Cancers

Research

21 pages, 3200 KiB

Open AccessArticle

Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes

by Prateek Kulkarni, Reetobrata Basu, Taylor Bonn, Beckham Low, Nathaniel Mazurek and John J. Kopchick

Cancers 2024, 16(15), 2636; https://doi.org/10.3390/cancers16152636 - 24 Jul 2024

Viewed by 1453

Abstract

Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to the resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive [...] Read more.

Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to the resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and the GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to the recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin, and MMP2, enhancing drug resistance and migration in the recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights into the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Graphical abstract

22 pages, 2669 KiB

Open AccessArticle

Activation of the Anaphase Promoting Complex Restores Impaired Mitotic Progression and Chemosensitivity in Multiple Drug-Resistant Human Breast Cancer

by Mathew Lubachowski, Cordell VanGenderen, Sarah Valentine, Zach Belak, Gerald Floyd Davies, Terra Gayle Arnason and Troy Anthony Alan Harkness

Cancers 2024, 16(9), 1755; https://doi.org/10.3390/cancers16091755 - 30 Apr 2024

Viewed by 1511

Abstract

The development of multiple-drug-resistant (MDR) cancer all too often signals the need for toxic alternative therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrate that the Anaphase Promoting Complex (APC) is impaired in [...] Read more.

The development of multiple-drug-resistant (MDR) cancer all too often signals the need for toxic alternative therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrate that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug-sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type, or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient-derived xenograft (PDX) model of human triple-negative breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemo-sensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, doxorubicin (DOX). Using cell cycle arrest/release experiments, we show that mitosis is delayed in MDR cells with elevated substrate levels. When pretreated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically MDR human triple-negative breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

9 pages, 609 KiB

Open AccessCommunication

Are We Losing the Final Fight against Cancer?

by Guy Storme

Cancers 2024, 16(2), 421; https://doi.org/10.3390/cancers16020421 - 19 Jan 2024

Cited by 1 | Viewed by 1570

Abstract

Despite our increasing understanding of the biology and evolution of the cancer process, it is indisputable that the natural process of cancer creation has become increasingly difficult to cure, as more mutations are found with age. It is significantly more difficult to challenge [...] Read more.

Despite our increasing understanding of the biology and evolution of the cancer process, it is indisputable that the natural process of cancer creation has become increasingly difficult to cure, as more mutations are found with age. It is significantly more difficult to challenge the curative method when there is heterogeneity within the tumor, as it hampers clinical and genetic categorization. With advances in diagnostic technologies and screening leading to progressive tumor shrinkage, it becomes more difficult over time to evaluate the effects of treatment on overall survival. New treatments are often authorized based on early evidence, such as tumor response; disease-free, progression-free, meta-static-free, and event-free survival; and, less frequently, based on clinical endpoints, such as overall survival or quality of life, when standard guidelines are not available to approve pharmaceuticals. These clearances usually happen quite rapidly. Although approval takes longer, relative survival demonstrates the genuine worth of a novel medication. Pressure is being applied by pharmaceutical companies and patient groups to approve “new” treatments based on one of the above-listed measures, with results that are frequently insignificantly beneficial and frequently have no impact on quality of life. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

23 pages, 4745 KiB

Open AccessArticle

A Comprehensive Bioinformatic Analysis of RNA-seq Datasets Reveals a Differential and Variable Expression of Wildtype and Variant UGT1A Transcripts in Human Tissues and Their Deregulation in Cancers

by Dong Gui Hu, Shashikanth Marri, Julie-Ann Hulin, Ross A. McKinnon, Peter I. Mackenzie and Robyn Meech

Cancers 2024, 16(2), 353; https://doi.org/10.3390/cancers16020353 - 13 Jan 2024

Viewed by 1743

Abstract

The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins [...] Read more.

The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3′ terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

Review

Jump to: Research, Other

14 pages, 991 KiB

Open AccessReview

Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies

by Andres Bravo-Gonzalez, Maryam Alasfour, Deborah Soong, Jose Noy and Georgios Pongas

Cancers 2024, 16(20), 3434; https://doi.org/10.3390/cancers16203434 - 10 Oct 2024

Viewed by 1889

Abstract

B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton’s tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent [...] Read more.

B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton’s tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

25 pages, 1910 KiB

Open AccessReview

The Roles of RAC1 and RAC1B in Colorectal Cancer and Their Potential Contribution to Cetuximab Resistance

by Claudia C. Wahoski and Bhuminder Singh

Cancers 2024, 16(13), 2472; https://doi.org/10.3390/cancers16132472 - 6 Jul 2024

Cited by 1 | Viewed by 1730

Abstract

Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for [...] Read more.

Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for CRC. Unfortunately, many patients develop resistance to these treatments. Cetuximab, the first targeted therapy approved to treat advanced CRC, is a monoclonal antibody that targets the epidermal growth factor receptor and inhibits downstream pathway activation to restrict tumor cell growth and proliferation. CRC resistance to cetuximab has been well studied, and common resistance mechanisms include constitutive signal transduction through downstream protein mutations and promotion of the epithelial-to-mesenchymal transition. While the most common resistance mechanisms are known, a proportion of patients develop resistance through unknown mechanisms. One protein predicted to contribute to therapy resistance is RAC1, a small GTPase that is involved in cytoskeleton rearrangement, cell migration, motility, and proliferation. RAC1 has also been shown to be overexpressed in CRC. Despite evidence that RAC1 and its alternative splice isoform RAC1B play important roles in CRC and the pathways known to contribute to cetuximab resistance, there is a need to directly study the relationship between RAC1 and RAC1B and cetuximab resistance. This review highlights the recent studies investigating RAC1 and RAC1B in the context of CRC and suggests that these proteins could play a role in resistance to cetuximab. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

18 pages, 1834 KiB

Open AccessEditor’s ChoiceReview

Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer

by Iseult M. Browne and Alicia F. C. Okines

Cancers 2024, 16(12), 2259; https://doi.org/10.3390/cancers16122259 - 18 Jun 2024

Cited by 2 | Viewed by 2319

Abstract

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the [...] Read more.

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer’s mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

26 pages, 2421 KiB

Open AccessReview

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

by Hasan Slika, Aanya Shahani, Riddhpreet Wahi, Jackson Miller, Mari Groves and Betty Tyler

Cancers 2024, 16(12), 2249; https://doi.org/10.3390/cancers16122249 - 18 Jun 2024

Viewed by 1798

Abstract

Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, [...] Read more.

Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma’s response to therapeutic modalities. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

22 pages, 332 KiB

Open AccessReview

Ocular Surface Side Effects of Novel Anticancer Drugs

by Livio Vitiello, Filippo Lixi, Giulia Coco and Giuseppe Giannaccare

Cancers 2024, 16(2), 344; https://doi.org/10.3390/cancers16020344 - 13 Jan 2024

Cited by 5 | Viewed by 2590

Abstract

Surgery, anticancer drugs (chemotherapy, hormonal medicines, and targeted treatments), and/or radiation are common treatment strategies for neoplastic diseases. Anticancer drugs eliminate malignant cells through the inhibition of specific pathways that contribute to the formation and development of cancer. Given the ability of such [...] Read more.

Surgery, anticancer drugs (chemotherapy, hormonal medicines, and targeted treatments), and/or radiation are common treatment strategies for neoplastic diseases. Anticancer drugs eliminate malignant cells through the inhibition of specific pathways that contribute to the formation and development of cancer. Given the ability of such pharmacological medications to combat cancerous cells, their role in the management of neoplastic diseases has become essential. However, these drugs may also lead to undesirable systemic and ocular adverse effects due to cyto/neuro-toxicity and inflammatory reactions. Ocular surface side effects are recognized to significantly impact patient’s quality of life and quality of vision. Blepharoconjunctivitis is known to be a common side effect caused by oxaliplatin, cyclophosphamide, cytarabine, and docetaxel, while anastrozole, methotrexate, and 5-fluorouracil can all determine dry eye disease. However, the potential processes involved in the development of these alterations are yet not fully understood, especially for novel drugs currently available for cancer treatment. This review aims at analyzing the potential ocular surface and adnexal side effects of novel anticancer medications, trying to provide a better understanding of the underlying pharmacological processes and useful insights on the choice of proper management. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

Other

Jump to: Research, Review

12 pages, 1162 KiB

Open AccessSystematic Review

Molecular Factors Predicting Ovarian Chemotoxicity in Fertile Women: A Systematic Review

by Diego Raimondo, Antonio Raffone, Daniele Neola, Federica Genovese, Antonio Travaglino, Alberto Aguzzi, Valeria De Gobbi, Agnese Virgilio, Sara Di Santo, Rossella Vicenti, Valentina Magnani, Maurizio Guida, Tommaso Pippucci and Renato Seracchioli

Cancers 2024, 16(16), 2793; https://doi.org/10.3390/cancers16162793 - 8 Aug 2024

Viewed by 973

Abstract

Background: Recent advances in cancer diagnosis and treatment have significantly improved survival rates among women of reproductive age facing cancer. However, the potential iatrogenic loss of fertility caused by chemotherapeutic agents underscores the need to understand and predict chemotherapy-induced ovarian damage. This [...] Read more.

Background: Recent advances in cancer diagnosis and treatment have significantly improved survival rates among women of reproductive age facing cancer. However, the potential iatrogenic loss of fertility caused by chemotherapeutic agents underscores the need to understand and predict chemotherapy-induced ovarian damage. This study addresses this gap by systematically reviewing the literature to investigate genetic markers associated with chemotherapy-induced ovarian failure (CIOF). Objective: The primary objective is to identify genetic markers linked to CIOF, contributing to a comprehensive understanding of the factors influencing fertility preservation in female cancer survivors. Methods: A systematic review was conducted using PubMed, EMBASE, Web of Science, Scopus, and OVID electronic databases from inception through December 2023. Studies were included if they featured genomic assessments of genes or polymorphisms related to CIOF in women with histologically confirmed tumors. Exclusion criteria comprised in vitro and animal studies, reviews, and pilot studies. The resulting four human-based studies were scrutinized for insights into genetic influences on CIOF. Results: Of the 5179 articles initially identified, four studies met the inclusion criteria, focusing on alkylating agents, particularly cyclophosphamide, and anthracyclines. Su et al. explored CYP3A41B variants, revealing modified associations with CIOF based on age. Charo et al. investigated GSTA1 and CYP2C19 polymorphisms, emphasizing the need to consider age and tamoxifen therapy in assessing associations. Oktay et al. delved into the impact of BRCA mutations on anti-Müllerian hormone (AMH) levels post-chemotherapy, supported by in vitro assays. Van der Perk et al. focused on childhood cancer survivors and revealed significant associations of CYP3A43 and CYP2B6*2 SNPs with AMH levels. Conclusions: This systematic review analyzes evidence regarding genetic markers influencing CIOF, emphasizing the complex interplay of age, specific genetic variants, and chemotherapy regimens. The findings underscore the need for a personalized approach in assessing CIOF risk, integrating genetic markers with traditional ovarian reserve testing. The implications of this study extend to potential advancements in fertility preservation strategies, offering clinicians a comprehensive baseline assessment for tailored interventions based on each patient’s unique genetic profile. Further research is essential to validate these findings and establish a robust framework for integrating genetic markers into clinical practice. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

35 pages, 2926 KiB

Open AccessSystematic Review

Single-Domain Antibodies as Antibody–Drug Conjugates: From Promise to Practice—A Systematic Review

by Víctor Manuel Medina Pérez, Marta Baselga and Alberto J. Schuhmacher

Cancers 2024, 16(15), 2681; https://doi.org/10.3390/cancers16152681 - 27 Jul 2024

Viewed by 2540

Abstract

Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: [...] Read more.

Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs—such as their small size, enhanced tissue penetration, stability, and cost-effectiveness—make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Methods: Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. Results: VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood–brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH–drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. Conclusions: While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

25 pages, 1545 KiB

Open AccessPerspective

Emerging Therapeutic Strategies to Overcome Drug Resistance in Cancer Cells

by Pankaj Garg, Jyoti Malhotra, Prakash Kulkarni, David Horne, Ravi Salgia and Sharad S. Singhal

Cancers 2024, 16(13), 2478; https://doi.org/10.3390/cancers16132478 - 7 Jul 2024

Cited by 2 | Viewed by 3634

Abstract

The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The [...] Read more.

The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The intricate molecular insights into drug resistance, including genetic mutations, efflux pumps, altered signaling pathways, and microenvironmental influences, are discussed. Furthermore, the promising avenues offered by targeted therapies, combination treatments, immunotherapies, and precision medicine approaches are highlighted. Specifically, the synergistic effects of combining traditional cytotoxic agents with molecularly targeted inhibitors to circumvent resistance pathways are examined. Additionally, the evolving landscape of immunotherapeutic interventions, including immune checkpoint inhibitors and adoptive cell therapies, is explored in terms of bolstering anti-tumor immune responses and overcoming immune evasion mechanisms. Moreover, the significance of biomarker-driven strategies for predicting and monitoring treatment responses is underscored, thereby optimizing therapeutic outcomes. For insights into the future direction of cancer treatment paradigms, the current review focused on prevailing drug resistance challenges and improving patient outcomes, through an integrative analysis of these emerging therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

14 pages, 2244 KiB

Open AccessSystematic Review

Non-Vitamin K Antagonist Oral Anticoagulants versus Low Molecular Weight Heparin for Cancer-Related Venous Thromboembolic Events: Individual Patient Data Meta-Analysis

by Chun En Yau, Chen Ee Low, Natasha Yixuan Ong, Sounak Rana, Lucas Jun Rong Chew, Sara Moiz Tyebally, Ping Chai, Tiong-Cheng Yeo, Mark Y. Chan, Matilda Xinwei Lee, Li-Ling Tan, Chieh-Yang Koo, Ainsley Ryan Yan Bin Lee and Ching-Hui Sia

Cancers 2023, 15(24), 5887; https://doi.org/10.3390/cancers15245887 - 18 Dec 2023

Cited by 3 | Viewed by 1941

Abstract

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. Low molecular weight heparin (LMWH) has been the standard of care but new guidelines have approved the use of non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual [...] Read more.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. Low molecular weight heparin (LMWH) has been the standard of care but new guidelines have approved the use of non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual patient data (IPD) meta-analysis of randomised controlled trials (RCTs) comparing the outcomes of NOAC versus LMWH in cancer patients, we aim to determine an ideal strategy for the prophylaxis of VTE and prevention of VTE recurrence. Three databases were searched from inception until 19 October 2022. IPD was reconstructed from Kaplan–Meier curves. Shared frailty, stratified Cox and Royston–Parmar models were fit to compare the outcomes of venous thromboembolism recurrence and major bleeding. For studies without Kaplan–Meier curves, aggregate data meta-analysis was conducted using random-effects models. Eleven RCTs involving 4844 patients were included. Aggregate data meta-analysis showed that administering NOACs led to a significantly lower risk of recurrent VTE (RR = 0.65; 95%CI: 0.50–0.84) and deep vein thrombosis (DVT) (RR = 0.60; 95%CI: 0.40–0.90). In the IPD meta-analysis, NOAC when compared with LMWH has an HR of 0.65 (95%CI: 0.49–0.86) for VTE recurrence. Stratified Cox and Royston–Parmar models demonstrated similar results. In reducing risks of recurrent VTE and DVT among cancer patients, NOACs are superior to LMWHs without increased major bleeding. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Molecular Insights into Drug Resistance in Cancer

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (13 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI