N.E.T Pharmacy College, Raichur, Karnataka
Cancer is a group of diseases where normal cells lose control and begin to grow and spread recklessly, affecting people and families in profound ways. This review journeys through the modern understanding of how cancer arises from genetic and environmental disruptions, and explores the many shapes it takes in the human body. Recent years have brought hope through remarkable progress: new therapies like CAR-T cell treatments—where a patient's own immune cells are engineered to hunt down cancer—are changing outcomes especially for blood cancers. Similarly, immune checkpoint inhibitors are helping unlock the immune system's power to recognize and destroy tumor cells, offering a lifeline for difficult cancers. Advancements in targeted drugs mean some therapies home in on specific genetic mutations unique to an individual’s cancer, often working where older, broader chemotherapies failed. Noteworthy recent breakthroughs include biospecific antibodies for multiple myeloma, and personalized cancer vaccines that harness mRNA technology to train the immune system. Artificial intelligence aids in precise diagnosis and treatment planning, uncovering new drug targets and improving patient outcomes. The review also touches on promising experimental drugs, novel drug delivery systems, and the emerging role of AI in precision medicine. Together, these advances are not only extending lives but doing so with fewer side effects and a greater focus on quality of life. Ultimately, by weaving together the story of traditional science and innovative new treatments, this article gives patients, caregivers, and researchers a hopeful roadmap of where cancer therapy is today—and where it could be tomorrow.
Cancer is not a single disease, but a collection of over 100 related conditions characterized by uncontrolled cellular growth and division. Essentially, it arises when normal cells escape the body's regulatory systems and begin to proliferate independently. The term 'cancer,' derived from the Greek 'karkinoma' and Latin 'cancer,' reflects observations dating back to Hippocrates. Early epidemiological studies, such as the observation of scrotal cancer in chimney sweeps (1775) and lung cancer in pitchblende miners (mid-1800s), along with the late 19thcentury association of tobacco use with oral and throat cancers, suggested that external factors could contribute to cancer development. In a healthy body, the 30 trillion cells engage in a complex system of mutual regulation, ensuring appropriate tissue size and architecture. Cancer cells, however, disregard these signals, pursuing their own uncontrolled replication. These malignant tumors become increasingly aggressive, ultimately posing a threat to the organism's survival by disrupting essential tissues and organs. [1] Cancer development is driven by a set of fundamental principles, with tumours arising from a common ancestral cell. Malignant transformation occurs through the accumulation of mutations in specific genes, which are critical to understanding the molecular basis of cancer. Genes, located in the DNA of chromosomes within the cell nucleus, provide the instructions for protein synthesis. These proteins perform the functions encoded by the gene, and when the gene is activated, the cell responds by producing the corresponding protein. Mutations in genes can alter the amount or activity of these proteins, disrupting normal cellular function. Among the various gene classes, two specific categories, though constituting a small portion of the genome, play a central role in initiating cancer. Tumour development proceeds through several stages. Initially, a genetically altered cell gains a mutation that enhances its ability to proliferate, bypassing normal growth controls. In the second stage, known as hyperplasia, the mutated cell and its progeny continue to appear normal but proliferate excessively. Over time, one in a million of these cells acquires an additional mutation, further weakening the regulatory mechanisms governing cell growth. In the third stage, dysplasia occurs, where the descendants of the mutated cell become disorganized and exhibit abnormal shapes and orientations. The tissue now displays dysplastic characteristics, which signal a further deviation from normal cellular structure and function. At the fourth stage, the cells become even more abnormal in growth and appearance, marking the onset of in-situ cancer, where the tumour remains localized within its original tissue. In the fifth stage, these genetic alterations allow the tumour to invade surrounding tissues and disseminate cells into the bloodstream or lymphatic system, leading to metastasis. Once the tumour invades and spreads, it is considered malignant. The rogue cells may establish secondary tumours in distant organs, which can disrupt vital organ function and become life-threatening. This multistage process of cancer progression, driven by genetic mutations, highlights the complexity of tumorigenesis and underscores the importance of understanding these molecular mechanisms for the development of targeted therapies. [2]
Cancer research in 2024 continues to be at the forefront of scientific discovery, driven by advancements in genomics, immunotherapy, and personalized medicine. With cancer remaining one of the leading causes of death globally, ongoing research aims to uncover new mechanisms of tumorigenesis, refine early detection techniques, and develop more targeted, effective treatments. The rapid evolution of technologies such as artificial intelligence, machine learning, and CRISPR (Clustered Regularly Interspaces Short Palindromic Repeats) gene editing is enabling researchers to make unprecedented strides in understanding the genetic and molecular underpinnings of cancer. Advances in cancer immunotherapy, including CAR-T (Chimeric Antigen Receptor) cell therapies and checkpoint inhibitors, are showing promise in treating previously difficult-to-treat cancers. There is also a growing emphasis on cancer prevention, with studies exploring the roles of diet, lifestyle, and environmental factors in cancer risk reduction.
Efforts to identify biomarkers for early detection are crucial, as they can significantly improve survival rates by catching cancers at more treatable stages. As we look to 2024 and beyond, the focus of cancer research remains on providing better, more effective treatments, improving patient outcomes, and ultimately finding a cure for this complex and multifaceted disease.
Some genes involved in human Cancers:
Genes are known as proto-oncogenes code for proteins which stimulates the cell division; mutated forms, called oncogenes, can cause the stimulatory proteins to be over-active, with the result that cells proliferate excessively. Tumour suppressor genes code for proteins that inhibit the cell division. Mutations can cause the proteins to be inactivated and may thus deprive cells of needed restraints on proliferation. Investigators are still trying to decipher the specific functions of many tumour softener genes. [3]
Types of Cancers
There are multiple types of cancers today but, some of the common types of cancers are:
Basically, cancer is named after the part of that particular body from which it is originated. For example: if kidney cancer spreads to the lungs, that time it is still known as kidney cancer not lung cancer in this case lung cancer would be an example of a secondary tumour.[6][7]
Categories of Cancer: There are five broad categories which indicates the tissue and blood classifications of cancer.
MECHANISM OF CANCER:
Carcinogenesis is a multistep process involving molecular and cellular events at both the genetic and epigenetic levels, driven by the interplay of environmental, genetic, and metabolic factors. The concept of multistage carcinogenesis was first proposed by Berenblum and Schubik in 1948 and supported by later studies. This process is typically categorized into 3 main stages ----Initiation, Promotion and progression.[8]
Mechanisms of Oncogene Activation: Proto-oncogenes convert into oncogenes through various mechanisms:
Characteristics:
Key Factors: DNA damage, genetic mutations, and inflammation play critical roles in initiation. Recent research suggests that epigenetic changes may also be significant, potentially priming cells for future mutations. [8]
Mechanism: Promoting agents (e.g., hormones, growth factors) stimulate the growth of initiated cells, leading to their immortality and further mutations.
Characteristics:
Mechanism: Involves further mutations and chromosomal aberrations, leading to tumor heterogeneity and aggressive.[9]
Various factors drive angiogenesis, including:
These factors collectively drive angiogenesis in the tumour microenvironment, enabling sustained tumour growth and metastasis.
Understanding the progression stage is crucial for developing interventions to halt the carcinogenic process. By targeting factors that promote cancer cell growth and disrupting the pathways that support them, it may be possible to impede or slow the transformation of precancerous cells into malignancies.In the final stage of carcinogenesis, cells that have undergone initiation and promotion acquire the necessary mutations to invade surrounding tissues, marking the onset of invasive cancer.
Multilevel Mechanisms of Cancer Drug Resistance:
Cancer drug resistance is a major obstacle in oncology, limiting treatment success. Resistance develops through complex, interconnected genetic, epigenetic, and microenvironmental mechanisms.
Five key factors contribute to resistance: tumour heterogeneity, growth kinetics, undruggable genomic drivers, selective therapeutic pressure, and immune/microenvironment interactions.
Cancer stem cells play a role through enhanced DNA repair and altered metabolism. DNA repair mechanisms are crucial for resistance, including homologous recombination repair (HRR), nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR).
Genetic and epigenetic alterations drive resistance, including mutations, copy number variations, DNA methylation, histone modification, and non-coding RNA changes. The tumour microenvironment and immune system contribute to resistance through complex interactions.
Alternative signalling pathways can be activated to bypass drug targets. Inhibition of apoptosis (programmed cell death) is a key mechanism of resistance. Increased drug efflux (pumping drugs out of cells) is another mechanism of resistance. Hypoxia (low oxygen) in the tumour microenvironment can promote resistance. [11]
Activation of Alternative Signalling Pathways:
This part describes how cancer cells can develop resistance to drugs by activating alternative signalling pathways. Here's a breakdown:
Cell Communication and Signalling:
This excerpt discusses the role of extracellular vesicle (EVs) in mediating communication within the tumour microenvironment (TME) and how this contributes to multidrug resistance (MDR) in cancer.
EVs as Messengers: Cells in the TME communicate through a complex system, and EVs are crucial players in this communication. Different cell types within the TME release EVs, which can carry various molecules (proteins, RNAs, etc.) and influence recipient cells.
Key Players and Their EV Contributions:
Mesenchymal Stem Cells (MSCs): MSCs can promote tumour growth and metastasis through their EVs. However, the effects can be complex. For example, while some MSC-derived EVs promote tumour progression, others, modified with certain compounds (like EGCG from green tea), can have anti-tumour effects. MSC-derived EVs can also contribute to drug resistance, as seen in pancreatic cancer where they can transfer molecules that promote gemcitabine resistance.
Stromal Cells: Stromal cells, including bone marrow stromal cells, can secrete EVs that contribute to MDR in various cancers, including breast cancer and multiple myeloma. These EVs can activate intracellular pathways in cancer cells, leading to resistance.
Cancer-Associated Fibroblasts (CAFs): CAFs are a major component of the TME and play a significant role in tumour progression. They release EVs that can promote tumour growth, metastasis, and drug resistance. For instance, CAF-derived EVs can increase stemness and chemoresistance in urothelial bladder cancer and promote gemcitabine resistance in pancreatic cancer. Conversely, some compounds can reduce CAF activation by interfering with EV secretion.
Macrophages (especially TAMs - Tumour -Associated Macrophages): Macrophages, particularly those within the TME (TAMs), are often M2-polarized, promoting tumour growth and resistance. TAM-derived EVs can transfer microRNAs (miRNAs) that induce radiotherapy resistance in glioblastoma and contribute to gemcitabine resistance in pancreatic cancer. [12]
Other Cell Types (Tregs, Adipocytes): Even other cell types like regulatory T cells (Tregs) and adipocytes can contribute to drug resistance through their EVs. For example, adipocyte-derived EVs can protect multiple myeloma cells from chemotherapy-induced apoptosis.
Mechanisms of Action: EVs influence recipient cells by delivering their cargo, which can include:
Therapeutic Implications: Understanding the role of EVs in MDR opens up potential therapeutic avenues:
Targeting EV production or uptake: Interfering with EV secretion or how cancer cells take them up could reduce resistance.
Modifying EV cargo: Loading EVs with therapeutic molecules could be a way to deliver drugs specifically to cancer cells.
Using EVs as biomarkers: The composition of EVs might reflect the state of the tumour and could be used to predict treatment response or disease progression.
In summary, this section highlights the complex interplay between different cell types in the TME, mediated by EVs, and how these interactions contribute significantly to the development of drug resistance in cancer. This is an active area of research with the potential to lead to new therapeutic strategies. [12]
Different compounds & their derivatives used in cancer treatment:
Genistein Derivatives as anticancer agent:
Genistein, a soy isoflavone, has shown promise in cancer prevention and treatment. Researchers have synthesized genistein derivatives to enhance its anticancer activity. Two recent studies highlight this effort:
One study created 5-fluorouracil-genistein hybrids using a click reaction. Some of these hybrids showed greater antiproliferative activity against colon cancer cells (SW480 and SW620) than 5-fluorouracil and genistein alone. Specifically, compound 6a demonstrated the strongest activity. Another study synthesized triazine-genistein derivatives. These compounds also exhibited improved antiproliferative activity against various cancer cell lines (MDA-MB-231, HeLa, HCT-116, and Huh-7) compared to genistein. Compound 9i was particularly potent against MDA-MB-231 and HeLa cells and further studies showed it inhibited cell migration, invasion, and adhesion in vitro, and tumor growth in vivo.[13]
Synthesis of 5-Fluorouracil-genistein analogues. Reagents and conditions: a) DIPEA, DMF, 61–71 %; b) NaN3, DMF, 40°C, US, 78–89%; c) DIPEA, KI, DMF, US, 40%; d) Ascorbic acid,Cu(OAc)2, DMF-H2O, 40°C, US, 43–93%.
Synthesis of 1,3,5-triazine analogues of genistein. Reagents and conditions: a) Secondary amine, Acetone, K2CO3, ???? 20°C; b) Acetone, K2CO3, rt, 69–81%.
Formononetin Derivatives for cancer treatment:
Formononetin, a phytoestrogen found in red clover, has shown various biological activities. Researchers have synthesized formononetin derivatives to enhance its anticancer potential. Several studies highlight this:
Synthesis of formononetin-dithiocarbamate conjugate 19. Reagents And conditions: a) 1,3-dibromopropane, K2CO3, THF, reflux, 70–83% yield; (b) CS2, tert-butyl piperazine-1-carboxylate, Na3PO4·12H2O, acetone, rt, 78–85% yield
Synthesis of formononetin hydrazide derivative 22. Reagents and conditions: a) ethyl bromoacetate, acetone, K2CO3, reflux, 10 h, 95%; b) hydrazine hydrate, ethanol, reflux, 10 h, 87 %; c) 4-benzyloxybenzaldehyde, glacial acetic acid, ethanol, reflux, 6 h, 69 %.
Glaziovianin A Derivatives in cancer therapy:
Glaziovianin A, isolated from a Brazilian tree, exhibits potent cytotoxic activity and inhibits microtubule dynamics. Researchers have synthesized glaziovianin A and its derivatives to explore its therapeutic potential. Modifications to the A and B rings have yielded compounds with improved activity. One derivative, 6-O-benzylglaziovianin A (31), inhibits α,β-tubulin, while the 7-O-benzyl derivative, gatastatin (32), is a specific γ-tubulin inhibitor, though less potent. Further modifications of gatastatin at the C-6 position led to the development of gatastatin G2 (33), a more active γ-tubulin inhibitor. These derivatives are synthesized using Suzuki-Miyaura coupling reactions, starting from readily available precursors like sesamol and isovanillin.[13]
Nitro-fatty acids as anticancer:
Nitro-fatty acids (NO2-FAs) are naturally occurring lipid mediators with promising therapeutic potential for inflammatory and fibrotic diseases. Recent preclinical studies suggest they also hold promise as cancer treatments due to their anti-tumor and chemosensitizing effects. NO2-FAs are naturally occurring lipid mediators with diverse anti-inflammatory and cytoprotective actions. They exert their effects through post-translational modifications (PTMs), specifically nitroalkylation, of regulatory proteins, enzymes, and transcription factors. These modifications alter protein structure and function, influencing cell signaling and gene expression. Preclinical studies have demonstrated NO2-FA benefits in various conditions, including inflammation, fibrosis, and ischemia/reperfusion injury.
Following successful Phase 1 trials, NO2-FAs entered Phase 2 trials for inflammatory fibrotic diseases. Recent reports highlight their potential as cancer therapeutics due to observed tumor-suppressive and chemosensitizing effects in colon and triple-negative breast cancer cells. Their ability to inhibit tumor-promoting conditions like inflammation and fibrosis further strengthens this potential.[14]
Fluoroquinolones & its derivative in cancer treatment:
Fluoroquinolones, known for their broad antimicrobial activity, also exhibit anticancer potential. Modifications at the 7 and 3 positions of the fluoroquinolone core, like ciprofloxacin, significantly impact their properties. Recent research focuses on synthesizing new derivatives with enhanced anticancer activity against aggressive cancers. One study explored conjugating ciprofloxacin with various fatty acids to create amide derivatives. Using acids with varying chain lengths and degrees of unsaturation, researchers synthesized a range of compounds. These derivatives were then tested for their effects on colon cancer (SW480 and SW620) and prostate cancer (PC3) cell lines.
Several derivatives demonstrated stronger antiproliferative activity than ciprofloxacin itself, particularly against PC3 cells. Conjugates with crotonic, oleic, and elaidic acids showed the most potent inhibitory effects. Against colon cancer cells, derivatives with polyunsaturated fatty acids like sorbic, geranium, elaidic, and DHA were most effective. Importantly, these compounds exhibited selectivity towards cancer cells, showing no significant toxicity to normal skin cells. Further analysis revealed that some derivatives also induced apoptosis, particularly the ciprofloxacin-oleic acid conjugate, demonstrating the strongest pro-apoptotic ability. These findings suggest that modifying ciprofloxacin with fatty acids can enhance its anticancer activity and selectivity. [15]
Tea in cancer therapy:
Tea consumption, likely due to its main constituent EGCG (Epigalloctocatechin gallate), has shown promise in reducing tumor formation in various organs. EGCG's cancer-preventive effects may be linked to its ability to inhibit the NF-κB pathway, as demonstrated in mouse epidermal cells where it blocked TPA-induced NF-κB activation. EGCG also inhibits UV induced NF-κB activation in human skin cells. Furthermore, tea and EGCG have been shown to inhibit Wnt/βcatenin signaling, another pathway implicated in cancer development. In mouse models, tea inhibited PhIP induced intestinal polyp formation. EGCG inhibited β-catenin/TCF reporter activity in HEK293 cells and reduced tumorigenic proliferation and invasiveness in breast cancer cells by inducing the Wnt signaling suppressor HBP1. EGCG and other tea catechins have demonstrated inhibitory effects on P-glycoprotein function, a protein often implicated in multidrug resistance in cancer cells. Using a multidrug-resistant human epidermal carcinoma cell line (KB-C2) that overexpresses P-glycoprotein, researchers found that these catechins increased the cellular accumulation of daunorubicin and rhodamine 123, both fluorescent P-glycoprotein substrates. The potency of these catechins in enhancing accumulation followed the order: (-)-epigallocatechin < (-)-epicatechin gallate < EGCG. (-)-Epicatechin had no effect. While the lipophilicity of the catechins (measured by the n-octanol/PBS partition coefficient) varied, it did not correlate with their inhibitory effect on P-glycoprotein. For example, EGCG, despite being relatively hydrophilic, had a stronger inhibitory effect than quercetin, which is more lipophilic. This suggests that EGCG's amphiphilic nature, rather than just its hydrophobicity, may be key to its interaction with Pglycoprotein. [16]
Cuproptosis for cancer therapy:
Cuproptosis, a novel form of cell death triggered by excessive copper accumulation, has emerged as a promising target for cancer therapy. This review explores the intricate mechanisms of Cuproptosis, its interplay with other cell death pathways, and innovative strategies to harness its potential for tumor treatment.
Mechanisms of Cuproptosis:
Cuproptosis is characterized by the accumulation of copper within cells, leading to the aggregation of dihydrolipoamide S-acetyltransferase (DLAT) and the loss of iron-sulfur cluster proteins. This cascade of events triggers proteotoxic stress and ultimately culminates in cell death.
Cuproptosis and Other Cell Death Pathways
Cuproptosis exhibits a complex relationship with other forms of regulated cell death, including ferroptosis, apoptosis, autophagy, and pyroptosis. These interactions highlight the intricate signaling networks governing cell fate and offer potential avenues for synergistic therapeutic approaches. [17]
Targeting Cuproptosis for Cancer Therapy
Researchers are actively exploring various strategies to exploit Cuproptosis for cancer treatment. These include:
Targeting Cuproptosis holds immense promise for overcoming drug resistance in cancer therapy and enhancing the effectiveness of immunotherapy. However, further research is warranted to fully elucidate the underlying mechanisms and optimize therapeutic strategies. The field of Cuproptosis research is rapidly evolving, with ongoing efforts focused on Identifying novel Cuproptosis inducers with improved efficacy and safety profiles. Elucidating the intricate interplay between Cuproptosis and other cell death pathways. Developing innovative nanomedicine approaches for targeted Cuproptosis induction. Exploring combination therapies that synergize with Cuproptosis to enhance anti-cancer activity. Cuproptosis represents a paradigm shift in our understanding of cell death mechanisms and offers a novel avenue for cancer therapy. By harnessing the power of Cuproptosis, we may be able to develop more effective and targeted treatments for a wide range of malignancies. [17]
Artemisinin and its derivatives as Promising anticancer agents:
Artemisinin, a natural compound derived from the Artemisia annua plant, has long been recognized for its potent antimalarial properties. However, recent research has shed light on its remarkable anticancer potential, opening up new avenues for cancer treatment. Artemisinin and its derivatives exhibit anticancer effects through various mechanisms, including the induction of apoptosis (programmed cell death) in cancer cells, inhibition of angiogenesis (new blood vessel formation), and disruption of the cell cycle. These compounds have demonstrated efficacy against a wide range of cancers, including breast cancer, lung cancer, liver cancer, and colorectal cancer.
One of the key advantages of artemisinin and its derivatives is their selective toxicity towards cancer cells, sparing healthy cells from harm. This selectivity reduces the risk of adverse side effects commonly associated with traditional chemotherapy. Moreover, these compounds have shown synergistic effects when combined with other anticancer drugs, enhancing their overall therapeutic efficacy.
Artemisinin and its derivatives hold great promise as novel anticancer agents. Their unique mechanisms of action, coupled with their selective toxicity and synergistic potential, make them attractive candidates for further development in the fight against cancer. Clinical trials are underway to evaluate their safety and efficacy in humans, paving the way for their potential integration into mainstream cancer treatment. [18]
Quinoxaline derivatives in cancer treatment:
The researchers have divided quinoxaline derivatives into several categories according to their mechanisms of action: disruption of the cytoskeleton, DNA impairment, regulation of cell metabolism, and inhibition of proliferation pathways.
Quinoxaline derivatives that disrupt the cytoskeleton target the tubulin-microtubule system, which is essential for cell division. These derivatives, similar to known drugs like colchicine, bind to the colchicine binding site of tubulin and prevent its polymerization, thereby inhibiting cell proliferation. Quinoxaline derivatives that impair DNA function can act as alkylating agents, topoisomerase inhibitors or PARP inhibitors. Alkylating agents damage DNA by adding alkyl groups, while topoisomerase inhibitors interfere with the enzymes responsible for DNA topology. PARP inhibitors, on the other hand, prevent the repair of damaged DNA, leading to cell death.
Quinoxaline derivatives also regulate cell metabolism by acting as folate antagonists or by disrupting the oxygen/ROS balance in cancer cells. Folate antagonists interfere with the synthesis of nucleotides, essential components of DNA, while compounds disrupting the oxygen/ROS balance can induce oxidative stress in cancer cells, leading to their death. Finally, some quinoxaline derivatives inhibit proliferation pathways by targeting specific proteins involved in cell signaling, such as FGF receptors, VEGF receptors or EGF receptors. By binding to these receptors, quinoxaline derivatives can block the signals that promote cell growth and division. In conclusion, quinoxaline derivatives represent a promising class of anticancer agents with diverse mechanisms of action. Further research and development in this area could lead to new and effective cancer therapies. [19]
RECENT ADVANCEMENTS IN CANCER THERAPY:
AI IN CANCER TREATMENT:
Many FDA-approved cancer drug combinations are considered superior to monotherapy due to patient-to-patient variability and independent drug action, not necessarily due to drug synergy or additivity. With independent drug action, each patient benefits from the drug to which their tumor is most sensitive. Even if drug combinations show synergy in preclinical models, patient variability and low cross-resistance make independent action the dominant mechanism in clinical settings. The researchers analyze clinical trial data, drug response databases, and computational models to distinguish between drug interaction and independence. For many effective combinations, therapeutic benefit arises from independent drug action rather than synergy. Using melanoma responsiveness to ipilimumab and nivolumab as an example, the researchers demonstrate the clinical significance of independent drug action. Their findings suggest a new approach to designing combination therapies: maximize the chance of response to at least one drug. Analysis of patient-derived tumor xenograft data reveals that independent action explains most of the benefit of combination therapy, with a few exceptions showing probable synergy. Finally, the researchers show that in simulations of patient heterogeneity in clinical trials, independent drug action is similar in effect to additivity or synergy.
AI has significantly benefited biomedical cancer research in several fields, including the creation of new medications and treatments, improved early cancer detection through image analysis, and personalized treatment plans. AI is also essential to precision medicine, which allows doctors to customize a patient's course of therapy based on a variety of criteria, including their genetic composition. AI speeds up the process of finding promising new drugs and expedites the identification phase of the drug discovery process. Together, these applications hold out the possibility of more effective, individualized, and efficient methods for fighting cancer in the realm of biomedical research. [20]
AI in Radiodiagnosis:
Modern medical imaging uses machine learning (ML) techniques like those found in computed tomography (CT) and magnetic resonance imaging (MRI). CT scans provide detailed volumetric and morphological information, while MRI excels at distinguishing soft tissues. Neural networks and deep learning (DL) algorithms are used for brain segmentation, classifying MRI scans into cancerous and healthy tissue. Breast cancer diagnosis often uses ultrasonography, but manual segmentation is time-consuming. Automated segmentation using convolutional neural networks (CNNs) can reliably classify breast ultrasound images into different tissue types, potentially improving clinical diagnosis. [20]
AI in Radiotherapy:
AI is significantly improving radiotherapy in cancer treatment. It helps precisely define tumor boundaries for more accurate treatment planning, minimizing harm to healthy tissues. AI algorithms process large datasets and images to optimize treatment and enable real-time monitoring, allowing for adjustments based on patient response. This leads to better outcomes, more personalized care, and contributes to advancements in cancer research. [20]
AI in Chemotherapy:
AI is revolutionizing chemotherapy by personalizing cancer treatments. By analyzing large datasets, AI helps oncologists tailor treatment plans to individual genetic and molecular profiles, improving success rates and reducing side effects. AI-powered models predict patient responses to chemotherapy, enabling targeted approaches. This integration enhances treatment outcomes and offers more effective, less invasive cancer care, advancing biomedical cancer research. [20]
AI in Immunotherapy:
In immunotherapy, AI is used to uncover immune patterns linked to responses and predict responses to immunotherapy. AI-driven analysis of genetic sequences and medical imagery yields valuable insights for cancer immunotherapy management, contributing to patient selection, treatment optimization, and personalized prognosis prediction. Cancer immunotherapy has emerged as a pivotal component of systematic cancer treatment, working in conjunction with traditional approaches such as chemotherapy, radiotherapy, and surgery. Through the restoration of the body's normal immune response and the resuscitation of immunological processes to regulate and eradicate malignant growths, cancer immunotherapy aims to treat tumors. The release and presentation of tumor antigens, the activation of effector T cells, the migration and infiltration of T cells into tumor tissues, and the subsequent recognition and destruction of tumor cells by these activated T cells are some of the crucial steps in this complex process. Many immunological markers and signatures are analyzed before treatment initiation to identify correlations with cancer patients' receptivity to immunotherapies. [20]
Targeted Therapy:
AI is revolutionizing targeted cancer therapy by enabling more precise and effective treatments. By analyzing complex datasets and patient profiles, AI helps tailor therapies to individual cancer characteristics, improving outcomes and reducing side effects. This contributes to advancements in biomedical cancer research by identifying specific molecular targets, guiding treatment decisions, and ushering in an era of precision medicine in cancer care. [20]
Surgery:
Computer-assisted surgery (CAS), a subdomain of AI, is significantly improving cancer care. Computer vision (CV) is used in image-guided navigation, helping surgeons plan and execute procedures by combining pre-operative images with real-time tracking of surgical instruments. While currently more common in neuro- and orthopedic surgery, AI-driven navigation is being developed for surgeries with significant anatomical changes, like abdominal surgery. Examples include visualizing vital structures in laparoscopic rectal surgery and creating liver maps for liver cancer surgery. Future applications may include mapping additional abdominal structures. Robotic surgery, particularly robotic prostatectomy, also benefits from AI, with the potential for integrated CV systems providing surgeons with real-time anatomical information and comparisons to reference images. [20]
Nanotechnology:
AI combined with nanotechnology, holds immense potential for revolutionizing cancer management. AI can analyze large datasets to create personalized nanomedicines, improving molecular profiling, early diagnosis, and nanomedicine development. It optimizes nanomedicine properties, drug synergy, and minimizes toxicity. Nanomedicines themselves address challenges like side effects and poor drug penetration in tumors. While still early, AI can predict nanocarrier-drug interactions, estimate drug encapsulation, and model drug release, optimizing nanopharmaceutical formulations.
While AI offers significant advantages in cancer research, like improved diagnosis, prognosis, and drug discovery, it also has limitations. These include the need for large, high-quality datasets, potential biases, and interpretability issues. Studies show AI can provide triage and diagnostic information comparable to human doctors, and decision support systems aid oncologists in treatment planning. AI is increasingly important in personalized medicine, but more clinical validation and ethical considerations are needed. Addressing these constraints is crucial to fully realize AI's potential for improving cancer patient outcomes and advancing cancer research. [20]
CAR-T CELL THERAPY:
CAR-T (Chimeric Antigen Receptor) cell therapy is a new type of immune cell therapy that changes a patient's T cells to express the CAR protein, which helps them recognize and kill cancer cells. It has been somewhat successful in treating blood cancers, but there are still problems in treating solid tumors, like antigen selection, tolerability and safety. In response to these issues, studies continue to improve the design of CAR-T cells in pursuit of improved therapeutic efficacy and safety. In the future, CAR-T cell therapy is expected to become an important cancer treatment, and may provide new ideas and strategies for individualized immunotherapy.
CAR-T CELL STRUCTURE:
CAR-T cell therapy involves modifying T cells to express CAR proteins, enabling them to target and destroy cancer cells. CAR proteins consist of an external recognition region (usually an scFv) that binds to specific antigens on cancer cells, and an internal signaling region that activates the T cell. The scFv targets the antigen, while the internal region, often including CD3ζ and co-stimulatory domains like CD28 or 4-1BB, triggers T cell activation and proliferation. CAR genes are introduced into T cells using viral or non-viral methods. First-generation CARs had limited effectiveness, so second, third, and fourth generations were developed. Second-generation CARs added co-stimulatory domains, third-generation added more, and fourth-generation CARs include cytokine secretion systems to further enhance the immune response. Preactivation domains are also being incorporated to boost initial T cell activation. To improve safety, researchers are designing CAR-T cells with narrower antigen recognition to avoid cross-reactivity with normal tissues, focusing on tumor-specific antigens. These improved CAR designs aim to increase CAR-T cell persistence, enhance killing capacity, reduce toxicity, and improve specific recognition, ultimately leading to better anti-tumor responses. [21]
Targeted killing mechanism of CAR-T cells:
CAR-T cell therapy targets tumor-specific or tumor-associated antigens on cancer cells. The CAR-T cell recognizes these antigens through an scFv on the CAR protein, triggering intracellular signaling. Once activated, CAR-T cells kill tumor cells through cytotoxin release, cytokine release, and recruiting other immune cells to attack the tumor.
CAR-T cell therapy treatment process:
The CAR-T cell therapy process involves several steps. First, patients are screened for eligibility. Then, their T cells are collected, genetically modified to express the CAR gene, and expanded in the lab. Patients undergo preparation, including lymphodepletion (to reduce competing immune cells) and sometimes bridging therapy (to control tumor progression while waiting for CAR-T cell production). Finally, the CAR-T cells are infused into the patient, who is closely monitored. Challenges exist throughout the process. T cell collection can be difficult due to poor sample quality or immune system suppression. Contamination and cell damage during collection, culture, or transport are also risks. The time required for CAR-T cell manufacturing can also lead to treatment delays and increased burdens for patients.[21]
Clinical utilization of CAR-T cell therapy:
CAR-T cell therapy has shown promising results in treating blood cancers like leukemia and lymphoma, with high remission rates. While still under investigation for solid tumors, some progress has been made in targeting antigens like GD2 in neuroblastoma and others in prostate cancer and soft-tissue sarcoma. However, challenges such as antigenic diversity, immune escape, and achieving sufficient proliferation and infiltration limit its application in solid tumors.[21]
Side effects and clinical challenges of CAR-T cell therapy:
While CAR-T cell therapy shows promise, it also presents challenges. Cytokine release syndrome (CRS) is a common side effect, causing varying degrees of inflammation and potentially leading to organ damage. Lymphodepletion, while necessary, can weaken the immune system. Neurological side effects are also possible. CAR-T cells can also attack healthy cells expressing the target antigen (on-target off-tumor effects). Efficacy is limited by antigen selection and heterogeneity. Tumors may lack specific antigens or have varied expression, making it difficult for CAR-T cells to target them. Relapse and drug resistance can also occur. The tumor microenvironment in solid tumors can suppress CAR-T cell activity, limiting infiltration and increasing immune escape.
CAR-T cell therapy also faces challenges like tonic signaling (activation without stimulation), antigen loss, and low antigen density. Researchers are addressing these by improving CAR-T cell design, incorporating switchable activation technology, and developing multi-antigen targeting CAR-T cells. Co-stimulatory molecules like BBC are being used to enhance CAR-T cell activity and promote memory cell formation for longer-lasting responses. Other TNF-R superfamily molecules like CD27 and OX40 are also being explored for improved memory formation and T cell survival.[21]
CAR-T cell therapy representative drugs:
Several CAR-T cell therapies have been approved for specific blood cancers, including tisagenlecleucel and axicabtagene ciloleucel for lymphoma and Tecartus for leukemia. Breyanzi is another approved therapy for large B-cell lymphoma. Many more CAR-T therapies are in clinical trials, targeting various cancers like multiple myeloma, B-ALL (B-cell acute lymphoblastic leukemia), colorectal cancer, and glioblastoma. Anti-BCMA (Anti-B-Cell Maturation Antigen) CAR-T therapy is a key treatment for multiple myeloma.
CAR-T drug dosage is personalized based on patient factors. Optimal doses vary depending on the target antigen (e.g., CD19 vs. BCMA). Increasing the dose may improve response rates up to a point, but excessive doses can increase toxicity. While higher doses may correlate with better response in some cases, the risk of CRS and neurotoxicity is a concern.
Dose fractionation is being explored as a way to improve safety. Administering CAR-T cells over multiple days instead of a single infusion may reduce the severity of side effects like CRS and neurotoxicity, particularly in patients with high tumor burden or those requiring higher doses. Slow, continuous administration may also lead to more stable outcomes. Strategies like dose stratification, using pharmacokinetic data in trials, and developing less toxic CAR-T cells are all being investigated to optimize dosing, improve the therapeutic window, minimize toxicity and resistance, and reduce adverse reactions.[21]
IMMUNOTHERPY:
Cancer immunotherapy is a new treatment option that works by activating the immune system to fight cancer. William Coley, the father of immunotherapy, first attempted to use the immune system to treat cancer in 1891.
All cancers are caused by genetic changes that occur over time. These changes can lead to tumor antigens, which the immune system can recognize as foreign and attack. However, cancer cells have developed ways to avoid being destroyed by the immune system. HNSCCs
(Head and Neck Squamous cell) are highly immunosuppressive cancers with a high number of mutations. Cancer cells have evolved multiple mechanisms, such as defects in antigen presentation machinery, the upregulation of negative regulatory pathways and the recruitment of immunosuppressive cell populations to escape immune surveillance. There has been extensive research on the complex and dynamic interaction between tumor cells and host immune cells which has led to the development of currently approved immunotherapies. Immunotherapy is designed to either actively target a specific antigen on the tumor or enhance the host’s immune system.
In 2013, Science magazine named cancer immunotherapy the "breakthrough of the year," The goal of cancer immunotherapy is to use the immune system's specific targeting and killing mechanisms to eliminate cancer cells. [22]
TUMOR IMMUNOLOGY:
The immune system has two parts: the innate (first-line defense) and adaptive (antigen-specific) systems. The innate system includes cells like dendritic cells and natural killer cells, while the adaptive system involves T and B lymphocytes. "Immunoediting" describes how tumor cells evolve mechanisms to escape immune recognition and destruction.
This process has three phases:
HNSCCs are highly immunosuppressive, evading immune destruction by changing their own characteristics and creating a suppressive tumor microenvironment.
IMMUNE CHECKPOINTS:
Immune checkpoints are molecules that help to keep the immune system in check and prevent it from attacking the body's own tissues. The main inhibitory checkpoint receptors are PD-1, CTLA4, lymphocyte activating gene 3 and T cell immunoglobulin (IgG) and mucin domain-containing 3. Immunotherapy can be broadly divided into active and passive approaches.
Active immunotherapy involves directing the host immune system to tumor-associated antigens on the surface of tumors. These antigens can be specific proteins or carbohydrates that are exclusively expressed or overly expressed in tumor cells.
Passive immunotherapy involves enhancing the standard anticancer response by the immune system using monoclonal antibodies (MoAbs), lymphocytes and cytokines. [22]
TYPES OF IMMUNOTHERAPIES:
1. Adoptive cell therapy (ACT) boosts anti-tumor immunity by transferring T cells. There are three types: TIL therapy (using unmodified tumor-infiltrating lymphocytes), engineered TCR therapy (genetically modified T cells with specific antigen receptors), and CAR-T cell therapy (T cells modified with chimeric antigen receptors).
2. Immune checkpoint inhibitors work by blocking checkpoint molecules (like CTLA4 and PD1) that normally suppress the immune system. This allows the immune system to attack cancer cells more effectively. Examples include Ipilimumab (anti-CTLA4) and Nivolumab and Pembrolizumab (anti-PD1).
3. Targeted monoclonal antibodies (MoAbs) are a form of active immunotherapy where MoAbs target specific antigens on cancer cells. They can be unconjugated or conjugated with cytotoxic drugs. Cetuximab and Panitumumab, which target EGFR, are used in HNSCC treatment. Other potential targets include VEGF/VEGFR and insulin-like growth factor receptor.
4. Oncolytic virus therapy uses genetically modified viruses to infect and destroy tumor cells. This triggers inflammation and enhances anti-tumor immunity. Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic virus therapy for melanoma. [22]
CANCER VACCINES:
Cancer vaccines are classified as prophylactic (preventative) or therapeutic. Prophylactic vaccines, like those for Hepatitis B and HPV, are given to healthy individuals to prevent cancer. Therapeutic vaccines, like BCG for bladder cancer and Sipuleucel-T for prostate cancer, are given to cancer patients to strengthen their immune response against existing cancer cells. Cytokines are signaling molecules that help immune cells communicate. Two cytokines approved for cancer treatment are Interferon α, used in renal cell carcinoma and melanoma, and Interleukin-2, used in metastatic melanoma. Interferon α can directly kill tumor cells and boost anti-tumor immune responses. Interleukin-2 increases NK cell and TIL levels.[22]
Minimally Invasive surgery:
Minimally invasive surgery (MIS) has revolutionized the treatment of many benign tumors, offering significant advantages over traditional open surgery. MIS involves smaller incisions, leading to reduced blood loss, faster healing, less pain and scarring, shorter hospital stays, and lower infection risk. Imaging techniques like arthroscopy and laparoscopy empower surgeons to diagnose, visualize internal structures, and perform procedures through these tiny incisions. While MIS is widely accepted for benign conditions, its application in malignant cancers has been more cautious. Cancer's ability to spread (metastasize) necessitates a focus on thorough removal of cancerous tissue, sometimes requiring more extensive surgery than MIS might allow. The concern is that incomplete removal, even of microscopic cancerous cells, can have dire consequences. This emphasis on complete resection has historically favored traditional open surgery for cancer treatment.
However, the benefits of MIS, such as reduced pain, infection rates, and recovery time, cannot be ignored in cancer care. For certain cancers, like early gastric, colon, and esophageal cancers, MIS has demonstrated comparable outcomes to traditional surgery, with the added benefits of MIS. Furthermore, MIS offers a valuable option for patients with advanced-stage cancer who may not be suitable candidates for more invasive procedures. These patients, often unable to tolerate open surgery or radiotherapy, can experience significant suffering, including pain and complications like paraplegia. MIS can provide a less invasive approach to palliative care, improving their quality of life. For example, minimally invasive techniques like targeted bone cement injection have shown promise in managing metastatic spinal cord compression, significantly improving both survival time and patient comfort. [23]
Ongoing advancements in surgical tools and digital technologies are expected to further expand the applicability of MIS in cancer treatment. This evolution in surgical practice reflects a growing recognition of the benefits of MIS in balancing the need for thorough cancer removal with minimizing patient morbidity and improving overall quality of life. [23]
MicroRNA Therapeutics:
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by binding to the 3'-untranslated region (3'-UTR) of target mRNAs, leading to mRNA degradation or translational repression. They are produced through a specific biogenesis pathway involving Drosha, DGCR8, Exportin-5, Dicer, and Ago proteins within the RISC complex. MiRNAs play crucial roles in development and tissue specificity, with thousands identified in humans. Their dysregulation is implicated in various diseases, notably cancer. Aberrant miRNA expression in cancer arises from genetic alterations, defects in miRNA processing, epigenetic changes, and hypoxia. MiRNAs can act as tumor suppressors (e.g., miR-15a/16-1) or oncogenes (e.g., miR-17-92), depending on their genomic location.
Beyond tumorigenesis and metastasis, miRNAs are also involved in drug resistance, a major obstacle in cancer treatment. They influence drug resistance by modulating genes involved in multi-drug resistance (MDR) mechanisms, including ABC transporters, apoptosis, autophagy, and drug metabolism. For instance, some miRNAs can increase drug sensitivity by downregulating ABC transporters, while others can promote resistance. They also regulate drug-metabolizing enzymes like cytochrome P450s (CYPs).
Given their role in cancer, miRNAs hold therapeutic potential. Strategies involving miRNA inhibition or replacement have shown promise in preclinical models. Similar to siRNAs, miRNAs can target oncogenic genes, but they differ in origin, mechanism, and target specificity. A single miRNA can target multiple mRNAs, while siRNAs are more specific. However, both can have off-target effects. Translating miRNA-based therapies to the clinic requires addressing several challenges: safe delivery, minimizing off-target effects, and reducing toxicity and immune responses.
The development of miRNA-based therapies follows a series of steps:
Nanotechnology-based formulations are being explored for delivering miRNA mimics or antimiRs in preclinical models of various cancers, including rare endocrine tumors. While promising, challenges remain in translating these findings to clinical practice. [24]
Main Approaches for Therapeutic Targeting of miRNAs:
Modulating miRNA expression is a promising anti-cancer strategy. This can be achieved by inhibiting overexpressed oncogenic miRNAs (oncomiRs) or restoring downregulated tumor suppressor miRNAs. Three main approaches exist for miRNA loss-of-function: miRNA sponges, antisense oligonucleotides (antagomiRs/ antimiRs), and CRISPR/ Cas9-based genetic knockouts. MiRNA sponges are vectors that express transcripts containing miRNA binding sites, effectively sequestering the targeted miRNAs and preventing them from binding to their target mRNAs. This approach has shown promise in reducing metastasis in preclinical models. Chemically modified oligonucleotides, like LNAs, offer high-affinity inhibition. CRISPR/Cas9, a powerful gene editing tool, can be used to knockout specific miRNAs, demonstrating its potential for miRNA-based therapy. For example, deleting miR210-3p has been shown to increase tumorigenesis.
MiRNA replacement therapy aims to restore downregulated or deleted tumor suppressor miRNAs. Since tumor suppressor miRNAs like miR-34 and let-7 are often downregulated in cancer, administering miRNA mimics can restore their levels. Restoring let-7 levels, for instance, can impede cell proliferation and tumor growth by targeting oncogenic factors like RAS, Myc, cyclins, and cyclin-dependent kinases. Similarly, re-expressing miR-34a can induce growth arrest and apoptosis by silencing pro-proliferative and anti-apoptotic gene
Delivery Platforms for miRNA Therapeutics
Effective delivery is crucial for miRNA therapeutics. miRNA mimics and antimiRs are unstable and easily degraded by nucleases. Several strategies address this, including chemical modifications (phosphorothioate linkages, 2'-Omethyl groups, LNAs) and encapsulation within functionalized nanoparticles. Nanoparticles offer protection from degradation, reduced immune response, enhanced circulation time, and targeted delivery using ligands like proteins, peptides, and antibodies.
1) Both viral and non-viral delivery systems have been used. While viral vectors (retroviruses, lentiviruses, adenoviruses, AAVs, VLNPs) offer high infection efficiency and persistent transgene expression (e.g., lentiviral delivery of miR-15a/16 in leukemia), they pose risks of insertional mutagenesis, immunogenicity, and manufacturing challenges. Non-viral vectors, especially polymeric nanoparticles, are favored due to lower immunogenicity, ease of production, and chemical flexibility.
2) Cationic polymers like PEI form complexes with nucleic acids and facilitate endosomal escape through the "proton sponge" effect. PEI/miR-145 complexes have shown promise in colon carcinoma models. Natural polymers like chitosan and dextran have also been used, but chitosan's strong binding can hinder drug release. Lipid chains or negatively charged polymers can improve chitosan-based delivery.
3) Inorganic nanoparticles like gold (Au) and silica offer tunable size, surface properties, and multifunctionality. AuNPs can be functionalized with thiol groups and stabilized with PEG for miRNA delivery, but biocompatibility and clearance remain concerns. Mesoporous silica nanoparticles (MSNs) offer high surface area and easy modification for targeted delivery (e.g., GD2-targeting MSNs for miR-34 delivery in neuroblastoma), but synthesis can be complex.
4) Lipid-based nanoparticles (LNPs), including liposomes and solid lipid nanoparticles (SLNs), are biocompatible and offer efficient cellular uptake. LNPs often contain cationic lipids, neutral lipids, and PEG. Targeted liposomes, coated with ligands like antibodies (e.g., anti-EGFR-CIL-miR-135a for gallbladder carcinoma), enhance tumorspecific delivery. SLNs offer advantages in loading capacity, stability, and controlled release for both hydrophilic and hydrophobic drugs (e.g., miR-34a/paclitaxel SLNs for melanoma).
5) Micelles, formed by self-assembling amphiphilic molecules, offer simple preparation and good tissue penetration. Modifications can improve stability and encapsulation efficiency (e.g., gemcitabine-conjugated micelles for gemcitabine/ miRNA-205 co-delivery in pancreatic cancer).
6) Bacterial nanocells (EDVs), which can package drugs and stimulate the immune system (e.g., miR-16 delivery in mesothelioma),
7) Exosome-mimetic nanosystems (EMNs), which mimic natural exosomes for miRNA delivery. While exosomes show promise, challenges remain in harvesting yields. [24]
CONCLUSION:
This review highlights the complexity of cancer driven by genetic and environmental factors. Recent therapeutic advances, including targeted agents and immunotherapies such as CAR-T, demonstrate significant clinical promise. Continued research into overcoming drug resistance and improving delivery methods is vital. Integrating emerging technologies with conventional approaches offers potential for more personalized, effective cancer treatments. These advancements are critical for improving patient survival and quality of life, underscoring the importance of ongoing innovation in cancer research and therapy.
REFERENCES
Shadab Azam Khan, I Aparna Lakshmi, Deepali Patil, Shahid Farooq, Shaik Imran Pasha, Sahil Bashir, Beyond Boundaries in Oncology: Exploring New Horizons in Cancer Mechanisms and Treatment, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 12, 3919-3944. https://doi.org/10.5281/zenodo.18086651
10.5281/zenodo.18086651
