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Frontiers in Antibody-Drug Conjugates: Mechanisms, Design Innovations, and Clinical Applications in Targeted Cancer Therapy.

Antibody-drug conjugates (ADCs) represent a transformative class of targeted therapies designed to deliver potent cytotoxic agents specifically to tumor cells, minimizing systemic toxicity. This review provides a comprehensive overview of ADCs, detailing their mechanisms of action, design strategies, and clinical advancements. ADCs utilize monoclonal antibodies to selectively bind tumor-associated antigens, enabling the precise delivery of toxic payloads to cancer cells. The review explores the critical components of ADCs, including the antibody, linker, and payload, and highlights how these e

NF-κB: master regulator of cellular responses in health and disease.

The NF-κB transcription control proteins play widespread roles in cellular behavior, regulating immune responses, inflammation, cell survival, proliferation, and development. Here, we attempt to comprehensively review these diverse functions and underlying mechanisms, leading readers to relevant references of both historic and topical importance. Because of the huge number of NF-κB control mechanisms and functions, and the vast literature that describes these, being comprehensive is a daunting task but we hope that readers will find clues to lead them to whatever understanding they may seek. A

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… More nuanced approaches are exploring context-specific modulation, such as targeting tissue-specific enhancers and epigenetic readers, or using proteolysis-targeting chimeras (PROTACs) to selectively degrade NF-κB subunits [ 153 ]. … PROTACs (Proteolysis-Targeting Chimeras) A NIK-directed PROTAC that recruits the ubiquitin–proteasome system to degrade NIK, a key regulator of the non-canonical NF-κB pathway. …

Nucleic acid aptamers in orthopedic diseases: promising therapeutic agents for bone disorders.

Precision medicine has become a cornerstone in modern therapeutic strategies, with nucleic acid aptamers emerging as pivotal tools due to their unique properties. These oligonucleotide fragments, selected through the Systematic Evolution of Ligands by Exponential Enrichment process, exhibit high affinity and specificity toward their targets, such as DNA, RNA, proteins, and other biomolecules. Nucleic acid aptamers offer significant advantages over traditional therapeutic agents, including superior biological stability, minimal immunogenicity, and the capacity for universal chemical modificatio

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio.

To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatme

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… NCT03291938 NCT02882321 Complex III Atovaquone | Complex III inhibition | FDA-approved for anti-malaria therapy; Clinical trials phase I | ( 62 , 63 ) Pyrazinib | OCR/ECAR reduction | Precise target unknown | ( 64 ) Other pathways ADI-PEG | Arginine depletion | Arginine deiminase and polyethylene glycol chimera … ADI-PEG 20, a chimera of the arginine deiminase (ADI) and polyethylene glycol (PEG) ( 347 ), consumes the cellular arginine by catalyzing the conversion of arginine to citrulline, a clinical marker for radiation-induced tissue toxicity ( 348 ). …

LAPTM proteins in neurological disorders - Autophagy-lysosome dysfunction and therapeutic targets: A review.

Lysosomal-associated protein transmembrane (LAPTM) family members-LAPTM4A, LAPTM4B, and LAPTM5-regulate lysosomal integrity, autophagy-lysosome flux, lipid homeostasis, and immune signaling, pathways increasingly implicated in neurological disease. This review synthesizes structure-function evidence for LAPTM proteins and examines how their dysregulation contributes to Alzheimer's and Parkinson's disease, ischemia-reperfusion injury, and gliomas. Based on a targeted narrative analysis of primary and translational studies, we highlight that LAPTM proteins influence lysosomal acidification and m

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… CRISPR/Cas9 screens confirm the roles of LAPTM4B and LAPTM5 in chemoresistance, while proteolysis-targeting chimera (PROTAC) degraders and high-throughput screening of transmembrane ligand pockets offer scalable strategies to restore lysosomal homeostasis across neurodegeneration, ischemia, and neuroinflammation …

CAR T-cells in hematologic malignancies: Advances, challenges, and future directions.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the management of hematologic malignancies, achieving high remission rates in relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma. By redirecting autologous or allogeneic T lymphocytes against tumor-associated antigens such as CD19 and TNFRSF17, CAR T-cells overcome resistance to conventional therapies. Progressive optimization of CAR design-from early constructs to armored and logic-gated platforms-has enhanced persistence, specificity, and safety. Pivotal trials and real-world e

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… Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-zeta vs Fc epsilon RI-gamma. J. Immunol. 2001;166:182–187. doi: 10.4049/jimmunol.166.1.182. 28. …

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia.

Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, select

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… An emerging strategy to target proteins with small-molecule degraders are proteolysis targeting chimeras (PROTACs), which rely on hijacking the cellular degradation machinery, the proteasome. …

MYC inhibitors in multiple myeloma.

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as MYC), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas. Multiple myeloma (MM), in

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… BET: Bromodomain and extra-terminal; PIs: proteasome inhibitors; IMiDs: immunomodulatory drugs; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; IRF4: interferon regulatory factor 4; CDK9: cyclin-dependent kinase 9; PROTAC: proteolysis targeting chimera; IL6R: interleukin-6 receptor …

History of hematopoietic cell transplantation: challenges and progress.

After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights fo

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… documented, with the help of blood genetic markers, that the radioprotection was due to repopulation of the irradiated marrow spaces by transplanted donor cells, thereby validating the “cellular hypothesis”. 5 , 6 Much of that early work has been comprehensively described in the 1967 book “Radiation Chimeras …

The Mediterranean Diet, a Rich Source of Angiopreventive Compounds in Cancer.

Diet-based chemoprevention of cancer has emerged as an interesting approach to evade the disease or even target its early phases, reducing its incidence or slowing down tumor progression. In its basis in the essential role of angiogenesis for tumor growth and metastasis, angioprevention proposes the use of inhibitors of angiogenesis in cancer prevention. The anti-angiogenic potential exhibited by many natural compounds contained in many Mediterranean diet constituents makes this dietary pattern especially interesting as a source of chemopreventive agents, defined within the angioprevention str

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… stromal tumors, and pancreatic neuroendocrine tumors Thalidomide (Synovir, Thalomid) | Amino acid | VEGF, bFGF | Multiple myeloma Temsirolimus (Torisel) | TKI | mTOR | RCC Vandetanib (Caprelsa) | TKI | VEGFR-2 | Unresectable or metastatic TC Ziv-Aflibercept (VEGF-Trap) (Zaltrap) | Fusion protein (VEGFR chimera …

Clostridium butyricum alleviates multiple myeloma by remodeling the bone marrow microenvironment and inhibiting PI3K/AKT pathway through the gut‒bone axis.

Emerging evidence reveals a strong connection between the gut microbiota and cancer. However, the exact role of gut microbiota dysbiosis in multiple myeloma (MM) is poorly understood, and the therapeutic potential of microbiota-targeted interventions represents a promising strategy that demands urgent mechanistic and translational investigation. First, we conducted a comprehensive microbiome-metabolite analysis between MM patients and healthy individuals. The result revealed a marked compositional difference characterized by reduced abundances of butyrate-producing bacteria and diminished buty

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… Chimeras were filtered from the quality-controlled sequence set to obtain high-quality sequences. These sequences were then clustered at 97% similarity using the cluster size module to generate an OTU table. Taxonomic annotation was conducted using QIIME2 (2019.4) and the nt database. …

Advancing Cancer-Targeted Nanotherapies with Tumor Homing Peptides.

The development of smart nanoparticles for precision medicine in anticancer drug delivery and controlled release has the potential to revolutionize cancer treatment. This progress is driven by expanding body of preclinical and early clinical studies on anticancer nanoparticles. Despite these advancements, a critical challenge remains achieving a selective and efficient tumor accumulation, along with effective extravasation and deep tissue penetration of nanoparticles into the tumor parenchyma. Affinity targeting strategies using ligands such as homing peptides and antibodies leverage molecular

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… Enhanced Tumor Targeting and Penetration of Proteolysis-Targeting Chimeras through iRGD Peptide Conjugation: A Strategy for Precise Protein Degradation in Breast Cancer. J. Med. Chem. 2023;66(24):16828–16842. doi: 10.1021/acs.jmedchem.3c01539. …

Преодоление препятствий: развитие клеточной терапии в области аутоиммунной борьбы с заболеваниями.

Аутоиммунные заболевания возникают в результате дисрегламента в иммунной системе, что приводит к агрессивному нападению на ткани самого организма. Патогенез этих условий является многофакторным, охватывающим сложные взаимосвязи между генетическими предрасположениями, экологическими детерминантами и гормональными колебаниями. Диапазон аутоиммунных заболеваний является широким и оказывает воздействие на множество систем органов, при этом можно привести такие примечательные примеры, как ревматуидный артрит (RA), системный волчан (SLE), множественный склероз (MS), псориаз и витилиго. Несмотря на з

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… In the quest for alternative immunotherapies for autoimmune diseases, the Proteolysis-targeting chimera (PROTAC) technology has emerged as a promising new therapeutic strategy. …

T-cell Immunotherapies and the Role of Nonclinical Assessment: The Balance between Efficacy and Pathology.

Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences. As these therapies begin to reach more patients, it

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… Ligand-mediated cytolysis of tumor cells: Use of heregulin-zeta chimeras to redirect cytotoxic T lymphocytes . Cancer Gene Ther 7 , 128 – 34 . 10678365 10.1038/sj.cgt.7700100 Muranski P. Boni A. Wrzesinski C. Citrin D. E. Rosenberg S. A. Childs R. Restifo N. P. ( 2006 ). …

Targeting BRD4: Potential therapeutic strategy for head and neck squamous cell carcinoma (Review).

As a member of BET (bromodomain and extra-terminal) protein family, BRD4 (bromodomain‑containing protein 4) is a chromatin‑associated protein that interacts with acetylated histones and actively recruits regulatory proteins, leading to the modulation of gene expression and chromatin remodeling. The cellular and epigenetic functions of BRD4 implicate normal development, fibrosis and inflammation. BRD4 has been suggested as a potential therapeutic target as it is often overexpressed and plays a critical role in regulating gene expression programs that drive tumor cell proliferation, survival, mi

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… Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy. J Control Release. 2023;354:155–166. doi: 10.1016/j.jconrel.2022.12.035. 70. Liu T, Zhang Z, Wang C, Huang H, Li Y. …

Emerging Therapies for Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and

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… In an immunocompetent model in which MM45T.Li mouse HCC cells were subcutaneously (s.c.) injected into syngeneic mice, ADs delivering HSV/TK and a chimera of monocyte chemoattractant protein-1 (MCP-1) and the membrane-spanning domain of CX3CL1 (fractalkine), displayed high antitumor efficacy upon GCV …

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets.

The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL1

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… Synthesis of Phosphorodiamidate Morpholino Oligonucleotides and Their Chimeras Using Phosphoramidite Chemistry. J. Am. Chem. Soc. 2016;138:15663–15672. doi: 10.1021/jacs.6b08854. 18. Nielsen P.E. PNA Technology. Mol. Biotechnol. 2004;26:233–248. doi: 10.1385/MB:26:3:233. 19. …

Molecular targets for anticancer therapies in companion animals and humans: what can we learn from each other?

Despite clinical successes in the treatment of some early stage cancers, it is undeniable that novel and innovative approaches are needed to aid in the fight against cancer. Targeted therapies offer the desirable feature of tumor specificity while sparing healthy tissues, thereby minimizing side effects. However, the success rate of translation of these therapies from the preclinical setting to the clinic is dramatically low, highlighting an important point of necessary improvement in the drug development process in the oncology field. The practice of a comparative oncology approach can addres

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… A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera. Int J Cancer. 2020;146:449–460. doi: 10.1002/ijc.32719. 50. Nagaya T, Okuyama S, Ogata F, Maruoka Y, Knapp DW, Karagiannis SN. et al. …

Целевые стратегии лечения рака цвета кожи: изучение использования аптемеров и золотых нанопчастей.

Рак цвета кожи (КЗК) является второй ведущей причиной смертности от рака и является причиной ~10% из всех случаев рака. По оценкам, во всем мире случаи, связанные с КПР 1.9 million и 930,000 смертями в 2022. Несмотря на расширение доступа к обследованиям и лечению в рамках КПР, ожидается, что показатели смертности резко возрастут в районах с низким уровнем ресурсов, что подчеркивает настоятельную необходимость принятия новаторских мер по лечению в рамках КПР. Текущая химиотерапия создает проблемы, такие, как плохая биодоступность, резистентность к многочисленным лекарствам и негативные побочны

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… Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras Nat. Biotechnol. 2006 24 1005 1015 10.1038/nbt1223 16823371 155. Soldevilla M.M. de Caso D.M.C. Menon A.P. Pastor F. …

JCMM Annual Review on Advances in Biotechnology for the Treatment of Haematological Malignancies: A Review of the Latest In-Patient Developments 2024-2025.

Advances in biotechnology are set to revolutionise the treatment of haematological malignancies. Current treatments have limited efficacy due to their high toxicity and poor long-term outcomes, particularly in acute myeloid leukaemia (AML). In 2024-2025, emerging targeted therapies promise improved results with reduced adverse effects. This review is the first of an annual series exploring the latest in-patient developments in several key areas, focusing on mechanisms. We present advances in the use and action of several therapies including epigenetic modulators, protein degraders, apoptotic i

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… A feature stemming from its molecular design that separates NX‐5948 from other BTK‐targeted proteolysis‐targeting chimeras (PROTACs) is its ability to cross the blood–brain barrier and degrade BTK intracranially, translating to preclinical efficacy in CNS lymphomas [ 40 ]. …