Pharmacological Response Research Articles

Adrenoreceptor phylogeny and novel functions of nitric oxide in ascidian immune cells

Nitric oxide (NO) is a simple molecule involved in many biological processes and functions in the cardiovascular, neural, and immune systems. In recent years, NO has also been recognized as a crucial messenger in communication between the nervous and immune systems. Together with NO, catecholamines are the main group of neurotransmitters involved in cross-talk between the nervous and immune systems. Catecholamines such as noradrenaline, can act on immune cells through adrenoreceptors (ARs) present on the cell surface, and NO can cross the cell membrane and interact with secondary messengers, modulating catecholamine production. Here, we analyzed the mutual modulation by noradrenaline and NO in Phallusia nigra immune cells for specific subtypes of ARs. We also investigated the involvement of protein kinases A and C as secondary messengers to these specific subtypes of ARs in the adrenergic signaling pathway that culminates in NO modulation, and the phylogenetic distribution of ARs in deuterostome genomes. This analysis provided evidence for single-copy orthologs of α1, α2 and β-AR in ascidian genomes, suggesting that NO and NA act on a less diverse set of ARs in urochordates. Pharmacological assays showed that high levels of NO can induce ascidian immune cells to produce catecholamines. We also observed that protein kinases A and C are the secondary messengers involved in downstream modulation of NO production through an ancestral β-AR. Taken together, these results provide new information on NO as a modulator of immune cells, and reveal the molecules involved in the signaling pathway of ARs. The results also indicate that ARs may participate in NO modulation. Finally, our results suggest that the common ancestor of urochordates possessed a less complex system of ARs required for immune action and diverse pharmacological responses, since the α-ARs are phylogenetically more related to D1-receptors than are the β-ARs.

A High-Throughput Microphysiological Liver Chip System to Model Drug-Induced Liver Injury Using Human Liver Organoids

Drug-induced liver injury (DILI) is a major failure mode in pharmaceutical development. This study aims to address the limitations of existing preclinical models by assessing a high-throughput, microfluidic liver-on-a-chip system, termed "Curio Barrier Liver Chips," and its capacity to recapitulate the effects of chronic hepatotoxic drug treatment through metabolic and phenotypic characterization. Curio Barrier liver chips (Curiochips), fabricated in an 8× 2 well configuration, were utilized to establish three dimensional liver organoid cultures. Human-induced pluripotent stem cells were differentiated into human liver organoids, and their viability, liver-specific functions, and pharmacological responses were assessed over 28 days. The Curiochips successfully maintained liver physiology and function, showing strong albumin secretion and cytochrome (CYP) P450 activities for 28 days. Unlike traditional models requiring millimolar drug concentrations to detect hepatotoxicity, this platform showed increased sensitivity for acetaminophen and fialuridine at micromolar concentrations. In situ differentiation of foregut spheroids to liver organoids was also achieved, further simplifying the establishment of liver chips. Furthermore, the chips demonstrated viability, function, and DILI responsiveness for 28 days, making this an improved model for studying idiosyncratic DILI with prolonged drug exposure and high-throughput capabilities compared to other available systems or primary human hepatocytes. The Curiochips offer an advanced, miniaturized invitro model for early-stage drug development and a sensitive, responsive, and cost-effective means to detect direct hepatotoxicity. Induced pluripotent stem cell liver organoids, in conjunction with the Curiochip, deliver a high-throughput platform with robust functionality and pharmacological responsiveness that make it a promising tool for improving the prediction and understanding of DILI risk prediction, especially with prolonged drug exposure. The model also opens new avenues for research in other chronic liver diseases.

A Deep Insight into Chemistry and Pharmacology of Genus Angelica.: An Up-to-date Systematic Review

Introduction: Healthcare providers globally need plant-derived bioactive compounds for the treatment of ailments. The present systematic review article emphasizes the chemistry and pharmacology parts of various Angelica species, family Apiaceae. The species of Angelica genus, native to the Indian Himalayan, are beneficial for several therapeutic and edible purposes. Aromatherapy uses essential oils obtained from various species of the Angelica genus. The population of various Angelica species is declining quickly due to premature destructive harvesting. The traditional medicinal system involves Angelica glauca Edgew and other Angelica species to treat respiratory, Central Nervous System (CNS) disorders and many more ailments. Method: An extensive literature survey on the chemistry and pharmacological aspects of various Angelica species, including A. glauca, secondary metabolites, mechanism behind various pharmacological activities, and marketed products of plants of Genus Angelica was conducted using scientific databases. The search terms Angelica species, botanical description, wild Angelica, important phytoconstituents and their pharmacological responses, plant parts used, and the molecular mechanism behind observed prominent activities were used for data collection. In total, 92 publications were included from year 1983 to 2023. Articles focusing on other than Angelica species and other than the English language were excluded from the study. Also, the papers with no full-text availability were excluded from the present study. Species of the Angelica genus have been known for a wide range of biological activities, including antioxidant, anti-inflammatory, antimicrobial and immunotoxic. Result: The present paper highlights the secondary metabolites present in the Angelica species and their scientific uses. Ancient Ayurvedic treatise claims several other pharmacological activities, but scientific validation of some indications, including the exact mechanism of action, is underway. : Ancient Ayurvedic treatise claims several other pharmacological activities, but scientific validation of some indications, including the exact mechanism of action, is underway. Conclusion: This review compiles 30 years of data on Angelica species related to their phytochemistry, pharmacology, molecular mechanisms of bioactivity, recent advancements and possible future scope of applied and translational research.

Predictors of Pharmacological Treatment Response in Children and Adolescents with Anxiety Disorders

Aim/Background: Anxiety disorders are frequently seen in children and adolescents and cause significant loss of functionality and a decrease in quality of life. This study aimed to investigate the factors affecting treatment response in children and adolescents with anxiety disorders. Methods: 340 children and adolescents aged 6-18 years who applied to child and adolescent psychiatry outpatient clinics of a university hospital between May 2018 and May 2023, diagnosed with anxiety disorder, and used only drug treatment were included in the study by retrospectively examining of the patient files. The age, gender, diagnosis, disorder severity, treatment and treatment response, comorbid disorders, physical diseases, and their treatments of the patients were recorded. Results: 116 of the patients were male, and 224 were female. While the most common diagnosis was generalized anxiety disorder (62.4%), the most frequently prescribed medication was sertraline (52.4%). Having specific phobia (p=0.026), attention-deficit hyperactivity disorder comorbidity (p=0.029) and using atypical antipsychotics (p=0.037) were negative predictors of treatment response. Other variables did not have any predictive effect on treatment response. Conclusions: Understanding the factors that influence treatment response in children and adolescents with anxiety disorders is crucial for determining the appropriate treatment and predicting the disorder's prognosis. Appropriate interventions addressing modifiable factors that have a negative impact on treatment response should be considered for treatment.

Emerging Technologies and Advanced Biomarkers for Enhanced Toxicity Prediction and Safety Pharmacology

Background: Biomarkers are important tools in toxicology that can improve risk assessment, early detection of organ injury, and monitoring of pharmacological responses. However, rigorous validation is necessary to justify use for regulatory decisionmaking. Purpose: This article reviews the current landscape surrounding established and emerging biomarkers of toxicity across multiple techniques, with a focus on assessment of merits, limitations, and validation needs. Main Body: An overview of common clinical chemistry biomarkers used for safety monitoring of liver, kidney, heart, and inflammation is first provided, highlighting their biological relevance and applications in detecting organ dysfunction. Novel protein biomarkers emerging for enhanced sensitivity of injury detection are then discussed, such as microRNAs for liver and clusterin for kidney. Metabolomic biomarker approaches to assess biofluids and mitochondrial toxicity are outlined, along with toxicogenomic markers of susceptibility like HLA alleles. Non-invasive imaging techniques including ultrasound, MRI, and PET tracers for organ function are explored as techniques that provide additional modalities for biomarker measurement. Emerging tools like organ microphysiological systems and high-throughput omics for biomarker discovery are also described. Conclusion: While great progress has been made, translation and qualification of novel biomarkers remains challenging. This review synthesizes key developments across biomarker categories, evaluates readiness for regulatory use, and outlines strategic considerations for fit-for-purpose biomarker validation to advance integration into drug development programs.

Phosphate Prodrugs: An Approach to Improve the Bioavailability of Clinically Approved Drugs.

The phosphate prodrug approach has emerged as a viable option for increasing the bioavailability of a drug candidate with low hydrophilicity and poor cell membrane permeability. When a phosphoric acid moiety is attached to the parent drug, it results in a several-fold elevation in aqueous solubility which helps to achieve desired bioavailability of the pharmaceutically active parental molecule. The neutral phosphate prodrugs have rapid diffusion ability through the plasma membrane as compared to their charged counterpart. The presence of phosphate mono ester breaking alkaline phosphatase (ALP) enzyme throughout the whole human body, is the main consideration behind the development of phosphate prodrug strategy. The popularity of this phosphate prodrug strategy is increasing nowadays due to the fulfillment of different desired pharmacokinetic characteristics required to get pharmaceutical and therapeutic responses without showing any serious adverse drug reactions (ADR). This review article mainly focuses on various phosphate prodrugs synthesized within the last decade to get an improved pharmacological response of the parent moiety along with various preclinical and clinical challenges associated with this approach. Emphasis is also given to the chemical mechanism to release the parent moiety from the prodrug.

Patient-Specific Optimal Hemodynamic Control with Minimal Myocardial Oxygen Consumption

In treating acute heart failure for each unique patient, the goals of drug therapy encompass multiple clinical considerations: controlling multiple hemodynamic targets such as blood pressure, cardiac output, and left atrial pressure, minimizing myocardial oxygen consumption, and rapidly adapting to the patient-specific pharmacological response. This paper proposes a proof-of-concept study of a practical, clinically feasible control system for treating acute heart failure. The simulation study demonstrates that our controller can achieve these multiple control goals simultaneously based on constrained nonlinear optimization.

A Comprehensive Review: Pharmacogenomics and Personalized Medicine Customizing Drug Therapy Based on Individual Genetics Profiles.

Numerous factors, such as genetics, environmental factors, and illness determinants, might contribute to an unpleasant pharmaceutical response. In an effort to increase efficacy and safety, as well as to gain a better understanding of drug disposition and clinical consequences, researchers in the two quickly emerging fields of pharmacogenetics (which focuses on single genes) and pharmacogenomics (which focuses on many genes) have studied the genetic personalization of drug response. This is due to the fact that a large number of pharmacological responses seem to be genetically based, and the relationship between medication response and genotype may be important for diagnosis. We now have a better understanding of the genetic basis of individual medication responses because to research on pharmaceuticals and genes. Pharmacogenomics aims to improve patient outcomes by developing personalized medicine by using the diversity of the human genome and how it affects medication response. Translational in nature, pharmacogenomics research encompasses everything from the discovery of genotype-phenotype associations to clinical investigations that might show therapeutic relevance. Though the conversion of pharmacogenomics research findings into clinical practice has been sluggish, advances in the field offer considerable potential for future therapeutic applications in specific people.

Pharmacogenetic basis of glaucoma

Personalized medical treatment is becoming more important in the current therapeutic scenario in order to gain greater efficiency and reduce adverse drug reactions. A few decades ago, pharmacogenetic studies entered the therapeutic field of glaucoma. Our group performed a study whose aim was the analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta‐blockers (BB) and prostaglandin analogues (PGA). It was a prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single‐nucleotide polymorphisms were genotyped by real‐time PCR assays: prostaglandin‐F2α receptor (rs3766355, rs3753380); cytochrome‐P450 2D6 (rs16947, rs769258); and beta‐2‐adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP) and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). 0.57 (41%) eyes were under 3 or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. Mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg respectively. Significant differences in tIOP were found in heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). MD values presented significant differences between wildtype rs3766355 (−2 ± 2.2 dB), HT (−3.87 ± 4 dB) and HM carriers (−9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between MD in wildtype rs3753380 (−6.1 ± 8.67 dB), HT (−9.02 ± 8.63 dB), and HM carriers (−9.51 ± 7.44 dB) (p = 0.017). In conclusion, patients carrying the variant rs3766355 in HM or HT presented clinically significant higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, the more alleles affected, the worse the MD value meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.

Solubility enhancement of Cefpodoxime acid by aqueous solution of paracetamol through acoustical, polarizable continuum model and antimicrobial activity studies

The pharmacological response of an antibiotic depends on the optimum concentration of homogenous solution of the drug and deviation from this may result in major problems with generic and formulation developments of new chemical entities (NCE’s). Further, the introduction of additional new drugs with greater pharmacokinetic activity is limited because of their poor aqueous solubility. In the present work, an attempt has been made to explore the enhancement of solubility and hence the bioavailability or antimicrobial activity of a pharmaceutically significant drug Cefpodoxime acid (CA), a metabolite of third generation cephalosporin antibiotic cefpodoxime proxetil (CP), by the addition of aqueous paracetamol (PA) solution. Ultrasonic investigation has been carried out on the aqueous solutions of PA containing different concentration of CA at ambient and physiological temperatures and at pressure 101.3 kPa. The measured values of ultrasonic velocity, density and dynamic viscosity and the computed acoustical parameters at 303.15 K, 310.15 K and 313.15 K reveal significant intermolecular interactions between unlike drug molecules. The polarizable continuum model (PCM) study for the two drugs in four different solvents is applied in the calculation of free energy of solution (ΔGsol) which provide valid information regarding the mutual solubility of the two drugs and possible enhancement of bioavailability of CA in presence of PA. Antimicrobial activity of CA in the presence of PA in aqueous medium confirms the improvisation of solubility of CA drug. The data obtained through antimicrobial activity studies support the increased pharmacokinetic activity of CA in the presence of PA in aqueous environment.

Molecular and Cellular Expressions in Breast Cancer Responsible for Drug Resistance

Breast cancer continues to be a prevalent and highly lethal cancer affecting women globally. Despite significant advancements in early detection and the development of specific therapeutic approaches, the issue of medication resistance remains a prominent challenge in managing this intricate ailment. The study offers a comprehensive analysis of the mechanisms behind the development of treatment resistance in breast cancer cells. The objective of this study is to provide a comprehensive understanding of the molecular and cellular mechanisms behind the occurrence of therapeutic ineffectiveness. This study elucidates several molecular subtypes of breast cancer and their pharmacological responses. The significance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in the development of treatment resistance is emphasized. Additional research on the intricacies of innate and acquired drug resistance mechanisms, including genetic modifications, tumor heterogeneity, and the presence of cancer stem cells, has shed light on the multifaceted nature of drug resistance and its dynamic evolution throughout treatment. Furthermore, this study provides a comprehensive analysis of the impact of microenvironmental variables, including hypoxia, immune evasion, and tumor-stroma connections, on the development of drug resistance. The investigation of the interplay between tumor suppressors and oncogenes in the emergence of drug resistance is now underway, yielding valuable insights into prospective targets for therapeutic intervention. Additionally, this study examines the limitations associated with conventional chemotherapy, endocrine therapies, and targeted medicines, while elucidating the mechanisms underlying treatment resistance and proposing potential strategies to overcome it. Emerging therapies like immunotherapies, epigenetic modulators, and new drug delivery methods are looked at to see if they have the potential to get around mechanisms of resistance and improve patient outcomes. This review aims to give clinicians, researchers, and other healthcare workers a full picture of breast cancer’s complex drug resistance mechanisms. By figuring out the molecular complexities and signaling pathways that lead to treatment resistance, we aim to speed up the development of new therapeutic approaches and personalized interventions. This will bring us closer to the long-awaited goal of beating drug resistance and making breast cancer a manageable, treatable condition.

Designing drug delivery systems through additive manufacturing

Additive manufacturing, also called 3D-printing is an emerging technique for the formulation of drug dosage forms in pharmaceutical formulation. This approach is widely used for its benefits over conventional drug formulations. 3D printing is giving an enhancement to the customization of drugs. This technique is able to carry many different drugs in a single dosage form. Customization is also seen in conventional drug dosage forms, but 3D printing gives more precision as per pharmacological response desired for each individual patient. Moreover, the customisation process is simple and instant production is obtained. Physically incompatible drugs can be added to one drug dosage form by providing barriers of polymers, etc. Here, we have discussed some of the tablets, capsules, transdermal patches, suppositories fabricated by 3D printing by researchers. Different types of techniques under 3D printing have also been discussed which are being used in fabricating the above-mentioned drug dosage forms. 3D printing is being considered in the pharmaceutical field due to its advantages of easy operation, the fewest possible steps, lower labour costs and many other factors. This technique shows the benefits of 3D printing of various desirable drugs. Keywords: 3-D Printing, Polymer, Dosage form, Customization, Capsule, Transdermal patches, suppositories. Abbreviations: HCl- Hydrochloric acid, FDM- Fused Deposition Modelling, FDA- Food and Drug administration, CADD- Computer aided drug design, API- Active pharmaceutical agent, SLA- Stereolithography, SLS- selective laser sintering, 3D- Three dimensional

Oxycodone, an opioid like the others?

The over-prescription of opioid analgesics is a growing problem in the field of addiction, which has reached epidemic-like proportions in North America. Over the past decade, oxycodone has gained attention as the leading opioid responsible for the North America opioid crisis. Oxycodone is the most incriminated drug in the early years of the epidemic of opioid use disorder in USA (roughly 1999-2016). The number of preclinical articles on oxycodone is rapidly increasing. Several publications have already compared oxycodone with other opioids, focusing mainly on their analgesic properties. The aim of this review is to focus on the genomic and epigenetic regulatory features of oxycodone compared with other opioid agonists. Our aim is to initiate a discussion of perceptible differences in the pharmacological response observed with these various opioids, particularly after repeated administration in preclinical models commonly used to study drug dependence potential.

Structural Basis of the Bivalency of the TRPV1 Agonist DkTx.

Bivalency is a prevalent natural mechanism to enhance receptor avidity. Various two-domain disulfide-rich peptides exhibiting bivalent action have been identified from animal venoms. A unique characteristic of these peptides is that they induce a pharmacological response different from that provoked by any of the constituent domains. The enhanced potency and avidity of such peptides is therefore a consequence of their domain fusion by a peptide linker. The role of the linker itself, beyond conjugation, remains unclear. Here, we investigate how the linker affects the bivalency of the capsaicin receptor (TRPV1) agonist DkTx. We recombinantly produced isotope labelled DkTx using a protein splicing approach, to solve the high-resolution solution structure of DkTx, revealing residual linker order stabilised by linker-domain interactions leading to biased domain orientations. The significance of this was studied using a combination of mutagenesis, spin relaxation studies and electrophysiology measurements. Our results reveal that disrupting the pre-organisation of the domains of DkTx is accompanied by reductions in potency and onset of avidity. Our findings support a model of pre-configured two-domain binding, in favour of the previously suggested sequential binding model. This highlights the significance of ordered elements in linker design and the natural evolution of these in bivalent toxins.

Structural Basis of the Bivalency of the TRPV1 Agonist DkTx

AbstractBivalency is a prevalent natural mechanism to enhance receptor avidity. Various two‐domain disulfide‐rich peptides exhibiting bivalent action have been identified from animal venoms. A unique characteristic of these peptides is that they induce a pharmacological response different from that provoked by any of the constituent domains. The enhanced potency and avidity of such peptides is therefore a consequence of their domain fusion by a peptide linker. The role of the linker itself, beyond conjugation, remains unclear. Here, we investigate how the linker affects the bivalency of the capsaicin receptor (TRPV1) agonist DkTx. We recombinantly produced isotope labelled DkTx using a protein splicing approach, to solve the high‐resolution solution structure of DkTx, revealing residual linker order stabilised by linker‐domain interactions leading to biased domain orientations. The significance of this was studied using a combination of mutagenesis, spin relaxation studies and electrophysiology measurements. Our results reveal that disrupting the pre‐organisation of the domains of DkTx is accompanied by reductions in potency and onset of avidity. Our findings support a model of pre‐configured two‐domain binding, in favour of the previously suggested sequential binding model. This highlights the significance of ordered elements in linker design and the natural evolution of these in bivalent toxins.

Characteristics associated with response to subcutaneously administered anti-CGRP monoclonal antibody medications in areal-world community cohort of persons living with migraine: Aretrospective clinical and genetic study.

To evaluate response to anti-calcitonin gene-related peptide (CGRP) migraine preventives in a real-world community cohort of persons living with migraine and to identify clinical and genetic characteristics associated with efficacious response. Erenumab-aooeb, fremanezumab-vrfm, and galcanezumab-gnlm target CGRP or its receptor; however, many patients are non-responsive. In this retrospective clinical and genetic study, we identified 1077 adult patients who satisfied the International Classification of Headache Disorders, 3rd edition, criteria for migraine without aura, migraine with aura, or chronic migraine and who were prescribed an anti-CGRP migraine preventive between May 2018 and May 2021. Screening of 558 patients identified 289 with data at baseline and first follow-up visits; data were available for 161 patients at a second follow-up visit. The primary outcome was migraine days per month (MDM). In 198 genotyped patients, we evaluated associations between responders (i.e., patients with ≥50% reduction in MDM at follow-up) and genes involved in CGRP signaling or pharmacological response, and genetic and polygenic risk scores. The median time to first follow-up was 4.4 (0.9-22) months after preventive start. At the second follow-up, 5.7 (0.9-13) months later, 145 patients had continued on the same preventive. Preventives had strong, persistent effects in reducing MDM in responders (follow-up 1: η2 = 0.26, follow-up 2: η2 = 0.22). At the first but not second follow-up: galcanezumab had a larger effect than erenumab, while no difference was seen at either follow-up between galcanezumab and fremanezumab or fremanezumab and erenumab. The decrease in MDM at follow-up was generally proportional to baseline MDM, larger in females, and increased with months on medication. At the first follow-up only, patients with prior hospitalization for migraine or who had not responded to more preventive regimens had a smaller decrease in MDM. Reasons for stopping or switching a preventive varied between medications and were often related to cost and insurance coverage. At both follow-ups, patient tolerance (1: 92.2% [262/284]; 2: 95.2% [141/145]) and continued use (1: 77.5% [224/289]; 2: 80.6% [116/145]) were high and similar across preventives. Response consistency (always non-responders: 31.7% [46/145]; always responders: 56.5% [82/145], and one-time only responders: 11.7% [17/145]) was also similar across preventives. Non-responder status had nominally significant associations with rs12615320-G in RAMP1 (odds ratio [95% confidence interval]: 4.7 [1.5, 14.7]), and rs4680-A in COMT (0.6[0.4, 0.9]). Non-responders had a lower mean genetic risk score than responders (1.0 vs. 1.1; t(df) = -1.75(174.84), p = 0.041), and the fraction of responders increased with genetic and polygenic risk score percentile. In this real-world setting, anti-CGRP preventives reduced MDM persistently and had similar and large effect sizes on MDM reduction; however, clinical and genetic factors influenced response.

Abstract C008: Phase I biomarker analysis of farletuzumab ecteribulin (FZEC), formerly MORAb-202, effects on cancer responses in patients with platinum resistant ovarian cancer

Abstract Background: FZEC (formerly MORAb-202) is an antibody-drug conjugate consisting of farletuzumab and eribulin. FZEC is cytotoxic to FRα+ cancer cells (via direct binding) and to adjacent tumor cells (via bystander effects); it also exerts noncytotoxic bystander effects in the tumor microenvironment (Zhang et al, EORTC 2022). Study 101 is a first-in-human dose escalation followed by dose expansion study in Japanese patients (pts) with selected solid tumors to determine safety and preliminary efficacy of FZEC; antitumor activity across several doses was demonstrated in pts with platinum-resistant ovarian cancer (PROC) and FRα+ tumors (Nishio ASCO 2022). This exploratory biomarker study evaluated association of FZEC-induced pharmacological effects and clinical responses in pts with PROC to examine the mechanism of action (MoA) of FZEC. Methods: Serum samples from up to 58 pts with PROC from a FZEC 0.9 mg/kg cohort (equivalent to 33 mg/m2) or from a combined dose cohort (FZEC 0.3, 0.45, 0.68, 0.9, 1.2 mg/kg) were collected predose on day 1 of treatment cycles 1–6 and analyzed using 139 exploratory Luminex, Simoa, or OLINK protein assays. While these doses are no longer being evaluated, as a result of a change to body-surface-area-based dosing, the biomarkers observed to be preliminarily associated with response in this analysis should be further explored in ongoing studies. Markers with >30% unevaluable data points were excluded. The 1-sample Wilcoxon signed-rank test and 2-sample Wilcoxon rank-sum test were used to assess changes from baseline and differences between 2 best overall response groups (responders [CR/PR] and nonresponders [SD/PD]) at each visit. Fisher’s method was used to summarize statistical difference across visits (meta P<0.05) between the 2 groups. Results: Changes from baseline to at least 1 visit postdose (P<0.05) in either the responder or nonresponder groups, and differences between responders and nonresponders (meta P<0.05), were seen in 29 markers in the combined-dose cohort, and in 14 markers in the 0.9 mg/kg cohort. There was an overlap of 11 markers in both the FZEC 0.9 mg/kg and combined-dose cohorts that showed a significant change from baseline and significant differences in changes between responders and nonresponders. Among these 11 markers, SP-D and IGFBP-2 showed persistent changes (≥3 visits) in responders. Decreases in markers with reported protumor functions (eg, ANG-2, KLK-5, KLK-7, MCP-1, FRTN, and MMP-12), and increases in SP-D, were persistent (≥4 of 5 visits) in responders. Some biomarkers (eg, IGFBP-1, FLT3LG, and VEGF-D) showed significant increases in nonresponders. Conclusions: The persistent responder-associated biomarker changes suggest that FZEC may modulate functions associated with these markers (eg, immune regulation, vascular remodeling, extracellular matrix protease activities, iron metabolism) and this may contribute to the antitumor effect of FZEC. In the limited number of pts analyzed, preliminary pharmacodynamic effects trended with the antitumor effects observed with FZEC 0.9 mg/kg. Citation Format: Yan Zhang, Bob Zimmermann, Shuyu Li, Toshimitsu Uenaka, Keiji Furuuchi, Kan Yonemori, Toshio Shimizu, Shin Nishio, Mayu Yunokawa, Koji Matsumoto, Kazuhiro Takehara, Kosei Hasegawa, Yasuyuki Hirashima, Hidenori Kato, Yohei Otake, Takuma Miura, Junji Matsui, Meijuan Li. Phase I biomarker analysis of farletuzumab ecteribulin (FZEC), formerly MORAb-202, effects on cancer responses in patients with platinum resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C008.

Abstract C166: Development of BLX-3030, a potent and selective inhibitor of CDK9 for the treatment of N-MYC driven NeuroEndocrine Prostate Cancers (NEPC)

Abstract Background: Cell lineage reprogramming in cancer cells is a major mechanism for cancers to develop drug resistance and escape targeted therapy. The use of new potent targeted therapies in prostate cancers has led to the development of highly aggressive cancers, including NEPC. Gene amplification of N-MYC and C-MYC oncogenes leads to its overexpression in NEPC and mCRPC patients. This overexpression is highly prevalent in these lethal subtypes of cancers, detected in 2% of all Prostate Cancers (PCa) and over 10-17% of mCRPC patients. N-MYC is a transcriptional target of CDK9, which acts as an oncogenic driver, sufficient to transform human-derived prostate cancer cells to take on NEPC phenotypic changes. This results in a more aggressive disease identified in late-stage human PCa patients. Additionally, N-MYC and C-MYC are required for tumor drug resistance and its downregulation, through CDK9 inhibition, lowers tumor growth. Our efforts have demonstrated that targeting both N-MYC and C-MYC as a driver of NEPC and mCRPC with a highly selective CDK9 inhibitor (BLX-3030) is a viable approach for therapeutic intervention of mCRPC and NEPC. Materials and Methods: We employed our MolecuLernTM fragment-based design strategies, in vitro cellular efficacies in single agent and combination experiments. Other assays are FACS/apoptosis, cell migration, live cell imaging, immunofluorescence. In vivo 22Rv1, LASCPC-0 and C4-2 cell engraftment mouse models, 7-day tox, PK, selectivity, NanoBRET, and ADME-Tox, in vitro safety and secondary pharmacological assays. Results: We synthesized a series of novel small molecule CDK9 agents that reversibly bind to CDK9, competitively block the ATP site with an IC50 of 4.2 nM in kinase and 23 nM in target engagement assays, elicit pharmacological responses in N-MYC, C-MYC, and other prostate cancer cells in vitro and in vivo. We detected the expression of CDK9 and N-MYC in LASCPC-01, 22Rv1, C4-2 and C4-2B cell lines. BLX-3030 exhibited potent cellular efficacy in PCa cells (IC50 of 22 to 590 nM) and in N-MYC expressed cells (IC50 of 76, 470, and 132 nM), respectively. BLX-3030 reduced pCDK9, C-MYC, Mcl-1, N-MYC and its downstream RNA Pol II (Ser-2) and pAR (Ser-81) in a dose dependent manner. Additionally, we performed FACS/apoptosis, cell migration, and live cell imaging, including immunofluorescence. We also conducted three separate in vivo efficacy mouse models (LASCPC-01, 22RV1, and C4-2) which demonstrated >55 to 70% Tumor Growth Inhibition. Several in vitro ADME-Tox, hERG, P450, safety panel screen, in vivo MTD and dose range finding experiments in SD rats and beagle dogs were conducted. Conclusion: In summary, a series of BLX-3030 and its analogs display a potency in MYC-driven PCa, with ideal PK properties in rodent, canine species ranging 28-83 % F, with low clearance, and >3.0 hr half-life. Within this profile, BLX-3030 was selected as a candidate that had the appropriate developable properties. Our plans for IND enabling studies and future clinical trial plans will also be discussed. Citation Format: Hariprasad Vankayalapati, Zhaoliang Li, Chenyu Lin, Kyle Medley, David J Bearss. Development of BLX-3030, a potent and selective inhibitor of CDK9 for the treatment of N-MYC driven NeuroEndocrine Prostate Cancers (NEPC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C166.

Ethnopsychopharmacology: Clinical and scientific writing pearls.

The concept of ethnopsychopharmacology aims to predict or explain the pharmacologic response to psychiatric medications based on the influence of biologic and nonbiologic factors. Interactions involving these factors are complex and influence patient outcomes in health care. Pharmacists and other clinicians working in patient care environments, research, or medical education should engage in lifelong learning to enhance ethnopsychopharmacologic knowledge gaps, which ultimately may improve and individualize care across diverse populations. Through two cases, this paper provides pearls on how biogeographical ancestry and cytochrome P450 status may influence pharmacotherapy selection, dosing, or response. A third scenario highlights a publication, like many other published works, with deficiencies in how data on ancestry, race, and ethnicity are collected or reported. Current recommendations on the use of inclusive language in scientific writing are reviewed, with attention to specific examples.

Dynamic Changes in ABL1 Kinase Domain Mutations and Comparative Efficacy of Third-Generation Tyrosine Kinase Inhibitors across Different Stages in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Blast Crisis Patients

*Drs.Zixuan Li and Danyue Peng contributed equally. Drs.Mei Hong and Qiuling Wu are co-corresponding authors Background The development of first-generation and second-generation tyrosine kinase inhibitors (TKIs) has played a crucial role in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). However, the emergence of mutations in the kinase domain (KD) of BCR-ABL1 has increasingly compromised the efficacy of TKIs and become the primary cause of TKI resistance. Testing BCR-ABL1 KD mutations in early phase accurately is of great value in predicting response and guiding therapeutic decisions. Next-generation sequencing (NGS) provided a more comprehensive and elaborate understanding of mutation status. Third-generation (3G) TKI has been designed to overcome resistance problems caused by BCR-ABL1 KD mutations, and it exhibited unique pharmacological profiles and response patterns relative to different mutations and disease characteristics. Therefore, the potential clinical relevance of mutations detected by NGS and the efficacy of 3G TKI are worth exploring. Methods NGS was used to analyze the dynamic changes of both clinically unreported mutations and reported resistant mutations in the ABL1 KD during three stages of the disease course (pretreatment, remission, and relapsed periods) in Ph+ ALL (n = 97) and chronic myeloid leukemia blast crisis (CML-BP) (n = 21) patients. Meanwhile, the comparative efficacy of three generations of TKIs in Ph+ ALL (n = 92) and CML-BP (n = 23) and the relationship between ABL1 KD mutations and different TKI selection were analyzed. Results In Ph+ ALL patients, single ABL1 KD unreported mutations were detected in 30.49% of patients before therapy and 39.73% in remission, which accounted for the highest proportion among other mutation types. Conversely, single ABL1 KD resistant mutations were found to be the most prevalent (54.5%) in relapsed patients ( P < 0.0001). Logistic analysis revealed that the presence of F401V/L in untreated Ph+ ALL patients was associated with a higher risk of relapse ( P < 0.1). Furthermore, through analyzing patients who received TKI treatment, we observed that 3G TKIs like olverembatinib exhibited advantages in prognosis, including achieving deep molecular response, rapid remission reduction, and decreased relapse probability, for both newly diagnosed and relapsed Ph+ ALL patients. Notably, 3G TKIs not only demonstrated strong inhibition against the T315I mutation, as previously reported, but also displayed superior effectiveness against certain ABL1 KD unreported mutations, such as R516L, K262T, and F401V. Similar trends were observed in CML-BP, although statistical significance was not reached likely due to the limited number of patients. Conclusion Overall, our findings indicate the prevalence and impact of ABL1 KD mutations in Ph+ ALL and CML-BP patients, highlighting the necessity for effective therapies targeting these mutations. The promising outcomes observed with 3G TKIs suggest their potential as a treatment option for both newly diagnosed and relapsed Ph+ ALL patients, offering advantages in terms of molecular response depth, rapid remission, and reduced relapse risk. Further investigations are warranted to explore the clinical significance of unreported ABL1 KD mutations and validate the effectiveness of 3G TKIs against them.