Transplacental treatment of foetal supraventricular tachycardia with triple antiarrhythmic combination to avoid intra-foetal intervention

Although a high percentage of foetuses with supraventricular tachycardia respond to single or dual antiarrhythmic therapy, on occasion when there is no response to these combination regimens, direct intra-foetal therapy remains the only choice, albeit such an approach carries a potential risk to the foetus. Data with regard to the safety and efficacy of triple antiarrhythmic combination have not been reported before. Here, we present a foetus with intractable tachycardia in whom arrhythmia termination was successfully achieved with triple oral antiarrhythmic therapy.

A Pilot Basket Study to Evaluate Multi-Analyte Liquid Biopsies for Personalized Treatments in Advanced Refractory Cancers

Prior attempts at personalizing anticancer treatments based on univariate tumor profiling (single gene variant) for selection of monotherapy with targeted agents (single drug) have generally yielded poor response rates. We report findings from the LIQUID IMPACT pilot trial where Multi-analyte Liquid Biopsy (MLB) profiling of circulating tumor analytes in peripheral blood was used to inform selection of personalized combination regimens in advanced refractory cancers. Among the 43 patients evaluable as per study protocol, 34 had targetable pathway activations. Partial Response (PR) was observed in 14 (41.1%) of the 34 patients with signaling pathway activation, including 5 (50%) of 10 cases with mTOR activation, 8 (44.4%) of 18 cases with activation of angiogenesis and 4 (50.0%) of 8 cases with EGFR / ERBB2 activation. PR was not reported among the 9 cases with no detectable pathway activation. Toxicities were manageable and there were no treatment related deaths. The study findings suggest that MLB may be able to inform safe and efficacious combination regimens in patients with advanced refractory cancers.

Comparative Safety of Immune Checkpoint Inhibitors and Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

Backgrounds: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the standard of care for first-line therapy in metastatic non-small cell lung cancer (NSCLC) patients without actionable mutations. The safety ranking of different ICI and CT combination regimens has not been investigated. This study was aimed to provide a toxicity profile and safety ranking of different ICI and CT combination regimens.Methods: We performed comprehensive searches of phase 2 and 3 randomized clinical trials (RCTs) comparing different ICI regimens (alone or combination) or CT for the first-line treatment of advanced NSCLC. Outcomes of interest were the cumulative incidence of any treatment-related adverse events (TRAEs), grade 3-5 TRAEs (grade 3-5), any immune-related adverse events (irAEs), and grade 3-5 irAEs (grade 3-5). Odds ratios and 95% credible intervals were calculated as summary statistics to quantify the effect of different ICI combination regimens. Results: We included 23 RCTs from 2016 to 2021 with a total of 14,378 patients. The incidence of any TRAEs and grade 3-5 TRAEs ranked from high to low were ICI-CT (probability: 74.88%), ICI-ICI-CT (50.60%), CT alone (74.79%), ICI-ICI (98.37%), and ICI monotherapy (99.37%). Adding CT to ICI regimens resulted in a higher incidence of any grade or grade 3-5 TRAEs compared to ICI-ICI combinations or ICI monotherapy. However, ICI-ICI-CT combinations did not result in a higher incidence of TRAEs than ICI-CT combinations. For any irAEs and grade 3-5 irAEs, the ranking was ICI-ICI (probability: 97.38), ICI monotherapy (96.98%), ICI-CT (99.44%), and CT alone (99.98%). Notably, the incidence of any grade and grade 3-5 irAEs was lower when adding CT to ICI monotherapy. Conclusion: Lack of head-to-head comparisons, these findings provide evidence for clinical decision-making when considering different ICI combination regimens for advanced NSCLC patients.

Alternating anti-prion regimens reduce combination drug resistance but do not further extend survival in scrapie-infected mice

Prion diseases are fatal and infectious neurodegenerative diseases in humans and other mammals caused by templated misfolding of the endogenous prion protein (PrP). Although there is currently no vaccine or therapy against prion disease, several classes of small-molecule compounds have been shown to increase disease-free incubation time in prion-infected mice. An apparent obstacle to effective anti-prion therapy is the emergence of drug-resistant strains during static therapy with either single compounds or multi-drug combination regimens. Here, we treated scrapie-infected mice with dynamic regimens that alternate between different classes of anti-prion drugs. The results show that alternating regimens containing various combinations of Anle138b, IND24 and IND116135 reduce the incidence of combination drug resistance, but do not significantly increase long-term disease-free survival compared to monotherapy. Furthermore, the alternating regimens induced regional vacuolation profiles resembling those generated by a single component of the alternating regimen, suggesting the emergence of strain dominance.

Carbonic Anhydrase IX Inhibitors as Candidates for Combination Therapy of Solid Tumors

Combination therapy is becoming imperative for the treatment of many cancers, as it provides a higher chance of avoiding drug resistance and tumor recurrence. Among the resistance-conferring factors, the tumor microenvironment plays a major role, and therefore, represents a viable target for adjuvant therapeutic agents. Thus, hypoxia and extracellular acidosis are known to select for the most aggressive and resilient phenotypes and build poorly responsive regions of the tumor mass. Carbonic anhydrase (CA, EC 4.2.1.1) IX isoform is a surficial zinc metalloenzyme that is proven to play a central role in regulating intra and extracellular pH, as well as modulating invasion and metastasis processes. With its strong association and distribution in various tumor tissues and well-known druggability, this protein holds great promise as a target to pharmacologically interfere with the tumor microenvironment by using drug combination regimens. In the present review, we summarized recent publications revealing the potential of CA IX inhibitors to intensify cancer chemotherapy and overcome drug resistance in preclinical settings.

Basic principles of combination therapy: focus on drug-drug interaction

The article is devoted to the issue of drug interactions in the combination regimens. Today, when drug therapy is the first-line approach for patients with noncommunicable diseases, and the world population ageing leads to an increase in the number of patients with severe comorbidity and polypharmacy, the problem of drug-drug interaction is especially relevant. The article discusses the main types of drug interactions — pharmacokinetic (related to absorption, distribution, metabolism and excretion of drugs) and pharmacodynamic ones, leading to synergy or antagonism of the pharmacological effects. The consequences of drug interactions can be desirable and undesirable, while the latter are much more common. Attention should be directed precisely to preventing such interactions. Also, using data from special scales and lists (Beers criteria, STOPP/START criteria), the options for various adverse drugdrug interactions are briefly described. In addition, the article provides a number of Internet resources that allow assessing the drug interaction risk when prescribing combination therapy.

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

Immunotherapy with checkpoint inhibitors opened new horizons in cancer treatment. Clinical trials for novel immunotherapies or unexplored combination regimens either need years of development or are simply impossible to perform like is the case in cancer patients with limited life expectancy. Thus, the need for preclinical models that rapidly and safely allow for a better understanding of underlying mechanisms, drug kinetics and toxicity leading to the selection of the best regimen to be translated into the clinic, is of high importance. Humanized mice that can bear both human immune system and human tumors, are increasingly used in recent preclinical immunotherapy studies and represent a remarkably unprecedented tool in this field. In this review, we describe, summarize, and discuss the recent advances of humanized mouse models used for cancer immunotherapy research and the challenges faced during their establishment. We also highlight the lack of preclinical studies using this model for radiotherapy-based research and argue that it can be a great asset to understand and answer many open questions around radiation therapy such as its presumed associated “abscopal effect”.

Venetoclax in Acute Myeloid Leukemia: Molecular Basis, Evidences for Preclinical and Clinical Efficacy and Strategies to Target Resistance

Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery.

Caffeic acid, a dietary polyphenol, as a promising candidate for combination therapy

Increased effectiveness and decreasing toxicity are prime objectives in drug research. Overwhelming evidence suggests the use of appropriate combination therapy for the better efficacy of drugs owing to their synergistic profile. Dietary active constituents play a major role in health outcomes. Therefore, it is possible to increase the effectiveness of the drug by combining contemporary medication with active natural/semi-synthetic constituents. One such dietary constituent, caffeic acid (CA), is a by-product of the shikimate pathway in plants and is a polyphenol of hydroxycinnamic acid class. Extensive research on CA has proposed its efficacy against inflammatory, neurodegenerative, oncologic, and metabolic disorders. The synergistic/additive effects of CA in combination with drugs like caffeine, metformin, pioglitazone, and quercetin have been reported in several experimental models and thus the present review is an attempt to consolidate outcomes of this research. Multi-target-based mechanistic studies will facilitate the development of effective combination regimens of CA.