Promising Cancer Therapeutic Drug Targets: Recent Advancements

Exorbitant cancer malignancy is at the helm of multiple organ malfunction in humans and is considered a cause of increased cancer mortality worldwide. Clustered regularly interspaced short palindromic repeats (CRISPR) are powerful machinery for the therapeutic approach to tumors because of their substantial peculiarity, focusing on modulatory molecules, both oncogenes and tumor suppressors, to preclude tumor metastasis and enable apoptosis. Exosomes are considered an ideal delivery system because of their specificity and ability to prevent premature release of cargo. Exosomes are accessed as an effective conveyance of CRISPR/Cas9 elements and other attractive biomolecules to recipient cancer cells. The CRISPR/Cas9 loaded exosomes are endocytosed for further alteration of cellular metabolic pathways, either by knock-in or knock-out of the designed destined gene using sgRNA and Cas9 protein. The current study provides a platform to address the alliance between the CRISPR/Cas9 model and exosomes, depicting a remarkable therapeutic approach against cancer and other fatal diseases.

Cancer stem cells (CSCs) are found to be responsible for chemoresistance and disease relapse because of their ability to self-renew and capacity to differentiate into heterogeneous lineages of cancer cells. The in-depth knowledge of molecular mechanisms and their characteristics that ultimately lead to treatment failure might help in finding novel targets and make the drugs effective for a longer time. In this chapter, we will try to understand the key features and characteristic mechanisms that regulate CSC function at the molecular level in drug resistance as well as recent developments in therapeutic approaches for targeting CSCs. The novel insights into the role of CSCs in chemo-resistance will provide better therapeutic rationales for treating cancer. This chapter will also discuss the basics of conventional chemotherapies, different theories of CSC, molecular and cellular mechanisms of CSC self-defense, and how all these factors are ultimately involved in chemoresistance.

Breast cancer is a serious concern among women and the second most common cancer worldwide with an estimated 2.3 million new cases reported in the year 2020 alone. Most breast cancers are carcinomas, which can be further classified into invasive and in-situ carcinomas depending on their infiltrating ability. Also, another classification of breast cancers exists based on the presence or absence of hormone receptors on the cell surface namely Triple-negative breast cancer (TNBC), Basal-like BC, Claudin low, HER2+, Luminal A and Luminal B. The diagnosis and treatment for the above-mentioned subtypes prove to be quite challenging. A special form of autophagy in which the damaged or defective mitochondria are detected by the autophagy machinery and are finally digested by the lysosomes is known as mitophagy. Recent investigations have reported that the mechanisms governing mitochondrial activities are critical for cancer therapy. Since most of the chemically synthesised drugs in recent times have not been shown to increase the overall survival rates in BC patients and on the contrary have resulted in many side effects, new strategies, and innovative chemo-preventive agents are required to augment the efficacy of existing cancer regimens. Phytochemicals, naturally occurring plant compounds, are important sources for new medications in cancer therapies which may thus prove to be better than their existing chemotherapeutic counterparts. Hence, the incorporation of such phytochemicals favouring mitophagic dysregulations alongside existing treatment regimes (endocrine therapy, chemotherapy, surgical exclusions) may prove to be effective in minimizing the side effects associated with these treatments.

STAT3 is regarded as a latent transcription factor, which is activated by tyrosine phosphorylation at position 705 by non-receptor tyrosine kinase, leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Activation of STAT3 is important for the transcription of genes related to cell cycle, growth, proliferation, migration, and angiogenesis. Under normal physiological conditions, its upstream signaling that leads to its activation is tightly regulated, but in cancer, the activation of STAT3 is dysregulated. Studies on various cancer models suggest that it is constitutively activated in cancer cells and plays a crucial role in the growth, progression, and metastasis of cancer. It is involved in the induced expression of procarcinogenic cytokines, such as interleukin-13, and suppressed expression of Anti-cancer cytokines, such as interleukin-12, indicating shifting of the balancer of tumor immunity toward tumor growth and progression. Thus it appears to be a potential target for cancer therapeutics. Several bioactive compounds from natural sources have been found to interfere with the signaling leading to deregulated STAT3 activation in cancer cells and subsequent cancer suppression/rejection. This chapter discusses a wide range of natural bioactive compounds that show antitumor effects by inhibiting STAT3 activation both in vitro and in vivo, as well as their future perspectives in anti-cancer therapeutics.

Early detection and effective treatment are daunting challenges in the field of cancer biology. Ovarian cancer has emerged as a third-ranked health issue among women worldwide. In recent decades, there have been numerous pieces of evidence regarding ovarian cancer depicting a high-grade cellular transformation leading to selfrenewal, defining cancer stemness, aggressive growth, and distribution to other organs. Deregulated biological processes are activated, including the Wnt pathway, AKT/MAPK, and STAT3, in typical cells that turn down the governed cell division into uncontrolled expansion through cancer stem cell markers SOX2, CD133, CD44, CD117, and Aldehyde dehydrogenase, thereby suppressing the cell immune system and apoptotic activity. Currently, there has been the advent of innovative therapy for cancer known as “Exosomes,” which are nanovesicles secreted by all cells conveying nucleic acids, proteins, lipids, and carbohydrates to the recipient cells. The upper-hand use of exosomes is marked by their immune tolerability, stability, and systemic delivery to target cells, which will contribute to cancer therapy. In this analysis, we will focus on the behavior of cancer stem cells in the EMT mechanism that promotes ovarian cancer and discusses exosome-based therapeutic applications that require further research to prevent tumor growth.

Gastrointestinal cancer is a malignant condition of the gastrointestinal tract including the esophagus, stomach, small and large intestine, rectum, and anus. About 4.8 million new cases of gastrointestinal cancer were recorded in 2020. Current treatment options of gastrointestinal cancers have failed to treat the disease condition and newer approaches are under investigation. One such approach includes targeting the sphingosine kinase, a critical enzyme in sphingolipid metabolism. Known as structural molecules of the cellular membrane, sphingolipids, and their metabolism have emerged as important components of cellular functions like cell proliferation, cell survival, and cell apoptosis. Over the last few years, most of the enzymes involved in the metabolism of sphingolipids have been extensively studied, which has enlightened the primary roles of these metabolic enzymes in the sphingolipid metabolic pathway. Ceramide and sphingosine are synthesized mainly by oxidative stress, and chemotherapy/radiation which mediates apoptosis, and cell cycle arrest, while sphingosine-1-phosphate (S1P) converted from ceramide, has proliferation and antiapoptotic properties. Findings regarding the nature of ceramide and/or S1P lead to evaluating the potential target enzymes, which are involved in the metabolism of ceramide and S1P. Sphingosine kinase HK1 (SPHK1) and sphingosine kinase HK2 (SPHK2) are diacylglycerol kinase family which converts ceramide into S1P. The overexpression of SPHK1 and SPHK2 has been documented in various cancers. Many in vitro and in vivo studies have been carried out to evaluate the role of sphingosine kinase in cancer. Based on the findings, few pharmacological interventions are under clinical study. This chapter includes sphingolipid metabolism and its essential enzymes, the role of sphingolipids and metabolic enzymes in cancer, potential enzyme targets for the treatment of cancer, and molecules under investigation.

Globally, liver cancer is a severe health problem, which affects both men and women. A large number of scientific studies have suggested dysregulation of signaling cascades as a major characteristic feature in cancer. Hippo is one of the key pathways, which is dysregulated in several human cancers including liver cancer. Therefore, targeting such dysregulated signaling pathways with small molecules and phytochemicals offers significance for liver cancer therapeutics. Numerous phytochemicals were tested for their effect against the dysregulated hippo pathway. This chapter will focus on the phytochemicals that were reported in regulating the hippo pathway in experimental liver cancer.

According to WHO/ Pan American Health Organization, 10 million global cancer deaths have been estimated in 2023. The International Agency for Research on Cancer (IARC) declares that over the ensuing two decades, the burden of cancer will augment by about 60%. For several years, the main treatment modalities for cancer were entailing chemotherapy, radiotherapy, and surgery. Conventional chemotherapies were not tumor-tissue specific and presented a large toll of toxicities for normal cells. But in the last two decades, the idea of targeted therapy, where drug or protein molecules are delivered to specific cells, is a captivating approach to treating malignancy. Immunotoxins comprising a toxin together with an antibody or growth factor hinder the growth and progression of cancer by disrupting specific genes that employ tumor growth and development. With further advances, it is expected that immunotoxins will exhibit a brilliant role and will bring a new era in the treatment of malignancy. 

In the human body, Hedgehog (Hh) signaling is an essential pathway and plays a major role in embryo development, tumorigenesis, distant metastasis, poor prognosis, and tissue patterning. The Hh pathway has three ligands in mammals: Sonic Hedgehog (SHh), Desert Hedgehog (DHh), and Indian Hedgehog (IHh). Malfunctions of this pathway are associated with diseases that include cancer. Cancer is one of the leading causes of death worldwide and factors like dietary habits, family history, obesity, environmental conditions, tobacco, and genetic factors affect the likelihood of developing cancer. The Hh signaling pathway through sporadic mutations is explicitly associated with cancer development and progression in various solid malignancies. Abnormal expression of the Hh signaling cascade has been reported in the development of basal cell carcinoma, breast, liver, prostate, colon, pancreas, and stomach cancer. Most researchers target the inhibition of the Hh signaling pathway and therefore it has emerged as a popular and validated therapeutic for the treatment of a wide range of cancers. A novel class of drugs such as sonidegib and vismodegib inhibits the Hedgehog pathway. There has been significant progress regarding the development of multifactorial drugs blocking Hh signaling. The discovery of multifactorial drugs to block the pathway has led to a new treatment that may significantly improve clinical outcomes in cancer patients. Several of these molecules have been included in the clinical testing stage. Yet finding a sustainable multifactorial inhibitor is still a challenge. This book chapter describes the Hh signaling pathway as a vital and multifactorial therapeutic target for cancer.

Micro-RNAs, a family of small non-coding RNAs of 20-22 nucleotides, are evolutionarily preserved, and regulatory RNAs that negatively control gene expression also play an important role in all biological pathways in multicellular organisms by inducing feedback mechanisms that safeguard key biological processes including cell proliferation, differentiation, and apoptosis. The 3′ UTR of the target mRNAs is the binding site of micro-mRNAs, to induce translational repression by mRNA degradation or inhibition of protein synthesis from m-RNA while miRNA interaction with promoter region has been reported to induce transcription. Many natural products and dietary phytochemicals possess anti-cancer properties along with their tested antioxidant, antiinflammatory, and anti-proliferative effects. Natural agents including (-)-resveratrol, curcumin, indole-3-carbinol, isoflavone, epigallocatechin-3-gallate, and 3,3'- diindolylmethane could modify miRNA expression, therefore reverse the epithelialmesenchymal transition, causing the induction of apoptosis as well as the inhibition of cancer cell growth leading towards the advances of the efficacy of conventional cancer therapeutics. This review paper focuses on the precise targeting of mi-RNAs by natural agents that could open a newer line of attack for the complete eradication of tumors by killing drug-resistant cells to improve survival outcomes in patients with malignancy. In this chapter, we have paid attention to the use of natural products for mi-RN- -mediated chemo-preventive and therapeutic approaches in various cancers, with the aim to extensively identify their pharmacological prospective. 

In recent years, there has been significant progress in understanding the cellular, molecular, and systemic factors that contribute to the development and spread of cancer. This has been made possible by advancements in sequencing methods and data analysis, which have allowed for the identification of various genomic alterations in tumors. While there are currently several specific therapies available, there is a growing focus on target-specific treatments that show better results in cancer treatment. Cancer is widely recognized as the second deadliest disease in the world. For many years, the main forms of treatment for cancer have been chemotherapy and radiotherapy for advanced stages. However, recent advancements in science and technology have led to the discovery of new chemotherapeutic drugs. Additionally, repurposing existing drugs has proven to be a cost-effective strategy for discovering new treatments that target specific cancer regimens and inhibit the growth of cancer cells. The next generation of cancer treatment is largely focused on targeting specific factors that contribute to the development and spread of cancer. This includes therapies that target hypoxia, p53, ERK, and specific proteins through the use of monoclonal antibodies. These treatments have shown promising results in inhibiting the growth of cancer cells and have been effective against various types of cancer. In this article, we will primarily focus on the mechanisms of next-generation therapies and the significance of repurposing drugs. We will also discuss the biology behind targeted cancer treatments and how they work to inhibit the growth of cancer cells.

Apoptosis or programmed cell death refers to a form of death in cells critical to physiological homeostasis occurring in almost every organ system and is characterized by distinct morphological features and a cascade of energy-dependent biochemical processes. This modulation ability of cells is recognised for its immense therapeutic potential. Cancer being the outcome of a spectrum of genetic alterations transforms a healthy body into a cancerous one. Oncologists have been targeting newer therapies for the elimination of cancer cells by apoptosis. Understanding the underlying mechanism of the ordered and orchestrated cellular mechanism plays a pivotal role in disease pathogenesis. There are two major pathways for the induction of apoptosis in malignant cells: Intrinsic and Extrinsic pathways. In this chapter, we summarise the various treatment strategies and therapeutic classes for curbing the different tumor types. This chapter also highlights the utilization of plants and their bioactive compounds in medicine for the treatment of various types of cancer. 

Apoptosis is the programmed cell death that regulates the cell survival or cell death balance in animals. Defects in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals mostly contribute to protecting the genomic integrity whereas defective apoptosis might lead to carcinogenesis. The signals of carcinogenesis alter the central points of the apoptotic pathways, which include the FLICE-inhibitory protein (c-FLIP) and the inhibitor of apoptosis (IAP) proteins. The tumor cells trigger the expression of antiapoptotic proteins such as Bcl-2 or downregulate the proapoptotic proteins like BAX. Most of these changes lead to intrinsic resistance to the most common anticancer therapy, chemotherapy. Apoptosis-resistant cells and transduction pathways that inhibit apoptosis can stimulate non-apoptotic mechanisms of cell death and senescence; this preserves the antitumor effect of several anticancer agents. The development of some promising cancer treatment strategies has been discussed below, which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for the induction of apoptosis.