Development Of Cancer Therapeutics Research Articles

Abstract 4897: Personalized cell surface target identification from pan-cancer RNA-seq and proteomics profiling of tumors

Abstract In its third phase, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) program collected pan-cancer data from 1,069 patients profiling the transcriptome, proteome, and phospho-proteome of tumors and adjacent tissues from ten cancer types. To identify potential immunotherapeutic candidates from this CPTAC cohort, we searched for cell-surface proteins that are highly expressed in tumor subtypes compared to their expression in normal tissues and cell types from ARCHS4 and the Genotype-Tissue Expression (GTEx) resources. For each cancer type, tumor samples were first clustered into subtypes based on RNA-seq data, and then cell surface targets were prioritized for each cluster. These targets were subsequently confirmed for high protein expression in the tumor subtypes. Tumor samples were also processed by their classification into immune subtypes to identify targets specific to hot (CD8+/IFNG+) and cold (CD8-/IFNG-) tumors of each cancer type. For each cancer type, the computational pipeline identified ~30 cell surface proteins that are highly expressed in the tumor and lowly expressed across tissues and cell types in both the ARCHS4 and GTEx backgrounds. Many of these targets are also robustly differentially expressed at the proteome level. Several targets were shared across tumor types, including VTCN1 and TMPRSS4. Altogether, this rational approach to identify potential targets demonstrates a pipeline that can be applied for personalized cancer diagnosis and therapeutic development. Citation Format: Giacomo B. Marino, Eden Z. Deng, Daniel J.B. Clarke, Weiping Ma, Pei Wang, Adam C. Resnick, Avi Ma'ayan. Personalized cell surface target identification from pan-cancer RNA-seq and proteomics profiling of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4897.

Abstract 1981: Profiling of protein interactome with cysteine-reactive libraries led to the discovery of EML4ALK dimerizers

Abstract Cysteine covalent binders enable direct interactions with previously deemed undruggable protein targets, revolutionizing cancer therapeutics development. The primary focus has been on tailoring single-warhead compounds to target specific cysteine residues within the functional domains of target proteins. However, the biochemical properties including dimerization, induced conformational changes, and interactome disruption have been underexplored, presenting an ongoing limitation in current drug discovery approaches. In this study, we generated a library of 32 cysteine-reactive warhead compounds using various combinations of scaffolds and warheads to represent diverse reactivities. A combinatory assay approach, including cysteine druggability mapping (CDM) to discover reactive residues and SDS-PAGE fractionation assays to identify disrupted protein interaction events, was employed. Characterization of the library revealed distinct reactive cysteines and dimerization profiles among the 32 unique compounds. Compound 1C9, identified as a lead compound, demonstrated significant dimerization of EML4, a common fusion gene partner in lung cancer. Using the EML4ALK fusion gene as a proof of concept, we explored potential mechanisms underlying the compound-induced dimerization of EML4. Subsequent structure-activity relationship (SAR) studies and screening of 70 additional compounds were conducted to optimize ALK dimerization and minimize off-target effects. The enhanced compound disrupted the ALK cellular signaling pathways AKT and ERK upon dimerization of the EML4ALK fusion gene. Additionally, we discovered that covalent dimerization induced EML4ALK degradation without requiring a ubiquitin ligase like a PROTAC. In conclusion, our work has uncovered a novel class of cysteine covalent binders, which we believe are valuable tools to modulate protein-protein interactions in previously undruggable proteins in cancer. This discovery holds significant therapeutic potential for future drug development. Citation Format: Diane Yang, Stefan Harry, Elizabeth Codd, Stefan T. Kaluziak, Alexander D. Carlin, Edwin Zhang, Zavontae Oppong-Holmes, Wenxin Yang, Abigail Smith, Dawn Mitchell, Mariko Hara, Siwen Zhang, Maristela Onozato, Liron Bar-Peled, Anthony J. Iafrate. Profiling of protein interactome with cysteine-reactive libraries led to the discovery of EML4ALK dimerizers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1981.

Liver X Receptors (LXRs) in cancer-an Eagle's view on molecular insights and therapeutic opportunities.

Cancer has become a serious health burden that results in high incidence and mortality rates every year, mainly due to various molecular alterations inside the cell. Liver X receptors (LXRs) dysregulation is one among them that plays a vital role in cholesterol metabolism, lipid metabolism and inflammation and also plays a crucial role in various diseases such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular diseases, Type 2 diabetes, osteoporosis, and cancer. Studies report that the activation of LXRs inhibits cancer growth by inhibiting cellular proliferation, inducing apoptosis and autophagy, regulating cholesterol metabolism, various signalling pathways such as Wnt, and PI3K/AKT, modulating the expression levels of cell-cycle regulators, and promoting antitumor immunity inside the tumor microenvironment. In this review, we have discussed the role, structure, and functions of LXRs and also summarized their ligands along with their mechanism of action. In addition, the role of LXRs in various cancers, tumor immunity and tumor microenvironment (TME) along with the importance of precision medicine in LXR-targeted therapies has been discussed to emphasize the LXRs as potent targets for the development of novel cancer therapeutics.

DDX3X and Stress Granules: Emerging Players in Cancer and Drug Resistance.

The DEAD (Asp-Glu-Ala-Asp)-box helicase 3 X-linked (DDX3X) protein participates in many aspects of mRNA metabolism and stress granule (SG) formation. DDX3X has also been associated with signal transduction and cell cycle regulation that are important in maintaining cellular homeostasis. Malfunctions of DDX3X have been implicated in multiple cancers, including brain cancer, leukemia, prostate cancer, and head and neck cancer. Recently, literature has reported SG-associated cancer drug resistance, which correlates with a negative disease prognosis. Based on the connections between DDX3X, SG formation, and cancer pathology, targeting DDX3X may be a promising direction for cancer therapeutics development. In this review, we describe the biological functions of DDX3X in terms of mRNA metabolism, signal transduction, and cell cycle regulation. Furthermore, we summarize the contributions of DDX3X in SG formation and cellular stress adaptation. Finally, we discuss the relationships of DDX3X, SG, and cancer drug resistance, and discuss the current research progress of several DDX3X inhibitors for cancer treatment.

The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity.

The use of vitamin C (VC) in high doses demonstrates a potent tumor suppressive effect by mediating a glucose-dependent oxidative stress in Kirsten rat sarcoma (KRAS) mutant cancer cells. VC with arsenic trioxide (ATO) is a promising drug combination that might lead to the development of effective cancer therapeutics. Considering that a tumor suppressive effect of VC requires its high-dose administration, it is of interest to examine the toxicity of two enantiomers of VC (enantiomer d-optical isomer D-VC and natural l-optical isomer L-VC) in vitro and in vivo. We show that the combinations of L-VC with ATO and D-VC with ATO induced a similar cytotoxic oxidative stress in KrasG12D-expressing mutant cancer cells as indicated by a substantial increase in reactive oxidative species (ROS) production and depolarization of mitochondria. To examine the L-VC and D-VC toxicity effects, we administered high doses of D-VC and L-VC to CD1 mice and carried out an evaluation of their toxic effects. The daily injections of L-VC at a dose of 9.2 g/kg for 18 days were lethal to mice, while 80% of mice remained alive following the similar high-dose administration of D-VC. Following the drug injection courses and histopathological studies, we determined that a natural form of VC (L-VC) is more harmful and toxic to mice when compared to the effects caused by the similar doses of D-VC. Thus, our study indicates that the two enantiomers of VC have a similar potency in the induction of oxidative stress in cancer cells, but D-VC has a distinctive lower toxicity in mice compared to L-VC. While the mechanism of a distinctive toxicity between D-VC and L-VC is yet to be defined, our finding marks D-VC as a more preferable option compared to its natural enantiomer L-VC in clinical settings.

Marine-Derived Bisindoles for Potent Selective Cancer Drug Discovery and Development.

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications.

SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

Abstract PR02: Modeling breast cancer through somatic precision gene editing with high flexibility and efficiency

Abstract CRISPR/Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR/Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either Kras or Pik3ca in both normal and hyperplastic mammary glands led to swift tumorigenesis. The resulting tumors shared some histological, transcriptome, and proteome features with tumors induced by lentivirus-mediated expression of the respective oncogenes, but they also exhibited some distinct characteristics, particularly showing less inter-tumor variation, thus potentially offering more consistent models for cancer studies and therapeutic development. Therefore, this technological advance fills a critical gap between the power of CRISPR technology and high-fidelity mouse models for studying human tumor evolution and preclinical drug testing. Citation Format: Wen Bu, Yi Li, Chad J Creighton, Kelsey S Heavener, Carolina Gutierrez, Yongchao Dou, Weiyu Jiang, Bing Zhang, Amy T Ku, Shixia Huang. Modeling breast cancer through somatic precision gene editing with high flexibility and efficiency [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR02.

Biochanin A – A G6PD inhibitor: In silico and in vitro studies in non-small cell lung cancer cells (A549)

Secondary metabolites from medicinal plants have a well-established therapeutic potential, with many of these chemicals having specialized medical uses. Isoflavonoids, a type of secondary metabolite, have little cytotoxicity against healthy human cells, making them interesting candidates for cancer treatment. Extensive research has been conducted to investigate the chemo-preventive benefits of flavonoids in treating various cancers. Biochanin A (BA), an isoflavonoid abundant in plants such as red clover, soy, peanuts, and chickpeas, was the subject of our present study. This study aimed to determine how BA affected glucose-6-phosphate dehydrogenase (G6PD) in human lung cancer cells. The study provides meaningful insight and a significant impact of BA on the association between metastasis, inflammation, and G6PD inhibition in A549 cells. Comprehensive in vitro tests revealed that BA has anti-inflammatory effects. Molecular docking experiments shed light on BA's high binding affinity for the G6PD receptor. BA substantially decreased the expression of G6PD and other inflammatory and metastasis-related markers. In conclusion, our findings highlight the potential of BA as a therapeutic agent in cancer treatment, specifically by targeting G6PD and related pathways. BA's varied effects, which range from anti-inflammatory capabilities to metastasis reduction, make it an appealing option for future investigation in the development of new cancer therapeutics.

A positive feedback between PDIA3P1 and OCT4 promotes the cancer stem cell properties of esophageal squamous cell carcinoma

BackgroundIncreasing evidence has indicated that long non-coding RNAs (lncRNAs) have been proven to regulate esophageal cancer progression. The lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) has been shown to promote cancer stem cell properties; however, its mechanism of action remains unclear. In this study, we investigated the regulation of esophageal cancer stem cell properties by the interaction of PDIA3P1 with proteins.MethodsThe GEPIA2 and Gene Expression Omnibus databases were used to analyze gene expression. PDIA3P1 expression in human esophageal squamous cell carcinoma (ESCC) tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Loss-of-function experiments were performed to determine the effects of PDIA3P1 on ESCC cell proliferation, migration, and invasion. The sphere formation assay, number of side population cells, and CD271 + /CD44 + cells were detected by flow cytometry to identify the cancer stem cell properties. RNA immunoprecipitation (RIP), RNA pull-down, co-immunoprecipitation (co-IP), dual luciferase reporter, and cleavage under targets and tagmentation (CUT&Tag) assays were performed to elucidate the underlying molecular mechanisms.ResultsPDIA3P1 expression was upregulated in ESCC cell lines and tissues. Functionally, higher PDIA3P1 expression promoted cell proliferation, invasion, and metastasis and inhibited apoptosis in esophageal cancer. Importantly, PDIA3P1 promoted cancer stem cell properties in ESCC. Mechanistically, PDIA3P1 interacted with and stabilized octamer-binding transcription factor 4 (OCT4) by eliminating its ubiquitination by the ubiquitinating enzyme WW domain-containing protein 2 (WWP2). Moreover, as a transcription factor, OCT4 bound to the PDIA3P1 promoter and promoted its transcription.ConclusionsOur research revealed a novel mechanism by which a positive feedback loop exists between PDIA3P1 and OCT4. It also demonstrated that the PDIA3P1-WWP2-OCT4 loop is beneficial for promoting the cancer stem cell properties of ESCC. Owing to this regulatory relationship, the PDIA3P1-WWP2-OCT4-positive feedback loop might be used in the diagnosis and prognosis, as well as in the development of novel therapeutics for esophageal cancer.

CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways.

Cytochrome b5 reductase 3 (CYB5R3) is involved in various cellular metabolic processes, including fatty acid synthesis and drug metabolism. However, the role of CYB5R3 in cancer development remains poorly understood. Here, we show that CYB5R3 expression is downregulated in human lung cancer cell lines and tissues. Adenoviral overexpression of CYB5R3 suppresses lung cancer cell growth in vitro and in vivo. However, CYB5R3 deficiency promotes tumorigenesis and metastasis in mouse models. Transcriptome analysis revealed that apoptosis- and endoplasmic reticulum (ER) stress-related genes are upregulated in CYB5R3-overexpressing lung cancer cells. Metabolomic analysis revealed that CYB5R3 overexpression increased the production of nicotinamide adenine dinucleotide (NAD+) and oxidized glutathione (GSSG). Ectopic CYB5R3 is mainly localized in the ER, where CYB5R3-dependent ER stress signaling is induced via activation of protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme 1 alpha (IRE1α). Moreover, NAD+ activates poly (ADP-ribose) polymerase16 (PARP16), an ER-resident protein, to promote ADP-ribosylation of PERK and IRE1α and induce ER stress. In addition, CYB5R3 induces the generation of reactive oxygen species and caspase-9-dependent intrinsic cell death. Our findings highlight the importance of CYB5R3 as a tumor suppressor for the development of CYB5R3-based therapeutics for lung cancer.

Evaluation of Stability and In vitro Anti-Cancer Activity of Dihydroquercetin Nanoemulsion

Background: Dihydroquercetin (DHQ), also known as taxifolin, is a flavonoid commonly found in many plants. Dihydroquercetin has been documented to have powerful antioxidant activity and many beneficial properties for human health, especially its ability to inhibit certain types of cancer cells. However, its low solubility and bioavailability are major obstacles to biomedical applications. Moreover, DHQ is chemically unstable and quickly degrades when exposed to alkaline conditions. background: Dihydroquercetin (DHQ), also known as taxifolin, is a flavonoid and commonly found in many plants. Dihydroquercetin has been documented to have powerful antioxidant activity and many beneficial properties for human health, especially its ability to inhibit certain types of cancer cells. However, its low solubility and bioavailability are major obstacles to biomedical applications. Moreover, DHQ is chemically unstable and quickly degrades when exposed to alkaline conditions. Objective: In the present study, a DHQ nanoemulsion formulation was prepared by Self Nano- Emulsifying Drug Delivery System (SNEDDS) technique to overcome the above disadvantages. Methods: The obtained nanoemulsion system was evaluated for its micro-properties, stability, and in vitro cytotoxic activity against some cancer cells using tetrazolium dyes (MTS assay). Results: Measurement results showed that the DHQ nanoemulsion was successfully synthesized with typical mean droplet sizes from 9 to 11 nm, and revealed excellent stability over time. Dihydroquercetin in nanoemulsion form is more stable than the non-encapsulated form, as evidenced by the maintenance of droplet size in the nanometer range when dispersed in aqueous solution for up to 48 hours. This stability is particularly pronounced in both acidic and neutral environments. In vitro experiments on cytotoxic activities against A549, Hela, and HepG2 cancer cell lines indicated that the prepared DHQ nanoemulsion effectively inhibited the growth of all these cell lines with IC50 values (μg/mL) of 8.0, 20.4, and 29.5 respectively. Conclusion: From the detailed results above, it is evident that the solubility and bioavailability of DHQ can be improved by creating its nanostructure in the form of nanoemulsions. Furthermore, the nano form of DHQ carried within stable nanoemulsions exhibited better performance in inhibiting cancer cells compared to free DHQ. Therefore, further research is required to explore the development of cancer therapeutics utilizing nano DHQ emulsions.

Insightful t-SNE guided exploration spotlighting Palbociclib and Ribociclib analogues as novel WEE1 kinase inhibitory candidates

In the era of targeted therapeutics, protein kinases like WEE1 have become pivotal drug targets, especially for cancer therapy. Utilizing a multi-faceted approach, our study adds fresh insights to this endeavour. We employed the t-SNE algorithm, combined with ECFP4 fingerprints, to analyse the molecular similarity between FDA-approved drugs and known clinical trial inhibitors. Our t-SNE analysis identified the closest clusters to known inhibitors and selected 11 FDA-approved drugs for further study. Using the DrugSpaceX platform, we generated analogues for these 11 FDA-approved drugs. These analogues were refined according to Lipinski’s Rule of Five and Synthetic Accessibility scores, yielding 68,640 analogues for additional scrutiny. Among these, derivatives of Palbociclib and Ribociclib stood out as the most promising WEE1 inhibitors, based on docking scores and interaction patterns. Molecular dynamics simulations validated the stability of these protein-ligand interactions, particularly for DE50607359, a top-ranked Palbociclib analogue, which also met most pharmacokinetic parameters within acceptable limits. Our study uncovers new candidates for WEE1 inhibition not previously reported. With our multi-layered computational strategy, we provide a solid foundation for future experimental validation and targeted drug development in cancer therapeutics. Communicated by Ramaswamy H. Sarma

Target interactions for macrophage regulation: toward the development of therapeutics for cancer and inflammatory diseases

Target interactions for macrophage regulation: toward the development of therapeutics for cancer and inflammatory diseases

Plant-derived exosomes: a green approach for cancer drug delivery.

Plant-derived exosomes (PDEs) are natural extracellular vesicles (EVs). In the current decade, they have been highlighted for cancer therapeutic development. Cancer is a global health crisis and it requires an effective, affordable, and less side effect-based treatment. Emerging research based on PDEs suggests that they have immense potential to be considered as a therapeutic option. Research evidences indicate that PDEs' internal molecular cargos show impressive cancer prevention activity with less toxicity. PDEs-based drug delivery systems overcome several limitations of traditional drug delivery tools. Extraction of PDEs from plant sources employ diverse methodologies, encompassing ultracentrifugation, immunoaffinity, size-based isolation, and precipitation, each with distinct advantages and limitations. The core constituents of PDEs comprise of lipids, proteins, DNA, and RNA. Worldwide, a few clinical trials on plant-derived exosomes are underway, and regulatory affairs for their use as therapeutic agents are still not understood with clarity. This review aims to comprehensively analyze the current state of research on plant-derived exosomes as a promising avenue for drug delivery, highlighting anticancer activity, challenges, and future orientation in effective cancer therapeutic development.

A Quinquennial Review of Potent LSD1 Inhibitors Explored for the Treatment of Different Cancers, with Special Focus on SAR Studies.

Cancer bears a significant share of global mortality. The enzyme Lysine Specific Demethylase 1 (LSD1, also known as KDM1A), since its discovery in 2004, has captured the attention of cancer researchers due to its overexpression in several cancers like acute myeloid leukaemia (AML), solid tumours, etc</i>. The Lysine Specific Demethylase (LSD1) downregulation is reported to have an effect on cancer proliferation, migration, and invasion. Therefore, research to discover safer and more potent LSD1 inhibitors can pave the way for the development of better cancer therapeutics. These efforts have resulted in the synthesis of many types of derivatives containing diverse structural nuclei. The present manuscript describes the role of Lysine Specific Demethylase 1 (LSD1) in carcinogenesis, reviews the LSD1 inhibitors explored in the past five years and discusses their comprehensive structural activity characteristics apart from the thorough description of LSD1. Besides, the potential challenges, opportunities, and future perspectives in the development of LSD1 inhibitors are also discussed. The review suggests that tranylcypromine derivatives are the most promising potent LSD1 inhibitors, followed by triazole and pyrimidine derivatives with IC₅₀ values in the nanomolar and sub-micromolar range. A number of potent LSD1 inhibitors derived from natural sources like resveratrol, protoberberine alkaloids, curcumin, etc</i>. are also discussed. The structural-activity relationships discussed in the manuscript can be exploited to design potent and relatively safer LSD1 inhibitors as anticancer agents.

Study of Drug Targets Associated With Oncogenesis and Cancer Cell Survival and the Therapeutic Activity of Engineered Ashwagandha Extract Having Differential Withanolide Constitutions.

Ashwagandha (Withania somnifera) has gained worldwide popularity for a multitude of health benefits inclusive of cancer-preventive and curative effects. Despite numerous research data supporting the benefits of this wonder herb, the actual use of ashwagandha for cancer treatment in clinics is limited. The primary reason for this is the inconsistent therapeutic outcome due to highly variable composition and constitution of active ingredients in the plant extract impacting ashwagandha's pharmacology. We investigate here an engineered yield: an ashwagandha extract (Oncowithanib) that has a unique and fixed portion of active ingredients to achieve consistent and effective therapeutic activity. Using the MCF7 cell line, Oncowithanib was studied for its anti-neoplastic efficacy and drug targets associated with cell cycle regulation, translation machinery, and cell survival and apoptosis. Results demonstrate a dose-dependent decline in Oncowithanib-treated MCF7 cell viability and reduced colony-forming ability. Treated cells showed increased cell death as evidenced by enhancement of Caspase 3 enzyme activity and decreased expressions of cell proliferation markers such as Ki67 and Aurora Kinase A. Oncowithanib treatment was also found to be associated with expressional suppression of key cellular kinases such as RSK1, Akt1, and mTOR in MCF7 cells. Our findings indicate that Oncowithanib decreases MCF7 cell survival and propagation, and sheds light on common drug targets that might be good candidates for the development of cancer therapeutics. Further in-depth investigations are required to fully explore the potency and pharmacology of this novel extract. This study also highlights the importance of the standardization of herbal extracts to get consistent therapeutic activity for the disease indication.

Personalizing Oncolytic Immunovirotherapy Approaches.

Development of successful cancer therapeutics requires exploration of the differences in genetics, metabolism, and interactions with the immune system among malignant and normal cells. The clinical observation of spontaneous tumor regression following natural infection with microorganismhas created the premise of their use as cancer therapeutics. Oncolytic viruses (OVs) originate from viruses with attenuated virulence in humans, well-characterized vaccine strains of known human pathogens, or engineered replication-deficient viral vectors. Their selectivity is based on receptor expression level and postentry restriction factors that favor replication in the tumor, while keeping the normal cells unharmed. Clinical trials have demonstrated a wide range of patient responses to virotherapy, with subgroups of patients significantly benefiting from OV administration. Tumor-specific gene signatures, including antiviral interferon-stimulated gene (ISG) expression profile, have demonstrated a strong correlation with tumor permissiveness to infection. Furthermore, the combination of OVs with immunotherapeutics, including anticancer vaccines and immune checkpoint inhibitors [ICIs, such as anti-PD-1/PD-L1 or anti-CTLA-4 and chimeric antigen receptor (CAR)-T or CAR-NK cells], could synergistically improve the therapeutic outcome. Creating response prediction algorithms represents an important step for the transition to individualized immunovirotherapy approaches in the clinic. Integrative predictors couldinclude tumor mutational burden (TMB), inflammatory gene signature, phenotype of tumor-infiltrating lymphocytes, tumor microenvironment (TME), and immune checkpoint receptor expression on both immune and target cells. Additionally, the gut microbiota has recently been recognized as a systemic immunomodulatory factor and could further be used in the optimization of individualized immunovirotherapy algorithms.

Enhanced therapeutic efficacy of doxorubicin/cyclophosphamide in combination with pitavastatin or simvastatin against breast cancer cells

Fighting breast tumors mandates finding different agents devoid of chemotherapy side effects. Repurposing existing drugs, such as statins, presents a promising avenue for the development of novel cancer therapeutics. Based on the different effects of statin members, this study aims to evaluate the effect of two of the most promising lipophilic statins, Simvastatin and Pitavastatin, and their combination with a conventional chemotherapeutic regimen of doxorubicin and cyclophosphamide on breast cancer cells. MDA-MB-231 and MCF7 cell lines were used to analyze the effects of Pitavastatin and simvastatin in combination with doxorubicin/cyclophosphamide. Cell viability and cell cycle were analyzed and certain apoptosis-related genes such as Bax, Bcl2, and caspase-3, besides cyclin D1 were analyzed using qPCR. The viability of breast cancer cells decreased significantly after treatment with a doxorubicin/cyclophosphamide combination in the presence of Pitavastatin or simvastatin compared with dual doxorubicin/cyclophosphamide with a higher effect in MDA-MB-231 cells than MCF7. In MDA-MB-231, The triple combination of Pitavastatin or simvastatin with doxorubicin/cyclophosphamide resulted in an increase in the expression levels of apoptotic markers than treatment with doxorubicin/cyclophosphamide combination (Bax (p-value = 0.09& 0.02, respectively), Bax/Bcl2 ratio (p-value = 0.0002& <0.0001, respectively)). However, the increase in caspase3 wasn’t significant (p-value = 0.45& 0.09, respectively). Moreover, the expression of cyclin D1 decreased (p-value = 0.0002& <0.0001, respectively) and the cell cycle was arrested in the G1 phase. Combination of Pitavastatin or simvastatin with doxorubicin/ cyclophosphamide may induce apoptosis in breast cancer cells via upregulation of the Bax/Bcl2 pathway, potentially providing a promising new therapeutic strategy for breast cancer.

Unlocking the potential of aromatase inhibitors: recent advances in drug design, synthesis, docking activity, and in vitro bioactivity evaluations

Breast cancer, a global health concern claiming approximately 685,000 lives in 2020, necessitates continual advancements in therapeutic strategies. Estrogen and aromatase play pivotal roles in hormone-responsive breast cancer, with 80% of patients exhibiting estrogen receptor-positive tumors. Aromatase inhibitors (AIs), notably non-steroidal inhibitors like anastrozole and letrozole, have significantly improved outcomes, yet challenges persist, including side effects. This review focuses on recent developments in AIs, exploring xanthone derivatives, imidazole derivatives, and curcumin derivatives as potential inhibitors of aromatase. Molecular docking studies, employing Auto Dock and other tools, reveal the binding affinities and interactions of these compounds with the aromatase enzyme. Among xanthones, Erythrommone emerges as a potent inhibitor, holding promise for clinical trials. Imidazole derivatives, synthesized through the Debus-Radziszewski reaction, demonstrate anticancer potential, with compounds like 1a exhibiting superior efficacy against MCF7 cells. ADME-Tox analyses indicate promising drug-likeness but reveal potential mutagenic effects and environmental impacts. Curcumin derivatives, particularly 1,5-diaryl-1,4-pentadien-3-ones, present alternatives to address curcumin's bioavailability challenges. A study of 25 compounds (DKC) identifies DKC-10 as a potent inhibitor, outperforming established breast cancer drugs in terms of binding affinity and interactions with aromatase and ERα+ receptors. These findings underscore the importance of exploring diverse chemical structures in developing AIs, paving the way for more effective and well-tolerated therapeutics. The integration of computational techniques, such as molecular docking studies, accelerates drug discovery by predicting interactions at the molecular level. Overall, this comprehensive review provides valuable insights into the evolving landscape of aromatase inhibitors, offering a roadmap for future research and the development of advanced breast cancer therapeutics.