Drug Administration Strategies Research Articles

Optimal administration strategy in chemotherapy regimens using multi-drug cell-cycle specific tumor growth models

During the last decades, various chemotherapeutic drugs have been developed to treat cancer, which makes the chemotherapy design more complicated. To determine optimal drug regimens for patients with colorectal cancer, this study extends two multi-drug cell-cycle specific tumor growth models with distinct action mechanisms. To this end, two of the most commonly used drugs in treating colorectal cancer, namely 5-FU and CPT-11, are assumed. In the extended compartmental models, drug resistance and toxicity are taken into account, and two constraints are imposed to limit the drug dosages during the therapy. Two different drug administration strategies are proposed. In the first strategy, drugs are injected sequentially, while in the second, drugs are simultaneously administered. To minimize the tumor size at the end of therapy or equivalently to prolong the patient’s survival time, an optimal control problem is defined and solved using the genetic algorithm (GA). The in silico results for a variety of scenarios based on the patient’s health conditions demonstrate that the simultaneous approach outperforms the sequential strategy and yields superior results. To verify the resultant findings, a robust evaluation with uncertain model parameters is also performed, which again shows the superiority of the simultaneous strategy.

Prevalence of Plasmodium falciparum gametocytaemia in asymptomatic school children before and after treatment with dihydroartemisinin-piperaquine (DP)

BackgroundAsymptomatic Plasmodium carriers form the majority of malaria-infected individuals in most endemic areas. A proportion of these asymptomatically infected individuals carry gametocytes, the transmissible stages of malaria parasites, that sustain human to mosquito transmission. Few studies examine gametocytaemia in asymptomatic school children who may form an important reservoir for transmission. We assessed the prevalence of gametocytaemia before antimalarial treatment and monitored clearance of gametocytes after treatment in asymptomatic malaria children. MethodsA total of 274 primary school children were screened for P. falciparum parasitaemia by microscopy. One hundred and fifty-five (155) parasite positive children were treated under direct observation with dihydroartemisinin-piperaquine (DP). Gametocyte carriage was determined by microscopy seven days prior to treatment, day 0 before treatment, and on days 7, 14 and 21 post initiation of treatment. ResultsThe prevalence of microscopically-detectable gametocytes at screening (day −7) and enrolment (day 0) were 9% (25/274) and 13.6% (21/155) respectively. Following DP treatment, gametocyte carriage dropped to 4% (6/135), 3% (5/135) and 6% (10/151) on days 7, 14 and 21 respectively. Asexual parasites persisted in a minority of treated children, resulting in microscopically detectable parasites on days 7 (9%, 12/135), 14 (4%, 5/135) and 21 (7%, 10/151). Gametocyte carriage was inversely correlated with the age of the participants (p = 0.05) and asexual parasite density (p = 0.08). In a variate analysis, persistent gametocytaemia 7 or more days after treatment was significantly associated with post-treatment asexual parasitaemia at day 7 (P = 0.027) and presence of gametocytes on the day of treatment (P < 0.001). ConclusionsThough DP provides both excellent cure rates for clinical malaria and a long prophylactic half-life, our findings suggest that after treatment of asymptomatic infections, both asexual parasites and gametocytes may persist in a minority of individuals during the first 3 weeks after treatment. This indicates DP may be unsuitable for use in mass drug administration strategies towards malaria elimination in Africa.

Modelling mass drug administration strategies for reducing scabies burden in Monrovia, Liberia.

Scabies is a parasitic infestation with high global burden. Mass drug administrations (MDAs) are recommended for communities with a scabies prevalence of >10%. Quantitative analyses are needed to demonstrate the likely effectiveness of MDA recommendations. In this study, we developed an agent-based model of scabies transmission calibrated to demographic and epidemiological data from Monrovia. We used this model to compare the effectiveness of MDA scenarios for achieving scabies elimination and reducing scabies burden, as measured by time until recrudescence following delivery of an MDA and disability-adjusted-life-years (DALYs) averted. Our model showed that three rounds of MDA delivered at six-month intervals and reaching 80% of the population could reduce prevalence below 2% for threeyears following the final round, before recrudescence. When MDAs were followed by increased treatment uptake, prevalence was maintained below 2% indefinitely. Increasing the number of and coverage of MDA rounds increased the probability of achieving elimination and the number of DALYs averted. Our results suggest that acute reduction of scabies prevalence by MDA can support a transition to improved treatment access. This study demonstrates how modelling can be used to estimate the expected impact of MDAs by projecting future epidemiological dynamics and health gains under alternative scenarios.

Intranasally administered thermosensitive gel for brain-targeted delivery of rhynchophylline to treat Parkinson’s disease

The aim of this study is to overcome the obstacle of the blood-brain barrier (BBB) in therapeutic drugs of Parkinson's disease (PD), like rhynchophylline (RIN) entry by intranasal administration and to solve the problem of short residence time of drugs in the nasal cavity by the dosage form design of thermosensitive gel. We first conducted a study of the screening of absorption enhancers and 3% hydroxypropyl-β-cyclodextrin (HP-β-CD) was effective to improve the nasal mucosal permeability of RIN. By adjusting the ratio of different components in order to make the gel with adhesion and rapid gelation which were determined to be Poloxamer 407 (P407) 20%, Poloxamer 188 (P188) 1%, polyethylene glycol 6000 (PEG-6000) 1% and HP-β-CD 3%. In addition, the characterization showed that the thermosensitive gel was network cross-linked, rapidly gelation upon entry into the nasal cavity and was stable as semi-solid state with adhesion as well as sustained release properties. Moreover, pharmacokinetic study was performed to evaluate the bioavailability and brain targeting of RIN thermosensitive gel and which were 1.6 times and 2.1 times higher than those of oral administration. We also evaluated the anti-PD effects of RIN thermosensitive gel in-vitro as well as in-vivo. The results showed that RIN thermosensitive gel was effective in repairing the motor function impairment, dysregulated expression levels of oxidative stress factors, and positive neuronal damage within the substantia nigra and dopamine caused by PD. The constructed intranasal drug administration strategy through thermosensitive gel provided a new choice for targeted treatment of PD together with other central nervous system diseases.

A bibliometric research based on hotspots and frontier trends of denosumab.

Denosumab is a monoclonal antibody that targets and inhibits the osteoclast activating factor receptor activator for nuclear factor-κB ligand (RANKL). It has been widely used in the treatment of osteoporosis, giant cell tumors of bone, and in the prevention of malignant skeletal-related events (SREs). We collected the research results and related MeSH terms of denosumab from 2011 to 2021 through the Web of Science and PubMed, respectively. The literature was visualized and analyzed by CiteSpace and bibliometric online analysis platforms. The MeSH terms were biclustered using the Bibliographic Co-Occurrence Analysis System (BICOMB) and graph clustering toolkit (gCLUTO). The results show that the number of denosumab-related annual publications had increased from 51 to 215, with the United States leading and Amgen Inc. being the most influential in the past 10 years. Articles published in the Journal of Bone and Mineral Research had the highest total citations. Three scholars from Shinshu University in Matsumoto, Yukio Nakamura, Takako Suzuki, and Hiroyuki Kato, joined the field relatively late but produced the most. The clinical comparison and combination of denosumab with other drugs in the treatment of osteoporosis was the most significant focus of research. Drug withdrawal rebound and management strategies have gained more attention and controversy recently. MeSH analysis revealed eight major categories of research hotspots. Among them, exploring the multiple roles of the RANK-RANKL-OPG system in tumor progression, metastasis, and other diseases is the potential direction of future mechanism research. It is a valuable surgical topic to optimize the perioperative drug administration strategy for internal spinal fixation and orthopedic prosthesis implantation. Taken together, the advantages of denosumab were broad and cost-effective. However, there were still problems such as osteonecrosis of the jaw, severe hypocalcemia, a high recurrence rate of giant cells in the treatment of bone and individual sarcoidosis, and atypical femoral fractures, which need to be adequately solved.

Physiologically based pharmacokinetic (PBPK) modeling of flurbiprofen in different CYP2C9 genotypes.

The aim of this study was to establish the physiologically based pharmacokinetic (PBPK) model of flurbiprofen related to CYP2C9 genetic polymorphism and describe the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes. PK-Sim® software was used for the model development and validation. A total of 16 clinical pharmacokinetic data for flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups were used for the PBPK modeling. Turnover number (kcat) of CYP2C9 values were optimized to capture the observed profiles in different CYP2C9 genotypes. In the simulation, predicted fraction metabolized by CYP2C9, fraction excreted to urine, bioavailability, and volume of distribution were similar to previously reported values. Predicted plasma concentration-time profiles in different CYP2C9 genotypes were visually similar to the observed profiles. Predicted AUCinf in CYP2C9*1/*2, CYP2C9*1/*3, and CYP2C9*3/*3 genotypes were 1.44-, 2.05-, and 3.67-fold higher than the CYP2C9*1/*1 genotype. The ranges of fold errors for AUCinf, Cmax, and t1/2 were 0.84-1.00, 0.61-1.22, and 0.74-0.94 in development and 0.59-0.98, 0.52-0.97, and 0.61-1.52 in validation, respectively, which were within the acceptance criterion. Thus, the PBPK model was successfully established and described the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups. The present model could guide the decision-making of tailored drug administration strategy by predicting the pharmacokinetics of flurbiprofen in various clinical scenarios.

Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.

The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.

A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.

AURKA is a potential kinase target in various malignancies. The kinase‐independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN‐based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP‐based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the “mitotic cell cycle” and “stem cell” processes, while dAurA450 inhibits the “MYC/E2F targets” and “stem cell” processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial‐temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent cancer stem cell‐mediated drug resistance.

Dynamical analysis and optimal control of an age-since infection HIV model at individuals and population levels

To study the impact of HIV infection at the individual level on the transmission of HIV/AIDS at the population level, in this paper, we formulate a multi-scale HIV model coupled with a two stages viral model (lymphoid tissue and blood) and an infection-age structured HIV epidemic model. Then we establish the well-posedness problem, derive the basic reproduction numbers and analyze the stability of equilibria for the coupled model. In order to investigate the effect of giving treatments to individuals on the disease, we further consider an optimal control problem subject to multiple drug treatments for the within-host model. For such control problem, we can obtain the optimal drug administration strategies to minimize the total number of transmissions from an infected individual over the course of infection. Some numerical simulations are presented to investigate the impact of the optimal control quantitatively on the viral load within the host and the between-host transmission dynamics. Our results suggest that controlling the progression of HIV infections at the individuals level is an effective measure to decrease the HIV transmission at the population level.

Safe administration of medications by nursing professionals in the hospital environment: scoping review protocol

Objective: mapping strategies for safe drug administration by nursing professionals in the hospital environment. Method: scoping review conducted according to the Joanna Briggs Institute (JBI) methodology guided by the research question: What strategies for safe medication administration have been used by nursing professionals in the hospital context? The search will be carried out in six databases and in the gray literature, using the Rayyan software to manage the collection and selection of studies. The title and abstract of all identified studies will be evaluated, based on the established inclusion and exclusion criteria, by two reviewers independently and a third reviewer to resolve possible discrepancies. The data will be summarized in a descriptive way. A narrative summary will accompany the tabulated and mapped results and describe how the results relate to the objective and issue of the review.

Safe administration of medications by nursing professionals in the hospital environment: scoping review protocol

Objective: mapping strategies for safe drug administration by nursing professionals in the hospital environment. Method: scoping review conducted according to the Joanna Briggs Institute (JBI) methodology guided by the research question: What strategies for safe medication administration have been used by nursing professionals in the hospital context? The search will be carried out in six databases and in the gray literature, using the Rayyan software to manage the collection and selection of studies. The title and abstract of all identified studies will be evaluated, based on the established inclusion and exclusion criteria, by two reviewers independently and a third reviewer to resolve possible discrepancies. The data will be summarized in a descriptive way. A narrative summary will accompany the tabulated and mapped results and describe how the results relate to the objective and issue of the review.

Safe administration of medications by nursing professionals in the hospital environment: scoping review protocol

Objective: mapping strategies for safe drug administration by nursing professionals in the hospital environment. Method: scoping review conducted according to the Joanna Briggs Institute (JBI) methodology guided by the research question: What strategies for safe medication administration have been used by nursing professionals in the hospital context? The search will be carried out in six databases and in the gray literature, using the Rayyan software to manage the collection and selection of studies. The title and abstract of all identified studies will be evaluated, based on the established inclusion and exclusion criteria, by two reviewers independently and a third reviewer to resolve possible discrepancies. The data will be summarized in a descriptive way. A narrative summary will accompany the tabulated and mapped results and describe how the results relate to the objective and issue of the review.

The economic value of genetically engineered mosquitoes as a malaria control strategy depends on local transmission rates.

This paper assesses the economic value of genetically engineered (GE) Anopheles gambiae mosquitoes as a malaria control strategy. We use an epidemiological-economic model of malaria transmission to evaluate this technology for a range of village-level transmission settings. In each setting, we evaluate public health outcomes following introduction of GE mosquitoes relative to a "status quo" baseline scenario. We also assess results both in contrast to-and in combination with-a Mass Drug Administration (MDA) strategy. We find that-in low transmission settings-the present value (PV) public health benefits of GE mosquito release are substantial, both relative to status quo dynamics and MDA. In contrast, in high transmission settings, the release of GE mosquitoes may increase steady-state infection rates. Our results indicate that there are substantial policy complementarities when GE mosquito release is combined with local MDA-the combined control strategy can lead to local eradication.

Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax.

Primaquine, an 8-aminoquinoline, is the only medication approved by the World Health Organization to treat the hypnozoite stage of Plasmodium vivax and P. ovale malaria. Relapse, triggered by activation of dormant hypnozoites in the liver, can occur weeks to years after primary infection, and provides the predominant source of transmission in endemic settings. Hence, primaquine is essential for individual treatment and P. vivax elimination efforts. However, primaquine use is limited by the risk of life-threatening acute hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. More recently, studies have demonstrated decreased efficacy of primaquine due to cytochrome P450 2D6 (CYP2D6) polymorphisms conferring an impaired metabolizer phenotype. Failure of standard primaquine therapy has occurred in individuals with decreased or absent CYP2D6 activity. Both G6PD and CYP2D6 are highly polymorphic genes, with considerable geographic and interethnic variability, adding complexity to primaquine use. Innovative strategies are required to overcome the dual challenge of G6PD deficiency and impaired primaquine metabolism. Further understanding of the pharmacogenetics of primaquine is key to utilizing its full potential. Accurate CYP2D6 genotype-phenotype translation may optimize primaquine dosing strategies for impaired metabolizers and expand its use in a safe, efficacious manner. At an individual level the current challenges with G6PD diagnostics and CYP2D6 testing limit clinical implementation of pharmacogenetics. However, further characterisation of the overlap and spectrum of G6PD and CYP2D6 activity may optimize primaquine use at a population level and facilitate region-specific dosing strategies for mass drug administration. This precision public health approach merits further investigation for P. vivax elimination.

Maintaining Low Prevalence of Schistosoma mansoni: Modeling the Effect of Less Frequent Treatment.

BackgroundThe World Health Organization previously set goals of controlling morbidity due to schistosomiasis by 2020 and attaining elimination as a public health problem (EPHP) by 2025 (now adjusted to 2030 in the new neglected tropical diseases roadmap). As these milestones are reached, it is important that programs reassess their treatment strategies to either maintain these goals or progress from morbidity control to EPHP and ultimately to interruption of transmission. In this study, we consider different mass drug administration (MDA) strategies to maintain the goals.MethodsWe used 2 independently developed, individual-based stochastic models of schistosomiasis transmission to assess the optimal treatment strategy of a multiyear program to maintain the morbidity control and the EPHP goals.ResultsWe found that, in moderate-prevalence settings, once the morbidity control and EPHP goals are reached it may be possible to maintain the goals using less frequent MDAs than those that are required to achieve the goals. On the other hand, in some high-transmission settings, if control efforts are reduced after achieving the goals, particularly the morbidity control goal, there is a high chance of recrudescence.ConclusionsTo reduce the risk of recrudescence after the goals are achieved, programs have to re-evaluate their strategies and decide to either maintain these goals with reduced efforts where feasible or continue with at least the same efforts required to reach the goals.

Iontophoresis-driven porous microneedle array patch for active transdermal drug delivery

A transdermal patch that combines microneedle array (MA) with iontophoresis can achieve synergistic and remarkable enhancement of drug delivery with precise electronic control. However, the development of an MA patch combined with iontophoresis that can enable in situ treatment, easy self-administration, and controllable delivery of liquid macromolecular drugs is still a challenge. Here, we presented an iontophoresis-driven porous MA patch (IDPMAP) for in situ, patient-friendly, and active delivery of charged macromolecular drugs. IDPMAP integrates porous MA with iontophoresis into a single transdermal patch, thus realizing the one-step drug administration strategy of “Penetration, Diffusion, and Iontophoresis.” Moreover, a matching portable iontophoresis-driven device was developed for drug self-administration of IDPMAP. In vitro and in vivo studies showed that IDPMAP had approximately 99% skin penetration rate, negligible cytotoxicity, and good biocompatibility without skin irritation and hypersensitivity. In vivo transdermal delivery of insulin in type 1 diabetic rats demonstrated that IDPMAP could effectively deliver insulin nanovesicles and produce a robust hypoglycemic effect on the rats (maintain normal blood glucose for approximately 5.4 h), with more advanced controllability and efficiency than that achieved by pristine MA or iontophoresis. IDPMAP and its portable iontophoresis-driven device are user-friendly and thus show a promising potential for drug self-administration at home.

Smartphone-powered iontophoresis-microneedle array patch for controlled transdermal delivery

The incidence rate of diabetes has been increasing every year in nearly all nations and regions. The traditional control of diabetes using transdermal insulin delivery by metal needles is generally associated with pain and potential infections. While microneedle arrays (MAs) have emerged as painless delivery techniques, the integration of MA systems with electronic devices to precisely control drug delivery has rarely been realized. In this study, we developed an iontophoresis-microneedle array patch (IMAP) powered by a portable smartphone for the active and controllable transdermal delivery of insulin. The IMAP in situ integrates iontophoresis and charged nanovesicles into one patch, achieving a one-step drug administration strategy of “penetration, diffusion and iontophoresis”. The MA of the IMAP is first pressed on the skin to create microholes and then is retracted, followed by the iontophoresis delivery of insulin-loaded nanovesicles through these microholes in an electrically controlled manner. This method has synergistically and remarkably enhanced controlled insulin delivery. The amount of insulin can be effectively regulated by the IMAP by applying different current intensities. This in vivo study has demonstrated that the IMAP effectively delivers insulin and produces robust hypoglycemic effects in a type-1 diabetic rat model, with more advanced controllability and efficiency than delivery by a pristine microneedle or iontophoresis. The IMAP system shows high potential for diabetes therapy and the capacity to provide active as well as long-term glycemic regulation without medical staff care.

P.024 Prevalence of obsessive-compulsive traits and of problematic Internet use in professional tennis players

We introduce an agent-based model describing a susceptible-infectious-susceptible (SIS) system of humans and mosquitoes to predict malaria epidemiological scenarios in realistic biological conditions. Emphasis is given to the transition from endemic behavior to eradication of malaria transmission induced by combined drug therapies acting on both the gametocytemia reduction and on the selective mosquito mortality during parasite development in the mosquito. Our mathematical framework enables to uncover the critical values of the parameters characterizing the effect of each drug therapy. Moreover, our results provide quantitative evidence of what was up to now only partially assumed with empirical support: interventions combining gametocytemia reduction through the use of gametocidal drugs, with the selective action of ivermectin during parasite development in the mosquito, may actively promote disease eradication in the long run. In the agent model, the main properties of human-mosquito interactions are implemented as parameters and the model is validated by comparing simulations with real data of malaria incidence collected in the endemic malaria region of Chimoio in Mozambique. Finally, we discuss our findings in light of current drug administration strategies for malaria prevention, which may interfere with human-to-mosquito transmission process.

Iontophoresis-Driven Porous Microneedle Array Patch for Active Transdermal Drug Delivery

Transdermal patch combined microneedle array (MA) with iontophoresis can achieve synergistic and remarkable enhancement for drug delivery with precise electronic control. However, development of a MA patch combined with iontophoresis, that is in situ treatment, easy self-administration, and controllable delivery of liquid macromolecular drugs, is still a challenge. Here, we presented a novel iontophoresis-driven porous MA patch (IDPMAP) for in situ, patient-friendly, and active delivery of charged macromolecular drugs. IDPMAP integrates porous MA with iontophoresis into a single transdermal patch, realizing one-step drug administration strategy of “Penetration, Diffusion and Iontophoresis”. Moreover, a matching portable iontophoresis-driven device was developed for drug self-administration of IDPMAP. In vitro and in vivo studies showed that IDPMAP had excellent skin penetration ability, negligible cytotoxicity and good biocompatibility without skin irritation and hypersensitivity. In vivo transdermal insulin delivery in type-1 diabetic rats demonstrated that IDPMAP could effectively deliver insulin nanovesciles and produce robust hypoglycemic effect on diabetic rats, with more advanced controllability and efficiency compared with pristine MA or iontophoresis. IDPMAP and its portable iontophoresis-driven device are user-friendly that shows a promising potential for drug self-administration at home.

Abstract 1801: Sequential inhibition of BCL-XL and MCL1 elicits massive apoptosis in anaplastic thyroid cancer cells

Abstract Despite advancements in cancer therapy, anaplastic thyroid cancer (ATC) remains a lethal disease. In fact, the effect of both current chemoradiation regimens and of investigative targeted therapies is at best cytostatic, as shown by the systematic lack of durable responses and the rarity even of achieving stable disease. While efficient induction of apoptosis would be the ideal and definitive therapeutic approach for this aggressive tumor, ATC cells are remarkably resistant to therapy-induced apoptotic stimuli, thanks to the high rate of TP53 loss, hallmark EMT, and frequent overexpression of anti-apoptotic BCL2 family members. BH3 mimetics are small molecules that bind to anti-apoptotic BCL2 proteins in the docking site where the BH3 domains of the death-promoting members of the family bind, thus releasing the latter from sequestration to induce apoptosis. This concept has been successfully applied to hematological malignancies, with the recent approval of venetoclax, a BCL2 inhibitor, for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia. Solid tumors have instead proven very refractory to these approaches, and the clinical activity of BH3 mimetics is extremely limited. To determine the effect of targeting key anti-apoptotic proteins that protect ATC cells from apoptosis, we have studied the response of a large panel of ATC cell lines to novel MCL1 (AZD5991) and BCL-2/BCL-XL (AZD4320) inhibitors. We found that every cell line tested was modestly sensitive to each inhibitor in monotherapy, and that the AZD5991 and AZD4320 showed identical or quite similar EC50s in the low micromolar range. These data strongly suggest that ATC cells are in fact co-addicted to MCL1 and BCL-XL, and that both proteins are essential to buffer the pro-apoptotic signals induced with the transformed state. This notion, however, cannot be readily translated into a therapeutic opportunity because concomitant treatment at doses that exhibit monotherapy activity results in rapid lethal toxicity. To begin exploring how to mitigate this toxicity, we hypothesized that inhibition of one critical anti-apoptotic protein (i.e. BCL-XL), in co-addicted cells, might shift the cells' dependence on the other protein (i.e. MCL1). Thus, we have tested whether intermittent and sequential dosing in vitro could improve efficacy compared to monotherapy, providing an opportunity for a therapeutic margin. Strikingly, pre-treatment with a dose of the BCL-2/BCL-XL inhibitor that has no effect in monotherapy resulted in an approximately 50-fold decrease in EC50 for the MCL1 inhibitor, and in massive caspase 3-mediated apoptosis occurring within 6-8 hours from MCL1 inhibition. These results provide a compelling proof-of-principle suggesting that ATC cells can be effectively killed using a rationally designed drug administration strategy that targets critical components of the cells' antiapoptotic machinery. Citation Format: Xhesika Shanja-Grabarz, Justin Cidado, Antonio Di Cristofano. Sequential inhibition of BCL-XL and MCL1 elicits massive apoptosis in anaplastic thyroid cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1801.