Development Of Cancer Therapeutics Research Articles

Pan-Cancer Drug Sensitivity Prediction from Gene Expression using Deep Learning.

Cancer is a group of complex diseases, with tumor heterogeneity, durable drug efficacy, emerging resistance, and host toxicity presenting major challenges to the development of effective cancer therapeutics. While traditionally used methods have remained limited in their capacity to overcome these challenges in cancer drug development, efforts have been made in recent years toward applying "big data" to cancer research and precision oncology. By curating, standardizing, and integrating data from various databases, we developed deep learning architectures that use perturbation and baseline transcriptional signatures to predict efficacious small molecule compounds and genetic dependencies in cancer. A series of internal validations followed by prospective validation in prostate cancer cell lines were performed to ensure consistent performance and model applicability. We report SensitivitySeq, a novel bioinformatics tool for prioritizing small molecule compounds and gene dependencies in silico to drive the development of targeted therapies for cancer. To the best of our knowledge, this is the first supervised deep learning approach, validated in vitro, to predict drug sensitivity using baseline cancer cell line gene expression alongside cell line-independent perturbation-response consensus signatures.

Abstract A030: Beyond the LNP: Self-amplifying RNA with LION nanoformulation technology for development of safe and effective cancer therapeutics

Abstract HDT Bio, a Seattle biotech company, has developed a platform technology based on self-amplifying RNA and a proprietary nanoparticle delivery system. mRNA have been increasingly used in the development of vaccines in both infectious diseases and oncology. Especially LNP- delivered mRNA has been deployed, following the success during the COVID pandemic, However, self-ampliying RNA (repRNA) possesses several features of particular relevance to cancer medicine. HDT has developed a nanoparticle technology named LION[TM] to safely and effectively deliver RNA to patients. In vivo studies showed that repRNA not only is capable of delivering robust cell-mediated immune responses but also doing so with a significanlty improved safety profile compared to administration using LNP-based formulations. These data will be presented in the context of clinical safety data with repRNA/LION. Furthermore, repRNA/LION was siuccessfully used to induce robust T-cell responses against tumor antigens, and will be discussed. Citation Format: Peter Berglund. Beyond the LNP: Self-amplifying RNA with LION nanoformulation technology for development of safe and effective cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A030.

Immune Cell-Derived Exosomes: A Cell-Free Cutting-Edge Tumor Immunotherapy.

Extracellular vesicles (EVs) are cellular communication molecules and are classified into three major subpopulations, such as microvesicles, apoptotic bodies, and exosomes. Among these, exosomes-based cancer research is a cutting-edge investigation approach to cancer understanding. During cancer progression , tumor-derived exosomes can reprogram the cellular system and promote cancer. Circulating exosomes in the body fluids such as blood, plasma, serum, saliva, CSF, sweat, and tears play a key role in identifying diagnostic and prognostic cancer biomarkers. Diverse therapeutic sources of exosomes including stem cells, plants, and immune cells, etc. exhibit significant cancer-healing properties. Although cancer-targeting immunotherapy is an effective strategy, it has limitations such as toxicity, and high costs. In comparison, immune cell-derived exosomes-based immunotherapy is a cell-free approach for cancer treatment and has advantages like less toxicity, biocompatibility, reduced immunogenicity, and efficient, target-specific cancer therapeutic development. This review highlights the therapeutic signature of immune cell-derived exosomes for cancer treatment.

A Call for Innovative Translational and Clinical Research to Address China's Unique Cancer Landscape.

The Chinese government has, in recent decades, implemented various administrative laws and regulatory policies to expedite cancer therapeutic development, boosting research and development pipelines for domestic pharmaceutical companies and clinical trials; however, China faces unique challenges given the high prevalence of certain cancer types and distinct disease burdens, some of which are frequently overlooked by international pharmaceutical companies. Given the substantial unmet need for China-specific cancer care, it is crucial to promote the development of innovative pharmaceutical and clinical research in China, with a particular emphasis on addressing tumors most prevalent in its population.

Translational Relevance and Future Integration of the Oncopig Cancer Model in Preclinical Applications.

Porcine cancer models offer a valuable platform for evaluating interventions such as devices, surgeries, and locoregional therapies, which are often challenging to test in mouse models. In addition to size and anatomical similarities with humans, pigs share greater similarities in genetics, immunity, drug metabolism, and metabolic rate with humans as compared to mouse models, increasing their translational relevance. This review focuses on the Oncopig Cancer Model, a genetically engineered porcine model designed to recapitulate human cancer. Harboring a transgenic cassette that expresses oncogenic mutant KRAS and TP53 under control of a Cre-Lox system, the Oncopig allows temporal and spatial control of tumor induction. Its versatility has enabled the development of diverse cancer models including liver, pancreatic, lung, and bladder cancer. Serving as a clinically relevant model for human cancer, the Oncopig addresses unmet clinical needs and holds immense promise for advancing preclinical cancer research and therapeutic development.

Differential effect of plakoglobin in restoring the tumor suppressor activities of p53-R273H vs. p53-R175H mutants.

The six most common missense mutations in the DNA binding domain of p53 are known as "hot spots" and include two of the most frequently occurring p53 mutations (p53-R175H and p53-R273H). p53 stability and function are regulated by various post-translational modifications such as phosphorylation, acetylation, sumoylation, methylation, and interactions with other proteins including plakoglobin. Previously, using various carcinoma cell lines we showed that plakoglobin interacted with wild-type and several endogenous p53 mutants (e.g., R280K, R273H, S241F, S215R, R175H) and restored their tumor suppressor activities in vitro. Since mutant p53 function is both mutant-specific and cell context-dependent, we sought herein, to determine if plakoglobin tumor suppressive effects on exogenously expressed p53-R273H and p53-R175H mutants are similarly maintained under the same genetic background using the p53-null and plakoglobin-deficient H1299 cell line. Functional assays were performed to assess colony formation, migration, and invasion while immunoblotting and qPCR were used to examine the subcellular distribution and expression of specific proteins and genes that are typically regulated by or regulate p53 function and are altered in mutant p53-expressing cell lines and tumors. We show that though, plakoglobin interacted with both p53-R273H and p53-R175H mutants, it had a differential effect on the transcription and subcellular distribution of their gene targets and their overall oncogenic properties in vitro. Notably, we found that plakoglobin's tumor suppressive effects were significantly stronger in p53-R175H expressing cells compared to p53-R273H cells. Together, our results indicate that exploring plakoglobin interactions with p53-R175H may be useful for the development of cancer therapeutics focused on the restoration of p53 function.

11 Oral: Transforming cancer care and therapeutic development by predicting individual patient responses to treatment

11 Oral: Transforming cancer care and therapeutic development by predicting individual patient responses to treatment

Machine learning optimized DriverDetect software for high precision prediction of deleterious mutations in human cancers.

The detection of cancer-driving mutations is important for understanding cancer pathology and therapeutics development. Prediction tools have been created to streamline the computation process. However, most tools available have heterogeneous sensitivity or specificity. We built a machine learning-derived algorithm, DriverDetect that combines the outputs of seven pre-existing tools to improve the prediction of candidate driver cancer mutations. The algorithm was trained with cancer gene-specific mutation datasets of cancer patients to identify cancer drivers. DriverDetect performed better than the individual tools or their combinations in the validation test. It has the potential to incorporate future novel prediction algorithms and can be retrained with new datasets, offering an expanded application to pan-cancer analysis for cross-cancer study. (115 words).

Landscape of exosomes to modified exosomes: a state of the art in cancer therapy.

Exosomes are a subpopulation of extracellular vesicles (EVs) that naturally originate from endosomes. They play a significant role in cellular communication. Tumor-secreted exosomes play a crucial role in cancer development and significantly contribute to tumorigenesis, angiogenesis, and metastasis by intracellular communication. Tumor-derived exosomes (TEXs) are a promising biomarker source of cancer detection in the early stages. On the other hand, they offer revolutionary cutting-edge approaches to cancer therapeutics. Exosomes offer a cell-free approach to cancer therapeutics, which overcomes immune cell and stem cell therapeutics-based limitations (complication, toxicity, and cost of treatment). There are multiple sources of therapeutic exosomes present (stem cells, immune cells, plant cells, and synthetic and modified exosomes). This article explores the dynamic source of exosomes (plants, mesenchymal stem cells, and immune cells) and their modification (chimeric, hybrid exosomes, exosome-based CRISPR, and drug delivery) based on cancer therapeutic development. This review also highlights exosomes based clinical trials and the challenges and future orientation of exosome research. We hope that this article will inspire researchers to further explore exosome-based cancer therapeutic platforms for precision oncology.

Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound’s selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.

Discovery and biological evaluation of 6-aryl-4-(3,4,5-trimethoxyphenyl)quinoline derivatives with promising antitumor activities as novel colchicine-binding site inhibitors

Tubulin, as the fundamental unit of microtubules, is a crucial target in the investigation of anticarcinogens. The synthesis and assessment of small-molecule tubulin polymerization inhibitors remains a promising avenue for the development of novel cancer therapeutics. Through an analysis of reported colchicine-binding site inhibitors (CBSIs) and tubulin binding models, a set of 6-aryl-4-(3,4,5-trimethoxyphenyl)quinoline derivatives were meticulously crafted as potential CBSIs. Notably, compound 14u exhibited potent anti-proliferative efficacy, displaying IC50 values ranging from 0.03 to 0.18 μM against three human cancer cell lines (Huh7, MCF-7, and SGC-7901). Mechanistic investigations revealed that compound 14u could disrupt tubulin polymerization, dismantle the microtubule architecture, arrest the cell cycle at G2/M phase, and induce apoptosis in cancer cells. Furthermore, compound 14u demonstrated significant inhibition of tumor proliferation in vivo with no discernible toxicity in the Huh7 orthotopic tumor model mice. Additionally, physicochemical property predictions indicated that compound 14u adhered well to Lipinski's rule of five. These findings collectively suggest that compound 14u holds promise as an antitumor agent targeting the colchicine-binding site on tubulin and warrants further investigation.

3D Modeling: Insights into the Metabolic Reprogramming of Cholangiocarcinoma Cells.

Developing accurate in vitro models that replicate the in vivo tumor environment is essential for advancing cancer research and therapeutic development. Traditional 2D cell cultures often fail to capture the complex structural and functional heterogeneity of tumors, limiting the translational relevance of findings. In contrast, 3D culture systems, such as spheroids, provide a more physiologically relevant context by replicating key aspects of the tumor microenvironment. This study aimed to compare the metabolism of three intrahepatic cholangiocarcinoma cell lines in 2D and 3D cultures to identify metabolic shifts associated with spheroid formation. Cells were cultured in 2D on adhesion plates and in 3D using ultra-low attachment plates. Metabolic exchange rates were measured using NMR, and intracellular metabolites were analyzed using LC-MS. Significant metabolic differences were observed between 2D and 3D cultures, with notable changes in central carbon and glutathione metabolism in 3D spheroids. The results suggest that 3D cultures, which more closely mimic the in vivo environment, may offer a more accurate platform for cancer research and drug testing.

Discovery of telomerase inhibitors: existing strategies and emerging innovations.

Telomerase, crucial for maintaining telomere length, is an attractive target for cancer therapy due to its role in cellular immortality. Despite three decades of research efforts, no small-molecule telomerase inhibitors have been clinically approved, highlighting the extensive challenges in developing effective telomerase-based therapeutics. This review examines conventional and emerging methods to measure telomerase activity and discusses existing inhibitors, including oligonucleotides and small molecules. Furthermore, this review highlights recent breakthroughs in structural studies of telomerase using cryo-electron microscopy, which can facilitate improved structure-based drug design. Altogether, advancements in structural methodologies and high-throughput screening offer promising prospects for telomerase-based cancer therapeutic development.

Pixantrone as a novel MCM2 inhibitor for ovarian cancer treatment

BackgroundMini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation. MethodsMolecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo. ResultsPixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety. ConclusionThese findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic.

Chemical characterization and cytotoxic effect of three edible fungi (Morchella) against breast cancer cells: A therapeutic approach

Current breast cancer therapeutics are associated with short-term efficacy, increased drug resistance, and severe adverse reactions, thus demanding the development of new therapeutic approaches. This present study aimed to explore the cytotoxic activity of Morchella extracts in the context of the MCF-7 cell line (breast cancer) and ultra-performance liquid chromatography mass spectroscopy (UPLC-MS) analysis. The cytotoxic activity of the Morchella conica, Morchella delicosa, and Morchella escuelnta extracts was examined against the breast cancer cell line (MCF-7), using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay (MTT assay). The Morchella extracts were screened for the presence of compounds using ultra-performance liquid chromatography mass spectroscopy (UPLC-MS/MS) based analysis. All the Morchella extracts actively restricted the viability and proliferation of breast cancer cells in a dose-dependent manner, with half maximal inhibitory concentration (IC50) values ranging from 0.017 to 0.68 mg/ml. The main compounds identified in Morchella include alkaloid, sterol, flavonoid, terpenoid, fatty acid, peptide, glutamic acid, amino acid, coumarin, and cyclopyrrolone. In conclusion, Morchella extracts exhibited cytotoxic effects against breast cancer cell lines and decreased the viability of MCF-7 cell line. The Morchella compounds might be the main components contributing to the inhibition of breast cancer cells. The findings of this research offer an innovative framework for advanced investigations for the development of cancer therapeutics from this fungus.

Tumor and cancer stem cells‐derived exosomes interplay: A secret of cancer complications

AbstractCancer stem cells (CSCs) are a small subset of tumor cells, efficient in self‐renewal within the tumor and also play a vital role in cancer resistance and metastasis. Recent cancer research has focused on exosomes, a tiny subpopulation of extracellular vesicles (EVs), known for their role in intercellular communication, and significantly contributing to tumor development and metastasis (Tumor derived exosomes‐TEXs). These exosomes complicate cancer treatment by promoting tumor and CSC formation and developing drug and therapeutic resistance. This article explores how tumor‐derived exosomes impact CSC survival, proliferation, and resistance to therapies, leading to tumor recurrence. In a tumor microenvironment (TME), exosomes facilitate tumor growth and metastasis. Targeting exosomes could disrupt CSC communication and improve cancer treatment efficacy. Current studies highlight the role of CSCs exosomes in cancer progression and therapeutic resistance. Understanding CSCs exosome‐based cell‐to‐cell communication in tumor opens a new horizon in cancer therapeutics development.

Mechanistic insights into xanthomicrol as the active anti-HCC ingredient of Phytolacca acinosa Roxb.: A network pharmacology analysis and transcriptomics integrated experimental verification

Ethnopharmacological relevancePhytolacca acinosa Roxb. (PAR) is a Traditional Chinese Medicinal (TCM) plant with a broad global distribution encompassing 35 species, four of which are found in the People's Republic of China. It occupies a significant role in both Oriental and American traditional medicine, employed in treating a range of conditions such as edema, inflammation, dermatitis, and rheumatism. PAR is also used as a molluscicide and for addressing tumors and bronchitis. The plant is documented in the Chinese Pharmacopoeia and has a longstanding history in TCM, particularly for its diuretic properties and in treating ailments such as edema, swelling, and ulcers. Notably, PAR has demonstrated potent inhibitory effects against the A549 human lung cancer cell line, underscoring its potential in contributing to the development of novel cancer therapeutics. Aim of the studyThe research aims to elucidate the active components of PAR and their mechanisms in treating hepatocellular carcinoma (HCC). Materials and methodsEmploying network pharmacology, this study predicted the principal active compounds and key targets of PAR. A holistic methodology incorporating biological network analysis, transcriptomics sequencing, molecular docking, and molecular dynamics (MD) simulations was utilized to forecast the effects of PAR on HCC, with empirical evidence supporting these findings. ResultsNetwork pharmacology identified xanthomicrol as the foremost active compound in PAR. The tumor-suppressive functions of PAR, as indicated by KEGG pathway analysis and transcriptomics sequencing, predominantly occur via the PI3K/AKT pathway. Molecular docking and dynamics simulations demonstrated the high affinity of xanthomicrol towards TNF, MMP9, PPARG, KDR, and MMP2. In vivo experiments verified the efficacy of xanthomicrol in curtailing HCC tumor growth, while in vitro assessments revealed its substantial impact on the proliferation and apoptosis of HepG2 and HCCLM3 cells. Moreover, the study indicates that xanthomicrol may modulate the expression of TNF, MMP9, PPARG, KDR, and MMP2 in HCC cells and inhibit the activation of the PI3K/AKT pathway. ConclusionsXanthomicrol, a principal active component of PAR, has been identified to impede the growth of HCC by targeting the PI3K/Akt/MMP9 pathway. This insight could enhance therapeutic approaches for HCC.

LAPTM4B counteracts ferroptosis via suppressing the ubiquitin-proteasome degradation of SLC7A11 in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.

Engineered cell versus modified exosomes in cancer therapy

AbstractCancer therapeutic development is the most challenging domain in cancer. Cell‐based cancer therapeutics come up with promising effectiveness. This approach was also cell‐modified for better targeting efficiency development. Cell engineering‐based cancer therapeutic is a cutting‐edge method in cancer therapy. Due to complications of this process, cost and post‐treatment side effects, this phenomenon came into the question mark. In this scenario, extracellular vesicle (EVs) research introduces a cell‐free cancer therapeutic approach. In the therapeutic aspect most used EVs, come from stem cells, plants, and engineered cells. Among several EVs populations, Exosomes are the most used worldwide cell‐free therapeutic tool for ageing cancer. The most interesting facts about exosomes are the biocompatible, non‐immunoreactive, cross‐biological barrier, and non‐toxic (depending on the parental cell's nature). In this article, we are exploring modified exosomes (biological or chemical) that create a remarkable outcome in cancer therapeutic development compared to engineered cell‐based therapeutics. Hope, in the future, modified exosomes become an effective, affordable, and specific cancer‐targeting precision medicine.

Structural basis for the bi-specificity of USP25 and USP28 inhibitors

The development of cancer therapeutics is often hindered by the fact that specific oncogenes cannot be directly pharmaceutically addressed. Targeting deubiquitylases that stabilize these oncogenes provides a promising alternative. USP28 and USP25 have been identified as such target deubiquitylases, and several small-molecule inhibitors indiscriminately inhibiting both enzymes have been developed. To obtain insights into their mode of inhibition, we structurally and functionally characterized USP28 in the presence of the three different inhibitors AZ1, Vismodegib and FT206. The compounds bind into a common pocket acting as a molecular sink. Our analysis provides an explanation why the two enzymes are inhibited with similar potency while other deubiquitylases are not affected. Furthermore, a key glutamate residue at position 366/373 in USP28/USP25 plays a central structural role for pocket stability and thereby for inhibition and activity. Obstructing the inhibitor-binding pocket by mutation of this glutamate may provide a tool to accelerate future drug development efforts for selective inhibitors of either USP28 or USP25 targeting distinct binding pockets.