Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress in agressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally, was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent. Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of there by causing apoptosis in aggressive cancer cells.

PURPOSE:The 4-point visual 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) PET/computed tomography (CT) 'Herder' score, in combination with clinical factors, is used to assess malignancy risk of solitary pulmonary nodules (SPNs) and guide management. We aim to assess the impact of four digital reconstructions on Herder visual score, Herder model probability, and subsequent management of SPNs. METHODS:[ 18 F]FDG PET/CT examinations for SPN assessment, performed on a Siemens Biograph Vision PET/CT, were retrospectively included (398 reconstructions; Gauss 6.0, Gauss 4.5, Gauss 4.5 with data-driven gating, and All Pass). Eight expert readers assessed anonymised reconstructions randomly (four pairs, 25 cases/100 reconstructions per pair). The Herder visual score was documented, and the Herder model probability score for each reconstruction was calculated using clinical parameters. A single observer performed semiquantitative analysis (SUV max and target-to-background ratios). RESULTS:73/100 cases showed Herder visual score concordance across all four reconstructions. Although the visual score changed for at least one reconstruction in 27 cases, the risk stratification based on the Herder model probability remained identical in 15/27. In 12 cases, changes in Herder visual score altered risk stratification. However, this did not change the subsequent management plan for any patient. Semiquantitative outputs were significantly different between Gauss 6.0 and All Pass ( P  < 0.001) and Gauss 4.5 and All Pass ( P = 0.03-0.05) with no significant difference between the other reconstructions. CONCLUSION:There is excellent concordance in Herder based SPN risk stratification across all four digital PET reconstructions. Although different reconstructions can alter risk stratification, this did not impact management in our cohort.

There is a clinical need for 18F -labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]- octreotate ([18F]FET-beta AG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-beta AG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-beta AG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole -body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-beta AG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor -tobackground ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-beta AG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor -to -background ratio of [18F]FET-beta AG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 +/- 1.9 vs. 3.5 +/- 2.3; P < 0.001). Conclusion: [18F]FET-beta AG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron -produced fluorine radioisotope.

Autophagy is a crucial mechanism that maintains the balance of cellular homeostasis by removing faulty or unneeded proteins as well as damaged or aged organelles in cells. Autophagy is triggered by the formation of autophagosomes, which sequester and enclose anomalous constituents. Subsequently, autophagosomes combine with lysosomes to efficiently recycle or eliminate degradative cargo. Autophagy regulation plays a dual role in both suppressing and promoting cancer in many types of malignancies in a context-dependent manner. In addition, autophagy regulates the characteristics of tumor formation, the spread of cancer, the occurrence of cancer stem cells, and the resistance to drugs used in cancer treatment. Autophagy regulators are employed to modify autophagy for the purpose of anticancer therapy. However, the dual functions of autophagy hinder their effectiveness in this therapy, thereby serving as the primary cause of treatment failure. The chapter provides a concise overview of the mechanisms behind autophagy and its correlation with carcinogenesis, metastasis, and resistance to anticancer drugs. Ultimately, we examine the potential and efficacy of addressing autophagy as a prospective therapeutic approach in anticancer treatment resistance.

The growing field of cancer research has revealed the complex interaction between epigenetic modifications and the development of drug resistance in response to chemotherapy. A heritable alteration in gene expression that is unrelated to variations in the sequence of nucleotides is known as epigenetic regulation. Histone modification, noncoding RNA regulation, and DNA methylation have all been thoroughly investigated as common epigenetic regulatory mechanisms. The chapter explores the molecular intricacies of DNA methylation and histone modifications, elucidating their influence on the establishment and maintenance of drug resistance in various cancer types. Epigenetic alterations not only serve as pathways for the evolution of drug-resistant phenotypes but also emerge as potential therapeutic targets for overcoming treatment resistance. By understanding the complex regulatory functions of epigenetic alterations, researchers can uncover novel strategies for therapeutic intervention. Emphasizing the pivotal roles of DNA methylation and histone modifications in cancer drug resistance opens new avenues for targeted interventions, ultimately paving the way for more effective and personalized cancer therapies.

Treating cancer has so many hurdles, and drug resistance is one of them. Treatment strategies are evolving for cancer due to innate and acquired resistance capacity in them. The mechanism behind the resistance is constantly evolving in response to new drug treatment strategies and is an outcome of the acquired or adaptive mutation expression in cancer cells. In a broader perspective, cancer drug resistance can be governed by genetic, epigenetic, proteomic, metabolic, or microenvironment cues that ultimately enable selected resistant cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance has been widely studied in cancer that progressively leads to the generation of new targets for novel anticancer drugs having better efficacy than previous ones. However, due to the high variability in resistance acquired by cancer cells toward existing drugs, novel strategic options with better efficacy need to be explored that overcome resistance. Combination therapy is a widely used alternative with a better success rate though the risk of amplified side effects is commonplace. However, recent groundbreaking immune therapy combination with the drugs is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent. However, more study is needed to be done at genetic, epigenetic, proteomic, and metabolic levels to identify targets of different cancers that can help to develop new therapies that are more effective to the existing challenge of cancer drug resistance. This chapter will focus on the recent challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level.

Intracellular compartments play a pivotal role in cellular function, housing diverse organelles that contribute to essential processes such as protein synthesis, energy production, and waste disposal. The intricate organization of these compartments creates distinct microenvironments that impact cellular responses to external stimuli, including drug exposure. Understanding the interplay between intracellular compartments and drug resistance is crucial for advancing therapeutic strategies. One prominent example is the endoplasmic reticulum (ER), a multifunctional organelle involved in protein folding and lipid synthesis. The ER's role in drug resistance is underscored by its participation in the unfolded protein response (UPR), a cellular stress response mechanism. Drug-induced ER stress can activate the UPR, promoting cell survival and contributing to resistance against certain chemotherapeutic agents. Likewise, mitochondria's involvement in drug resistance is multifaceted, encompassing alterations in energy production, reactive oxygen species (ROS) generation, and apoptotic signaling. Mitochondrial dysfunction can confer resistance to apoptosis-inducing drugs, allowing cancer cells to evade programmed cell death. Modulation of lysosomal function has also been linked to resistance against various anticancer drugs. Nuclear compartments, including the nucleolus and nuclear envelope, contribute to drug resistance by influencing gene expression and DNA repair mechanisms. A comprehensive understanding of intracellular compartments and drug resistance has substantial implications for therapeutic development. Targeting specific organelles or cellular processes involved in resistance mechanisms provides a promising avenue for overcoming treatment challenges.

Natural remedies from a range of sources, including plants, animals, microorganisms, and marine life, have made a significant contribution to the treatment of many ailments. Lavender is a Mediterranean shrub from the Lamiaceae family. Lavender flowers (Lavandula flores) include active ingredients (3%), anthocyanins, sugars, phytosterols, minerals, and tannins and are majorly used for herbal applications. Lavender essential oil's descriptive and analytical composition varies depending on genotype, growing region, climatic circumstances, propagation, and morphological characteristics. There are around 300 chemical components in essential oil. Linalool, terpinen-4-ol, linalyl acetate, ocimene, acetate lavandulol, and cineole are the most prominent constituents. Lavender oil has antibacterial and antioxidant properties. The lavender extract helps to prevent dementia and may slow cancer cell growth, while lavender oil is used to treat skin problems. This review will cover the recent medical, economic and regional advancements in levander propagation and how the Council of Scientific & Industrial Research Indian Institute of Integrative (CSIR IIIM) aroma mission is actively acting as a bridge between farmers and their economic improvement by attracting them to the field of medicinal plant cultivation.

The tumor microenvironment (TME) is an ecosystem that surrounds a tumor inside the body. TME contains a complex and dynamic system that consists of various cellular and noncellular components that cross talk with each other and with the tumor cells, thus supporting tumor progression. The intricate interplay between tumor cells and their surrounding microenvironment has emerged as a pivotal factor influencing the development of drug resistance in cancer treatment. This book chapter explores the multifaceted roles that the tumor microenvironment (TME) plays in mediating resistance to therapeutic interventions by elucidating the dynamic interactions between tumor cells, immune cells, stromal cells, extracellular matrix components, blood vessels, and soluble factors within the TME. It unravels the complexity of resistance mechanisms through a comprehensive exploration of key signaling pathways, cellular cross talk, and microenvironmental factors, and the chapter highlights the contribution of TME-driven adaptive strategies such as immune evasion, epithelial-mesenchymal transition, and angiogenesis to therapeutic resistance. It also highlights specific facets including the role of cancer-associated fibroblasts (CAFs) and mesenchymal stem cells in cancer drug resistance. The influence of the extracellular matrix (ECM) in fostering drug resistance and the active participation of the vascular system in sustaining resistance mechanisms are dissected in this chapter. Further digging into physiochemical exchanges, homotypic and heterotypic interactions, exosomes, cytokines, and chemokines as critical mediators of resistance. The chapter culminates by showcasing innovative strategies targeting the TME to overcome drug resistance, potentially revolutionizing cancer treatment paradigms. In essence, this chapter provides a comprehensive understanding of the TME's intricate role in drug resistance, spanning diverse elements and interactions while illuminating groundbreaking approaches to mitigate resistance challenges in oncology.

Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. Video Abstract.

The gut microbiota is becoming more and more of a research area in many diseases, including cancer, obesity, diabetes, brain disease, rheumatoid arthritis, and cardiovascular disease. The human digestive tract contains about 100 trillion microorganisms. Cancer is the most prevalent malignancy in the world. The likelihood of survival can be increased by an accurate, early diagnosis and the necessary medical care. Recent studies have demonstrated that the microbiome has an impact on cancer. Different microbial signatures with various patterns have been found in the cancer, depending on the stage and biological subgroups. In cancer, the gut microbiota has been shown to modulate the efficacy of anticancer drugs. The changed gut microbiota is linked to resistance to immunological checkpoint inhibitors (ICIs) and chemotherapy treatments, whereas the addition of certain species of bacteria can restore the responsiveness to anticancer medications. Various evidence suggested the potential of gut microbiota manipulation to increase the effectiveness of anticancer medications. In this book chapter, we focused on the gut microbiota population and its relationship to cancer therapy resistance, with a particular emphasis on its potential to serve as a biomarker for the disease. Despite the important results from preclinical models and patient clinical data, a deeper comprehension of the interactions between microbiota and cancer therapy aids in the identification of novel strategies for cancer prevention, the stratification of patients for more effective treatment, and the reduction of treatment complications.

This book chapter explores novel strategies for overcoming drug resistance in cancer, focusing on advancements in drug delivery using nanoparticles (NPs) and CRISPR-based techniques. Nanoparticles offer targeted delivery, improving drug bioavailability and minimizing off-target effects. The chapter reviews recent developments in NP-based formulations designed to overcome resistance mechanisms, emphasizing their potential to enhance therapeutic efficacy. CRISPR technologies enable targeted modifications to the cancer cell genome, disrupting resistance-associated pathways and sensitizing cells to treatment. The chapter evaluates CRISPR-based interventions, discussing their potential to tackle intrinsic and acquired resistance mechanisms. By synthesizing these two cutting-edge approaches, this chapter presents an integrative view of how nanoparticle drug delivery and CRISPR-based strategies can synergistically address drug resistance challenges in cancer therapy.

There is a complex and strong association between metabolic reprogramming and the phenomenon of drug resistance in cancer. Cancer cell metabolic modifications and crosstalk with cellular and noncellular components are essential to support their growth and proliferation and support anticancer therapy resistance. The chapter explores the unintended consequences of chemotherapy interventions, revealing how therapeutic measures can induce metabolic shifts in cancer cells that inadvertently contribute to the emergence of chemoresistance. The chapter navigates through the complicated interplay between key genetic players and the metabolic shifts that support drug resistance mechanisms. Finally, the chapter proposes innovative strategies to manipulate cancer cell metabolism as a promising avenue for overcoming drug resistance. This comprehensive examination not only elucidates the complex link between metabolic reprogramming and drug resistance but also suggests potential therapeutic interventions, presenting a roadmap for future research in the evolving landscape of cancer treatment.

The chapter on the "Role of Cancer Stem Cells in Drug Resistance" explores the intricate mechanisms underlying the resistance of cancer stem cells (CSCs) to therapeutic interventions. CSCs, a subpopulation within tumors endowed with self-renewal and differentiation capabilities, have been implicated in the persistence and recurrence of cancers. Moreover, the role of CSCs in promoting tumor heterogeneity and driving metastasis further complicates treatment strategies. The chapter explores the multifaceted ways in which CSCs contribute to drug resistance, including enhanced DNA repair mechanisms, activation of antiapoptotic pathways, and the ability to evade immune surveillance. It also explains the unique features of CSCs that differentiate them from typical cancer cells. The chapter examines recent advancements in targeting CSCs to overcome drug resistance, emphasizing the importance of developing novel therapeutic approaches that specifically address the unique biology of CSCs.

There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-βAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-βAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-βAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-βAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-βAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-βAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-βAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron-produced fluorine radioisotope.

Cancer therapy has witnessed remarkable advancements in eradicating cancer cells within the body, leading to improved patient outcomes and prolonged survival. This chapter provides an overview of current cancer therapies, encompassing radiation therapy, chemotherapy, targeted therapy, immunotherapy, and emerging therapeutic modalities such as viral and gene therapy. This chapter explores the intricate molecular mechanisms underpinning resistance in cancer and discusses contemporary therapeutic approaches designed to combat resistance against chemotherapy, radiation therapy, and immunotherapy. In conclusion, cancer therapy has evolved significantly, offering diverse treatment options. Continued research, clinical trials, and multidisciplinary collaboration are essential for further refining and optimizing cancer therapies, leading to improved outcomes and patient quality of life. Understanding resistance mechanisms and developing innovative therapeutic strategies are crucial for enhancing patient outcomes, making ongoing research and clinical trials indispensable.

The chapter explores the complicated relationship between immune cells and cancer drug resistance. The immune cell composition in the tumor microenvironment (TME), encompassing B cells, effector and regulatory T cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and tumor-associated neutrophils (TANs), plays a decisive role in tumorigenesis. Various studies showed that MDSCs can create immunosuppressive microenvironment, allowing cancer cells to evade drug-induced cytotoxicity. The dynamics of the tumor microenvironment, influenced by immune cells, play a crucial role in modulating drug responsiveness. The chapter navigates through the signaling pathways, molecular cross talk, and adaptive mechanisms that define the immune landscape in the context of cancer drug resistance. It explores the potential of immunotherapeutic interventions, such as immune checkpoint inhibitors, to recalibrate immune responses and overcome resistance mechanisms. In essence, this exploration underscores the pivotal role of immune cells in shaping the destiny of cancer drug resistance. By deciphering the intricacies of these interactions, the chapter aims to provide insights that pave the way for innovative therapeutic strategies, pushing the boundaries of cancer treatment toward greater efficacy and resilience against resistance.

Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its lethal outcome. The complex molecular events that promote metastasis are a combination of both, the acquired pro-metastatic properties of cancer cells and a metastasis-permissive or -supportive tumor micro-environment (TME). Yet, dissemination is a challenging process for cancer cells that requires a series of events to enable cancer cell survival and growth. Metastatic cancer cells have to initially detach themselves from primary tumors, overcome the challenges of their intravasal journey and colonize distant sites that are suited for their metastases. The implicated obstacles including anoikis and immune surveillance, can be overcome by intricate intra- and extracellular signaling pathways, which we will summarize and discuss in this review. Further, emerging modulators of metastasis, like the immune-microenvironment, microbiome, sublethal cell death engagement, or the nervous system will be integrated into the existing working model of metastasis.