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Nature Reviews. Cancer Jun 2022Normal cells explore multiple states to survive stresses encountered during development and self-renewal as well as environmental stresses such as starvation, DNA... (Review)
Review
Normal cells explore multiple states to survive stresses encountered during development and self-renewal as well as environmental stresses such as starvation, DNA damage, toxins or infection. Cancer cells co-opt normal stress mitigation pathways to survive stresses that accompany tumour initiation, progression, metastasis and immune evasion. Cancer therapies accentuate cancer cell stresses and invoke rapid non-genomic stress mitigation processes that maintain cell viability and thus represent key targetable resistance mechanisms. In this Review, we describe mechanisms by which tumour ecosystems, including cancer cells, immune cells and stroma, adapt to therapeutic stresses and describe three different approaches to exploit stress mitigation processes: (1) interdict stress mitigation to induce cell death; (2) increase stress to induce cellular catastrophe; and (3) exploit emergent vulnerabilities in cancer cells and cells of the tumour microenvironment. We review challenges associated with tumour heterogeneity, prioritizing actionable adaptive responses for optimal therapeutic outcomes, and development of an integrative framework to identify and target vulnerabilities that arise from adaptive responses and engagement of stress mitigation pathways. Finally, we discuss the need to monitor adaptive responses across multiple scales and translation of combination therapies designed to take advantage of adaptive responses and stress mitigation pathways to the clinic.
Topics: DNA Damage; Ecosystem; Humans; Immunotherapy; Neoplasms; Tumor Microenvironment
PubMed: 35264777
DOI: 10.1038/s41568-022-00454-5 -
International Journal of Molecular... Feb 2021Treatment of relapsed and refractory (R/R) B acute lymphoblastic leukemia (B-ALL) represents an unmet medical need in children and adults. Adoptive T cells engineered to... (Review)
Review
Treatment of relapsed and refractory (R/R) B acute lymphoblastic leukemia (B-ALL) represents an unmet medical need in children and adults. Adoptive T cells engineered to express a chimeric antigen receptor (CAR-T) is emerging as an effective technique for treating these patients. Areas covered: Efficacy and safety of CAR-T therapy in R/R B-ALL patients. Expert opinion: CD19 CAR-T infusion induce high CR rates in patients with poor prognosis and few therapeutic options, while real-life data demonstrate similar results with an interestingly lower incidence of grade 3/4 toxicity. Nevertheless, despite impressive in-depth responses, more than half of patients will experience a relapse. Therefore, rather than using CAR-T cell therapy as a stand-alone option, consolidation with allogeneic stem-cell transplant (Allo-SCT) after CAR-T treatment might increase long-term outcome. Moreover, CD19 is one target, but several other targets are being examined, such as CD20 and CD22 and dual-targeting CARs or combination therapy. Another issue is the time consuming process of CAR-T engineering. New platforms have shortened the CAR-T cell manufacturing process, and studies are underway to evaluate the effectiveness. Another way to mitigate waiting is the development of allogeneic "off the shelf" therapy. In conclusion, CD19-targeted CAR-modified T-cell therapy has shown unprecedented results in patients without curative options. Future work focusing on target identification, toxicity management and reducing manufacturing time will broaden the clinical applicability and bring this exciting therapy to more patients, with longer-term remissions without additional Allo-SCT.
Topics: Animals; Antigens, CD19; Clinical Trials as Topic; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 33670075
DOI: 10.3390/ijms22042150 -
Trends in Pharmacological Sciences May 2023Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are... (Review)
Review
Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation.
Topics: Humans; Proteolysis; Neoplasms; Drug Delivery Systems; Proteolysis Targeting Chimera
PubMed: 37059054
DOI: 10.1016/j.tips.2023.03.003 -
Journal of Controlled Release :... Jan 2023Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects.... (Review)
Review
Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro, in vivo, and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics.
Topics: Drug Delivery Systems; Colon; Pharmaceutical Preparations; Administration, Oral; Biological Availability
PubMed: 36528195
DOI: 10.1016/j.jconrel.2022.12.029 -
Biomolecules Jun 2020Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson's disease (PD) and must be developed concurrently because of... (Review)
Review
Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson's disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (), leucine-rich repeat kinase-2 () and glucocerebrosidase (. Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements.
Topics: Animals; Biomarkers; Genetic Heterogeneity; Genetic Therapy; History, 21st Century; Humans; Molecular Targeted Therapy; Mutation; Parkinson Disease
PubMed: 32560161
DOI: 10.3390/biom10060912 -
International Journal of Molecular... Jul 2020Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in... (Review)
Review
Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for hair loss treatment. Whereas a variety of growth factors and signaling pathways have been implicated in hair cycling process, the activation of Wnt/β-catenin signaling plays a central role in hair follicle regeneration. Several plant-derived chemicals have been reported to promote hair growth by activating Wnt/β-catenin signaling in various in vitro and in vivo studies. This mini-review sheds light on the role of Wnt/β-catenin in promoting hair growth and the current progress in designing hair loss therapies by targeting this signaling pathway.
Topics: Alopecia; Animals; Biological Products; Combined Modality Therapy; Female; Hair; Hair Follicle; Hair Preparations; Humans; Male; Mesenchymal Stem Cell Transplantation; Mice; Mice, Nude; Molecular Targeted Therapy; Phytotherapy; Regeneration; Wnt Signaling Pathway
PubMed: 32664659
DOI: 10.3390/ijms21144915 -
BMC Medicine Mar 2022Targeted therapy is the key for improving overall survival while decreasing the undesirable adverse effects of cancer treatment. Patients who received matched targeted...
Targeted therapy is the key for improving overall survival while decreasing the undesirable adverse effects of cancer treatment. Patients who received matched targeted therapies showed dramatically improved overall survival (OS) and progression-free survival (PFS) compared to those without matched therapies. However, each patient responds to targeted therapy differently due to their unique genomic profile. The discrepancy of treatment response between clinical trials and real-world clinical practice highlights an unmet need to develop tailored therapies for individual patients. The development of cutting-edge technologies, such as next-generation sequencing, has enabled us to identify more actionable targets. In this special issue of BMC Medicine, a collection of highly translational and clinical oncology papers presented a series of studies on targeted therapies for a variety of cancer types, aiming to bridge the gap between genomic testing and precision medicine and spark innovations on improving the efficacy of targeted therapies.
Topics: High-Throughput Nucleotide Sequencing; Humans; Molecular Targeted Therapy; Neoplasms; Precision Medicine; Proteomics
PubMed: 35272686
DOI: 10.1186/s12916-022-02287-3 -
International Journal of Molecular... Oct 2021Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new... (Review)
Review
Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new therapies that have contributed to the advances in treatment of certain malignancies. Immunotherapy, which has repeatedly proven to be a breakthrough therapy in melanoma, as well as B-ALL therapy with CAR T cells, are of great merit in this progress. These therapies are currently being developed by modifying bispecific antibodies and CAR T cells to improve their efficiency and bioavailability. Work on improving the therapy with oncolytic viruses is also progressing, and efforts are being made to improve the immunogenicity and stability of cancer vaccines. Combining various biological therapies, immunotherapy with oncolytic viruses or cancer vaccines is gaining importance in cancer therapy. New therapeutic targets are intensively sought among neoantigens, which are not immunocompromised, or antigens associated with tumor stroma cells. An example is fibroblast activation protein α (FAPα), the overexpression of which is observed in the case of tumor progression. Universal therapeutic targets are also sought, such as the neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a key genetic driver present in many types of cancer. This review also raises the problem of the tumor microenvironment. Stromal cells can protect tumor cells from chemotherapy and contribute to relapse and progression. This publication also addresses the problem of cancer stem cells resistance to treatment and presents attempts to avoid this phenomenon. This review focuses on the most important strategies used to improve the selectivity of biological therapies.
Topics: Animals; Antibodies; Biological Therapy; Cancer Vaccines; Humans; Molecular Targeted Therapy; Neoplasms; Recombinant Proteins; T-Lymphocytes
PubMed: 34769123
DOI: 10.3390/ijms222111694 -
Bioconjugate Chemistry Nov 2015Western medicine often aims to specifically treat diseased tissues or organs. However, the majority of current therapeutics failed to do so owing to their limited... (Review)
Review
Western medicine often aims to specifically treat diseased tissues or organs. However, the majority of current therapeutics failed to do so owing to their limited selectivity and the consequent "off-target" side effects. Targeted therapy aims to enhance the selectivity of therapeutic effects and reduce adverse side effects. One approach toward this goal is to utilize disease-specific ligands to guide the delivery of less-specific therapeutics, such that the therapeutic effects can be guided specifically to diseased tissues or organs. Among these ligands, aptamers, also known as chemical antibodies, have emerged over the past decades as a novel class of targeting ligands that are capable of specific binding to disease biomarkers. Compared with other types of targeting ligands, aptamers have an array of unique advantageous features, which make them promising for developing aptamer-drug conjugates (ApDCs) for targeted therapy. In this Review, we will discuss ApDCs for targeted drug delivery in chemotherapy, gene therapy, immunotherapy, photodynamic therapy, and photothermal therapy, primarily of cancer.
Topics: Animals; Antineoplastic Agents; Aptamers, Nucleotide; Drug Carriers; Drug Delivery Systems; Genetic Therapy; Humans; Immunotherapy; Models, Molecular; Neoplasms; Nucleic Acids; Photosensitizing Agents; Proteins
PubMed: 26083153
DOI: 10.1021/acs.bioconjchem.5b00291 -
Signal Transduction and Targeted Therapy Dec 2020Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little... (Review)
Review
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.
Topics: Antineoplastic Agents; Cell Proliferation; Drug Delivery Systems; Humans; Leukemia, Myeloid, Acute; Signal Transduction
PubMed: 33335095
DOI: 10.1038/s41392-020-00361-x