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Molecular Cancer Mar 2024While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired... (Review)
Review
While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are a new class of anticancer drugs comprising the coupling of antitumor mAbs with cytotoxic drugs. Compared with chemotherapeutic drugs, ADCs have the advantages of good tolerance, accurate target recognition, and small effects on noncancerous cells. ADCs occupy an increasingly important position in the therapeutic field. Currently, there are 13 Food and Drug Administration (FDA)‒approved ADCs and more than 100 ADC drugs at different stages of clinical trials. This review briefly describes the efficacy and safety of FDA-approved ADCs, and discusses the related problems and challenges to provide a reference for clinical work.
Topics: United States; Humans; Immunoconjugates; United States Food and Drug Administration; Neoplasms; Antineoplastic Agents; Treatment Outcome
PubMed: 38519953
DOI: 10.1186/s12943-024-01963-7 -
Journal of Experimental & Clinical... Oct 2023The insulin-like growth factor receptor (IGF-1R) was among the most intensively pursued kinase targets in oncology. However, even after a slew of small-molecule and... (Review)
Review
The insulin-like growth factor receptor (IGF-1R) was among the most intensively pursued kinase targets in oncology. However, even after a slew of small-molecule and antibody therapeutics reached clinical trials for a range of solid tumors, the initial promise remains unfulfilled. Mechanisms of resistance to, and toxicities resulting from, IGF-1R-targeted drugs are well-catalogued, and there is general appreciation of the fact that a lack of biomarker-based patient stratification was a limitation of previous clinical trials. But no next-generation therapeutic strategies have yet successfully exploited this understanding in the clinic.Currently there is emerging interest in re-visiting IGF-1R targeted therapeutics in combination-treatment protocols with predictive biomarker-driven patient-stratification. One such biomarker that emerged from early clinical trials is the sub-cellular localization of IGF-1R. After providing some background on IGF-1R, its drugging history, and the trials that led to the termination of drug development for this target, we look more deeply into the correlation between sub-cellular localization of IGF-1R and susceptibility to various classes of IGF-1R - targeted agents.
Topics: Humans; Neoplasms; Receptor, IGF Type 1; Antineoplastic Agents; Biomarkers
PubMed: 37858153
DOI: 10.1186/s13046-023-02850-7 -
Journal of Experimental & Clinical... Oct 2023Pancreatic cancer is one of the most common causes of cancer-related death, and the 5-year survival rate has only improved marginally over the last decade. Late... (Review)
Review
Pancreatic cancer is one of the most common causes of cancer-related death, and the 5-year survival rate has only improved marginally over the last decade. Late detection of the disease means that in most cases the disease has advanced locally and/or metastasized, and curative surgery is not possible. Chemotherapy is still the first-line treatment however, this has only had a modest impact in improving survival, with associated toxicities. Therefore, there is an urgent need for targeted approaches to better treat pancreatic cancer, while minimizing treatment-induced side-effects. Antibody drug conjugates (ADCs) are one treatment option that could fill this gap. Here, a monoclonal antibody is used to deliver extremely potent drugs directly to the tumor site to improve on-target killing while reducing off-target toxicity. In this paper, we review the current literature for ADC targets that have been examined in vivo for treating pancreatic cancer, summarize current and on-going clinical trials using ADCs to treat pancreatic cancer and discuss potential strategies to improve their therapeutic window.
Topics: Humans; Immunoconjugates; Antineoplastic Agents; Antibodies, Monoclonal; Pancreatic Neoplasms
PubMed: 37880707
DOI: 10.1186/s13046-023-02868-x -
Cell Death and Differentiation Dec 2023BCL2 is an apoptosis-inhibitory oncoprotein that also possesses apoptosis-unrelated activities. Pharmacological BCL2 inhibitors have been developed with the scope of... (Review)
Review
BCL2 is an apoptosis-inhibitory oncoprotein that also possesses apoptosis-unrelated activities. Pharmacological BCL2 inhibitors have been developed with the scope of driving BCL2-dependent cancer cells into apoptosis, and one BCL2 antagonist, venetoclax, has been clinically approved for the treatment of specific leukemias and lymphomas. Nonetheless, it appears that venetoclax, as well as genetic BCL2 inhibition, can mediate anticancer effects through an indirect action. Such an indirect effect relies on the enhancement of the immunostimulatory function of dendritic cells, hence increasing tumor immunosurveillance. Mechanistically, BCL2 inhibition involves improved antigen presentation by conventional type-1 dendritic cells (cDC1s) due to the activation of an interferon response, leading to a T cell-mediated anticancer immune response that can be further enhanced by PD-1 blockade. These findings support the emerging hypothesis that successful antineoplastic drugs generally mediate their effects indirectly, through the immune system, rather via merely cell-autonomous effects on malignant cells.
Topics: Proto-Oncogene Proteins c-bcl-2; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Cells; Cell Line, Tumor
PubMed: 37845384
DOI: 10.1038/s41418-023-01232-y -
Natural Product Reports Jul 2023Many researchers in the natural product sciences dream of discovering a successful drug. For almost all of us, this dream will never be realized. Among the heroes of our... (Review)
Review
Many researchers in the natural product sciences dream of discovering a successful drug. For almost all of us, this dream will never be realized. Among the heroes of our past, though, there is a team whose efforts led to the discovery of not one but two new drugs. Dr Monroe Wall and Dr Mansukh Wani isolated and solved the structures for taxol and camptothecin, plant-based compounds that continue to play a critical role in cancer therapy today. Since the 1960s and 1970s when Wall, Wani and collaborators did their seminal work, there have been tremendous technological advances in the natural product sciences. With access to most sophisticated technology, it might be expected that the rate of discovery of new drugs from plants and other sources would have sped up. However, this has not come to pass. Why is this? Is it that the promise of new drug candidates from plant-based sources has been exhausted? Has our fascination with new technologies and with the promise of the genomics revolution caused us to stop investing effort and resources in the practices that are proven to yield success? With this Viewpoint, we share the story of taxol's discovery, highlighting critical challenges that were overcome and considering their relevance to botanical natural products drug discovery today. We hope that consideration of lessons learned from the past will help fuel success by researchers currently studying plants with the goal of discovering promising therapeutic leads.
Topics: Humans; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Biological Products; Neoplasms; Paclitaxel; Plants; Population Health
PubMed: 37449327
DOI: 10.1039/d3np00017f -
Journal of Hematology & Oncology Jul 2023NEDDylation, a post-translational modification through three-step enzymatic cascades, plays crucial roles in the regulation of diverse biological processes.... (Review)
Review
NEDDylation, a post-translational modification through three-step enzymatic cascades, plays crucial roles in the regulation of diverse biological processes. NEDD8-activating enzyme (NAE) as the only activation enzyme in the NEDDylation modification has become an attractive target to develop anticancer drugs. To date, numerous inhibitors or agonists targeting NAE have been developed. Among them, covalent NAE inhibitors such as MLN4924 and TAS4464 currently entered into clinical trials for cancer therapy, particularly for hematological tumors. This review explains the relationships between NEDDylation and cancers, structural characteristics of NAE and multistep mechanisms of NEDD8 activation by NAE. In addition, the potential approaches to discover NAE inhibitors and detailed pharmacological mechanisms of NAE inhibitors in the clinical stage are explored in depth. Importantly, we reasonably investigate the challenges of NAE inhibitors for cancer therapy and possible development directions of NAE-targeting drugs in the future.
Topics: Humans; Ubiquitins; Neoplasms; Antineoplastic Agents; NEDD8 Protein
PubMed: 37525282
DOI: 10.1186/s13045-023-01485-7 -
Journal of Hematology & Oncology Jul 2023Antibody-drug conjugates (ADCs) combine the cytotoxicity of small-molecule drugs with antibody targeting. Due to their precise and powerful effect, they have become a...
Antibody-drug conjugates (ADCs) combine the cytotoxicity of small-molecule drugs with antibody targeting. Due to their precise and powerful effect, they have become a new hotspot and an important trend in the research and development of anti-tumor antibody drugs. Every year, exciting new developments and innovations in the treatment of urological tumors are introduced at the American Society of Clinical Oncology-Genitourinary (ASCO-GU) Cancers Symposium. In this article, we summarize some of the most impressive advances in new clinical trials and clinical data on ADCs in the 2023 ASCO-GU Cancers Symposium for the treatment of urothelial carcinoma.
Topics: Humans; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Immunoconjugates; Antineoplastic Agents; Urologic Neoplasms
PubMed: 37507780
DOI: 10.1186/s13045-023-01475-9 -
Molecular Cancer May 2024Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and... (Review)
Review
Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.
Topics: Humans; Neoplasms; Ferroptosis; Animals; Antineoplastic Agents
PubMed: 38702722
DOI: 10.1186/s12943-024-01999-9 -
Advances in Nutrition (Bethesda, Md.) Sep 2023Cancer is one of the primary causes of death worldwide, and its incidence continues to increase yearly. Despite significant advances in research, the search for... (Review)
Review
Cancer is one of the primary causes of death worldwide, and its incidence continues to increase yearly. Despite significant advances in research, the search for effective and nontoxic preventive and therapeutic agents remains greatly important. Cancer is a multimodal disease, where various mechanisms play significant roles in its occurrence and progression. This highlights the need for multitargeted approaches that are not only safe and inexpensive but also provide effective alternatives for current therapeutic regimens. β-Sitosterol (SIT), the most abundant phytosterol found in various plant foods, represents such an option. Preclinical evidence over the past few decades has overwhelmingly shown that SIT exhibits multiple anticancer activities against varied cancers, such as liver, cervical, colon, stomach, breast, lung, pancreatic, and prostate cancers, in addition to leukemia, multiple myeloma, melanoma, and fibrosarcoma. In this article, we present the latest advances and perspectives on SIT-systematically summarizing its antitumor mechanisms of action into 7 main sections and combining current challenges and prospects-for its use as a promising agent for cancer prevention and treatment. In particular, SIT plays a role in cancer prevention and treatment mainly by enhancing apoptosis, inducing cell cycle arrest, bidirectionally regulating oxidative stress, improving metabolic reprogramming, inhibiting invasion and metastasis, modulating immunity and inflammation, and combating drug resistance. Although SIT holds such great promise, the poor aqueous solubility and bioavailability coupled with low targeting efficacy limit its therapeutic efficacy and clinical application. Further research on novel drug delivery systems may improve these deficiencies. Overall, through complex and pleiotropic mechanisms, SIT has good potential for tumor chemoprevention and chemotherapy. However, no clinical trials have yet proven this potential. This review provides theoretical basis and rationality for the further design and conduct of clinical trials to confirm the anticancer activity of SIT.
Topics: Male; Humans; Antineoplastic Agents; Sitosterols; Prostatic Neoplasms; Chemoprevention
PubMed: 37247842
DOI: 10.1016/j.advnut.2023.05.013 -
Critical Reviews in Oncology/hematology May 2024Breast cancer is potentially a lethal disease and a leading cause of death in women. Chemotherapy and radiotherapy are the most frequently used treatment options. Drug... (Review)
Review
Breast cancer is potentially a lethal disease and a leading cause of death in women. Chemotherapy and radiotherapy are the most frequently used treatment options. Drug resistance in advanced breast cancer limits the therapeutic output of treatment. The leading cause of resistance in breast cancer is endocrine and hormonal imbalance, particularly in triple negative and HER2 positive breast cancers. The efflux of drugs due to p-gp's activity is another leading cause of resistance. Breast cancer resistant protein also contributes significantly. Strategies used to combat resistance include the use of nanoparticles to target drug delivery by co-delivery of chemotherapeutic drugs and genes (siRNA and miRNA) that help to down-regulate genes causing resistance. The siRNA is specific and effectively silences p-gp and other proteins causing resistance. The use of chemosensitizers is also effective in overcoming resistance. Chemo-sensitizers sensitize cancer cells to the effects of chemotherapeutic drugs. Novel anti-neoplastic agents such as antibody-drug conjugates and mesenchymal stem cells are also effective tools used to improve the therapeutic response in breast cancer. Similarly, combination of photo/thermal ablation with chemotherapy can act to overcome breast cancer resistance. In this review, we focus on the mechanism of breast cancer resistance and the nanoparticle-based strategies used to combat resistance in breast cancer.
Topics: Humans; Drug Resistance, Neoplasm; Breast Neoplasms; Female; Antineoplastic Agents; Nanoparticles; Drug Delivery Systems; Animals
PubMed: 38615873
DOI: 10.1016/j.critrevonc.2024.104351