quality-adjusted life years （QALY）as the output index. Sensitivity analysis was performed for key parameters. RESULTS The results of basic analysis showed that the ICER of D-Rd regimen versus Rd regimen was 2 719 038.08 yuan/QALY，far exceeding 3 times of GDP per capita in 2021（242 928 yuan）. The results of single factor sensitivity analysis showed that cost discount rate ，progression-free survival utility value ，utility discount rate，the cost of daratumumab and lenalidomide had a greater impact on ICER. Probabilistic sensitivity analysis suggested that the probability of economic advantage of D-Rd regimen was always 0 within the WTP range of 0-1 200 000 yuan. CONCLUSIONS Compared with Rd regimen ，D-Rd regimen has no cost-effectiveness advantage for the treatment of TNE-NDMM under the WTP of 3 times GDP per capita of China .